1
|
Wenhong L, Yang J, Zhao Y, Zhang N, Zhao B, Rongxian L, Shiyan G, Zuoshun H. Cadmium treatment induces oxidative damage and apoptosis in vitro skeletal muscle cells. Toxicology 2025; 515:154139. [PMID: 40188931 DOI: 10.1016/j.tox.2025.154139] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2025] [Revised: 03/05/2025] [Accepted: 04/04/2025] [Indexed: 04/10/2025]
Abstract
Cadmium is a prevalent environmental contaminant, and current research indicates that exposure to cadmium is a significant risk factor contributing to the increased incidence of sarcopenia. However, the precise mechanisms by which cadmium exposure leads to skeletal muscle damage remain to be fully elucidated. Utilizing an in vitro culture model of mouse C2C12 myoblasts, this study exposed cells to 0, 2, 4, and 8 μmol/L cadmium chloride for 24 hours to evaluate the cellular damage and explore the potential mechanisms. Our present data of this study demonstrate that cadmium treatment results in a reduction of C2C12 cell viability, an increased release of lactate dehydrogenase, and an imbalance in the oxidative-antioxidant system characterized by an excessive accumulation of reactive oxygen species, elevated malondialdehyde production, and decreased superoxide dismutase activity. Additionally, there is an upregulation of nuclear factor-erythroid 2-related factor 2, heme oxygenase-1, NAD(P)H quinone oxidoreductase 1, and glutamate-cysteine ligase catalytic subunit protein expression, along with a downregulation of superoxide dismutase 1 protein expression. Furthermore, cadmium exposure mediates an increase in cysteinyl aspartate specific proteinase-dependent apoptosis via the mitochondrial pathway, as indicated by an increased apoptosis rate, elevated Bcl-2 associated X protein and cysteinyl aspartate specific proteinase 3 protein expression, and a decreased expression of B-cell lymphoma-2 protein. Our findings elucidate the mechanisms of cadmium-induced cytotoxic damage in skeletal muscle cells from the perspectives of oxidative injury and apoptosis, thereby providing a theoretical basis for the prevention and treatment of cadmium toxicity.
Collapse
Affiliation(s)
- Li Wenhong
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Jie Yang
- College of Engineering, Dali University, Dali, Yunnan, China
| | - Yuan Zhao
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Nan Zhang
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Bo Zhao
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Li Rongxian
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China
| | - Gu Shiyan
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China.
| | - He Zuoshun
- School of Public Health, Dali University, Dali, Yunnan, China; Institute of Preventive Medicine, Dali University, Dali, Yunnan, China.
| |
Collapse
|
2
|
Wu W, Song X, Li B. Identification of VDAC1 as a mitochondria-related target of Duchenne muscular dystrophy based on bioinformatics analysis and in vitro experiments. Int Immunopharmacol 2025; 158:114836. [PMID: 40359883 DOI: 10.1016/j.intimp.2025.114836] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2025] [Revised: 04/10/2025] [Accepted: 05/07/2025] [Indexed: 05/15/2025]
Abstract
BACKGROUND Mitochondrial dysfunction is a well-recognized pathological feature of Duchenne Muscular Dystrophy (DMD). The potential regulatory role of mitochondria-related genes (MRGs) in DMD remains to be further explored. METHODS GEO datasets and MRGs were used to analysis mitochondrial scores and evaluate patients' immunological characteristics. Weighted gene co-expression network analysis, differentially expressed genes (DEGs) and MRGs were used to identify hub genes. A specific hub gene was selected, and the effects of this gene overexpression on a horse serum (HS) treated C2C12 cell in vitro model were investigated. RESULTS Mitochondrial score was decreased in DMD group. Significant differences were observed in 12 immune cell types in normal/DMD and high/low mitochondrial score groups. 9 hub genes were identified, with 7 validated. Among them, VDAC1 was selected for further study. Overexpression of VDAC1 in HS C2C12 myoblasts promoted cell proliferation, reduced apoptosis rate and the Bax expression (with concurrent Bcl2 upregulation), diminished LDH release to reduce cytotoxicity, decreased intracellular ROS levels to alleviate oxidative stress, inhibited the expression of autophagy (LC3) and atrophy (Atrogin-1 and MuRF-1) markers, and promoted differentiation. CONCLUSION In conclusion, VDAC1 may participate in the myoblast proliferation and myotube atrophy by influencing mitochondrial function, which may serve as a new target for DMD treatment.
Collapse
Affiliation(s)
- Wenjuan Wu
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China; Department of Neurology, Hebei Children's Hospital, The Key Laboratory of Pediatric Epilepsy and Neurology of Hebei Province, Shijiazhuang 050031, China
| | - Xueqin Song
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China; The Key Laboratory of Clinical Neurology (Hebei Medical University), Ministry of Education, Shijiazhuang 050000, China; Neurological Laboratory of Hebei Province, Shijiazhuang 050000, China.
| | - Baoguang Li
- Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, China; Department of Neurology, Hebei Children's Hospital, The Key Laboratory of Pediatric Epilepsy and Neurology of Hebei Province, Shijiazhuang 050031, China
| |
Collapse
|
3
|
Gundom T, Sukketsiri W, Panichayupakaranant P. Phytochemical analysis and biological effects of Zingiber cassumunar extract and three phenylbutenoids: targeting NF-κB, Akt/MAPK, and caspase-3 pathways. BMC Complement Med Ther 2025; 25:180. [PMID: 40380132 PMCID: PMC12083117 DOI: 10.1186/s12906-025-04907-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Accepted: 04/29/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND Zingiber cassumunar Roxb., belonging to the Zingiberaceae family, is a medicinal herb commonly found in tropical regions, particularly in Southeast Asia. This research aims to investigate the preventive effects and anti-inflammatory properties of a phenylbutenoid extract (PE) obtained from the rhizomes of Z. cassumunar. METHOD The PE extract was prepared using green microwave extraction and subsequently analyzed by high-performance liquid chromatography. To evaluate its anti-inflammatory activity, lipopolysaccharide (LPS)-stimulated RAW264.7 cell models were used to measure the release of nitric oxide (NO), tumor necrosis factor-α (TNF-α), and interleukin-1β (IL-1β) using the Griess assay and enzyme-linked immunosorbent assay, respectively. Additionally, the inhibitory effects of PE on apoptosis and reactive oxygen species (ROS) production were evaluated in hydrogen peroxide-induced C2C12 myoblast cells. The expression of inflammation- and apoptosis-related proteins was evaluated using western blotting. RESULTS The results indicated that the PE was enriched with (E)-(3,4-dimethoxyphenyl)butadiene (DMPBD), (E)-1-(3,4-dimethoxyphenyl)but-3-en-1-ol (compound D), and (E)-1-(3,4-dimethoxyphenyl)but-3-en-1-yl acetate (compound D acetate). The PE contained a total phenylbutenoid content of 1.42% w/w. The PE exhibited potent anti-inflammatory properties, with half maximal inhibitory concentration (IC50) values of 7.2 µg/mL for NO, 23.4 µg/mL for TNF-α, and 19.8 µg/mL for IL-1β. In comparison, DMPBD exhibited lower activity against NO and TNF-α (IC50 values of 16.3 and 37.2 µg/mL, respectively) but similar efficacy against IL-1β (IC50 of 17.7 µg/mL) in LPS-induced RAW264.7 cells. All test compounds significantly decreased the percentage of apoptotic cells and suppressed intracellular ROS production in hydrogen peroxide-induced C2C12 myoblast cells. Notably, PE exhibited the highest potency in reducing apoptotic cells, with the lowest IC50 value of 11.6 µg/mL. PE inhibited the expression of p-p38/p38, pERK/ERK, and pAkt/Akt in the LPS-induced inflammatory response in RAW264.7 cells. Additionally, PE significantly suppressed the cleaved/pro-caspase-3 ratio without affecting Bax and Bcl-2 protein levels. CONCLUSION These findings suggest that PE and its phenylbutenoids exhibit anti-inflammatory effects through the inhibition of p38, ERK, and Akt signaling pathways, and anti-apoptotic effects via the inhibition of the caspase-3 pathway, highlighting their therapeutic potential for managing inflammatory and degenerative conditions. CLINICAL TRIAL NUMBER Not applicable.
Collapse
Affiliation(s)
- Thidaporn Gundom
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, 90112, Songkhla, Thailand
| | - Wanida Sukketsiri
- Division of Health and Applied Sciences, Faculty of Science, Prince of Songkla University, Hat-Yai, Songkhla, 90112, Thailand.
| | - Pharkphoom Panichayupakaranant
- Department of Pharmacognosy and Pharmaceutical Botany, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, 90112, Songkhla, Thailand.
- Phytomedicine and Pharmaceutical Biotechnology Research Center, Faculty of Pharmaceutical Sciences, Prince of Songkla University, Hat-Yai, Songkhla, 90112, Thailand.
| |
Collapse
|
4
|
Liu H, Wang K, Shang T, Cai Z, Lu C, Shen M, Yu S, Yao X, Shen Y, Chen X, Xu F, Sun H. Astragaloside IV Improves Muscle Atrophy by Modulating the Activity of UPS and ALP via Suppressing Oxidative Stress and Inflammation in Denervated Mice. Mol Neurobiol 2025; 62:4689-4704. [PMID: 39480556 DOI: 10.1007/s12035-024-04590-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Accepted: 10/24/2024] [Indexed: 11/02/2024]
Abstract
Peripheral nerve injury is common clinically and can lead to neuronal degeneration and atrophy and fibrosis of the target muscle. The molecular mechanisms of muscle atrophy induced by denervation are complex and not fully understood. Inflammation and oxidative stress play an important triggering role in denervated muscle atrophy. Astragaloside IV (ASIV), a monomeric compound purified from astragalus membranaceus, has antioxidant and anti-inflammatory properties. The aim of this study was to investigate the effect of ASIV on denervated muscle atrophy and its molecular mechanism, so as to provide a new potential therapeutic target for the prevention and treatment of denervated muscle atrophy. In this study, an ICR mouse model of muscle atrophy was generated through sciatic nerve dissection. We found that ASIV significantly inhibited the reduction of tibialis anterior muscle mass and muscle fiber cross-sectional area in denervated mice, reducing ROS and oxidative stress-related protein levels. Furthermore, ASIV inhibits the increase in inflammation-associated proteins and infiltration of inflammatory cells, protecting the denervated microvessels in skeletal muscle. We also found that ASIV reduced the expression levels of MAFbx, MuRF1 and FoxO3a, while decreasing the expression levels of autophagy-related proteins, it inhibited the activation of ubiquitin-proteasome and autophagy-lysosome hydrolysis systems and the slow-to-fast myofiber shift. Our results show that ASIV inhibits oxidative stress and inflammatory responses in skeletal muscle due to denervation, inhibits mitophagy and proteolysis, improves microvascular circulation and reverses the transition of muscle fiber types; Therefore, the process of skeletal muscle atrophy caused by denervation can be effectively delayed.
Collapse
Affiliation(s)
- Hua Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, Nantong, Jiangsu Province, 226600, P. R. China
| | - Kexin Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Tongxin Shang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Zhigang Cai
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, Nantong, Jiangsu Province, 226600, P. R. China
| | - Chunfeng Lu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Nantong, Jiangsu Province, 226006, P. R. China
| | - Mi Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Shu Yu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Xinlei Yao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Xiaofang Chen
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, Nantong, Jiangsu Province, 226600, P. R. China.
| | - Feng Xu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Nantong, Jiangsu Province, 226006, P. R. China.
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China.
| |
Collapse
|
5
|
Ji Y, Jiang Q, Chen B, Chen X, Li A, Shen D, Shen Y, Liu H, Qian X, Yao X, Sun H. Endoplasmic reticulum stress and unfolded protein response: Roles in skeletal muscle atrophy. Biochem Pharmacol 2025; 234:116799. [PMID: 39952329 DOI: 10.1016/j.bcp.2025.116799] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/18/2025] [Accepted: 02/11/2025] [Indexed: 02/17/2025]
Abstract
Skeletal muscle atrophy is commonly present in various pathological states, posing a huge burden on society and patients. Increased protein hydrolysis, decreased protein synthesis, inflammatory response, oxidative stress, mitochondrial dysfunction, endoplasmic reticulum stress (ERS) and unfolded protein response (UPR) are all important molecular mechanisms involved in the occurrence and development of skeletal muscle atrophy. The potential mechanisms of ERS and UPR in skeletal muscle atrophy are extremely complex and have not yet been fully elucidated. This article elucidates the molecular mechanisms of ERS and UPR, and discusses their effects on different types of muscle atrophy (muscle atrophy caused by disuse, cachexia, chronic kidney disease (CKD), diabetes mellitus (DM), amyotrophic lateral sclerosis (ALS), spinal muscular atrophy (SMA), spinal and bulbar muscular atrophy (SBMA), aging, sarcopenia, obesity, and starvation), and explores the preventive and therapeutic strategies targeting ERS and UPR in skeletal muscle atrophy, including inhibitor therapy and drug therapy. This review aims to emphasize the importance of endoplasmic reticulum (ER) in maintaining skeletal muscle homeostasis, which helps us further understand the molecular mechanisms of skeletal muscle atrophy and provides new ideas and insights for the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy.
Collapse
Affiliation(s)
- Yanan Ji
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Quan Jiang
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, Nantong, Jiangsu Province 226600, PR China
| | - Bingqian Chen
- Department of Orthopedics, Changshu Hospital Affiliated to Soochow University, First People's Hospital of Changshu City, Changshu, Jiangsu Province 215500, PR China
| | - Xin Chen
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Aihong Li
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Dingding Shen
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Hua Liu
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, Nantong, Jiangsu Province 226600, PR China
| | - Xiaowei Qian
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province 226001, PR China.
| | - Xinlei Yao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province 226001, PR China.
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province 226001, PR China; Research and Development Center for E-Learning, Ministry of Education, Beijing 100816, PR China.
| |
Collapse
|
6
|
Tang W, Chen T, Luo Z, Chen J. Association between urinary volatile organic compound metabolites and sarcopenia in the US general population: a cross-sectional NHANES study from 2011 to 2018. Sci Rep 2025; 15:10735. [PMID: 40155648 PMCID: PMC11953313 DOI: 10.1038/s41598-025-94622-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 03/17/2025] [Indexed: 04/01/2025] Open
Abstract
Volatile organic compound (VOC) is a prevalent form of pollutant that has been linked to various human ailments, yet their connection to sarcopenia remains uncertain. This study seeks to examine the potential association between exposure to mixtures of metabolites of volatile organic compounds (mVOCs) and sarcopenia, while also investigating the potential mediating effects of oxidative stress and inflammation. Data from the 2011-2018 National Health and Nutrition Examination Survey (NHANES) were utilized for the analysis of the relationship between mVOCs and sarcopenia through logistic regression. The least absolute shrinkage and selection operator (LASSO) regression model was employed to identify key mVOCs, while the quantile-g computation model (qgcomp) and bayesian kernel machine regression (BKMR) models were utilized to examine the association between mVOC mixtures and sarcopenia. Potential mediating factors were explored through mediating analysis. Of the 2908 participants included in the study, 246 individuals (8.5%) were found to have sarcopenia. Logistic regression analysis revealed that five urinary VOC metabolites were positively correlated with an increased risk of sarcopenia. The key mVOCs identified through the LASSO method were further analyzed using qgcomp, which showed a 47% average increase in the risk of sarcopenia when exposed to a mixture of mVOCs (OR = 1.47, 95% CI 1.14-1.91). Four mVOCs components (DHBMA, 3HPMA, ATCA and 3,4MHA) have the largest weight. The BKMR results further confirm this joint association. Furthermore, Mediation analysis revealed that inflammation and oxidative stress mediate the relationship between exposure to mVOCs and sarcopenia. In conclusion, our study provides evidence suggesting that VOC exposure is linked to a heightened risk of sarcopenia, with inflammation and oxidative stress potentially serving as mediators in this relationship. It is recommended that additional cohort studies be conducted to validate these findings.
Collapse
Affiliation(s)
- Wei Tang
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Tuotuo Chen
- Department of Emergency Medicine, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Zixuan Luo
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
- Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, 410011, China
| | - Junxiang Chen
- Department of Nephrology, The Second Xiangya Hospital of Central South University, Changsha, 410011, China.
- Hunan Key Laboratory of Kidney Disease and Blood Purification, The Second Xiangya Hospital of Central South University, Changsha, 410011, China.
| |
Collapse
|
7
|
Wang YJ, Chen ZH, Shen YT, Wang KX, Han YM, Zhang C, Yang XM, Chen BQ. Stem cell therapy: A promising therapeutic approach for skeletal muscle atrophy. World J Stem Cells 2025; 17:98693. [DOI: 10.4252/wjsc.v17.i2.98693] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2024] [Revised: 12/09/2024] [Accepted: 01/23/2025] [Indexed: 02/24/2025] Open
Abstract
Skeletal muscle atrophy results from disruptions in the growth and metabolism of striated muscle, leading to a reduction or loss of muscle fibers. This condition not only significantly impacts patients’ quality of life but also imposes substantial socioeconomic burdens. The complex molecular mechanisms driving skeletal muscle atrophy contribute to the absence of effective treatment options. Recent advances in stem cell therapy have positioned it as a promising approach for addressing this condition. This article reviews the molecular mechanisms of muscle atrophy and outlines current therapeutic strategies, focusing on mesenchymal stem cells, induced pluripotent stem cells, and their derivatives. Additionally, the challenges these stem cells face in clinical applications are discussed. A deeper understanding of the regenerative potential of various stem cells could pave the way for breakthroughs in the prevention and treatment of muscle atrophy.
Collapse
Affiliation(s)
- Ying-Jie Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Ze-Hao Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Yun-Tian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Ke-Xin Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Yi-Min Han
- Medical College, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Chen Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Nantong University, Nantong 226000, Jiangsu Province, China
| | - Xiao-Ming Yang
- Co-Innovation Center of Neuroregeneration, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong 226000, Jiangsu Province, China
- Research and Development Center for E-Learning, Ministry of Education, Beijing 100816, China
| | - Bing-Qian Chen
- Department of Orthopaedics, Changshu Hospital Affiliated to Soochow University, Changshu 215500, Jiangsu Province, China
| |
Collapse
|
8
|
Chen H, Wu D, Chen Y, Shi A, Cai W, Yang X, Chen X. Association between the composite dietary antioxidant index and sarcopenia among United States adults: A cross-sectional study. JPEN J Parenter Enteral Nutr 2025; 49:103-111. [PMID: 39462187 DOI: 10.1002/jpen.2697] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Revised: 10/02/2024] [Accepted: 10/08/2024] [Indexed: 10/29/2024]
Abstract
BACKGROUND Diets high in antioxidants are associated with decreased prevalence of sarcopenia. This study aimed to investigate whether the composite dietary antioxidant index (CDAI) and sarcopenia have an underlying relationship. METHODS We used the data from the National Health and Nutrition Examination Survey 2011-2018. According to dietary antioxidant intake, the CDAI was calculated for each individual. Appendicular skeletal muscle mass index was employed to determine sarcopenia. Multivariate weighted logistic models and restricted cubic spline regression analysis was undertaken to determine the association between CDAI and sarcopenia. RESULTS A total of 7012 participants were enrolled in this study, including 473 with sarcopenia (weighted percentage, 5.6%). Compared with the lowest tertile, those in the highest tertile of the CDAI exhibited a greater likelihood of being male, with lower body mass index, higher education level and economic standard, and more chance of being single or separated. In multivariate weighted logistic models, model 3 revealed a noteworthy inverse association between the CDAI and sarcopenia (odds ratio = 0.94; 95% CI, 0.91-0.98; P = 0.003). Compared with the lowest tertile, the highest tertile of CDAI was associated with a 0.57-fold risk of sarcopenia (95% CI, 0.42-0.77; P < 0.001). The inverse association between CDAI and sarcopenia strengthened in the participants with elevated education levels (P for interaction = 0.003). CONCLUSION The CDAI was inversely correlated with the prevalence of sarcopenia. As a comprehensive measurement representing antioxidant status, the CDAI may help manage and prevent sarcopenia.
Collapse
Affiliation(s)
- Hao Chen
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Dongze Wu
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Yajin Chen
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Ang Shi
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Wanda Cai
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Xinxin Yang
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
- Department of Gastrointestinal Surgery, Second Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| | - Xiaodong Chen
- Department of Gastrointestinal Surgery, First Affiliated Hospital, Wenzhou Medical University, Wenzhou, China
| |
Collapse
|
9
|
Kang JH, Kim DH, Yoo J, Shin JH, Kim JH, Lee JW, Shin SH. Sinapine suppresses ROS-induced C2C12 myoblast cell death through MAPK and autophagy pathways. Food Sci Biotechnol 2024; 33:3629-3637. [PMID: 39493388 PMCID: PMC11525351 DOI: 10.1007/s10068-024-01718-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2024] [Revised: 09/05/2024] [Accepted: 09/18/2024] [Indexed: 11/05/2024] Open
Abstract
Oxidative stress in skeletal muscle can lead to muscle atrophy through reactive oxygen species (ROS)-induced damage and cell death. tert-Butyl hydroperoxide (TBHP), an exogenous ROS generator, induces oxidative stress and cell death in various cells. Sinapine from cruciferous plants possesses beneficial effects, but its role in protecting skeletal muscle cells against ROS-induced cell death remains unclear. This study demonstrates that sinapine pretreatment significantly reduced TBHP-induced cell death and ROS accumulation in a dose-dependent manner. TBHP activated mitogen-activated protein kinase (MAPK) pathways including Akt, p38, and JNK, and triggered autophagy. Sinapine suppressed the phosphorylation of Akt, MEK3/6, p38, MEK4, and JNK, and modulated key autophagy markers. Notably, the co-treatment of MAPK inhibitors attenuated TBHP-induced cell death and LC3B-II accumulation. These findings suggest that sinapine is a promising phytochemical for mitigating oxidative stress-mediated muscle injury, offering potential therapeutic strategies for maintaining skeletal muscle homeostasis and addressing muscle-related pathologies.
Collapse
Affiliation(s)
- Jung Hyun Kang
- Department of Food and Nutrition, Gyeongsang National University, Jinju, 52828 South Korea
| | - Dong Hwan Kim
- Department of Bio & Medical Bigdata (BK4 Program), Gyeongsang National University, Jinju, 52828 South Korea
| | - Jin Yoo
- Department of Food and Nutrition, Gyeongsang National University, Jinju, 52828 South Korea
| | - Jun Hong Shin
- Department of Food and Nutrition, Gyeongsang National University, Jinju, 52828 South Korea
| | - Ju Hyun Kim
- Department of Food and Nutrition, Gyeongsang National University, Jinju, 52828 South Korea
| | - Ji Won Lee
- Department of Food and Nutrition, Gyeongsang National University, Jinju, 52828 South Korea
| | - Seung Ho Shin
- Department of Food and Nutrition, Gyeongsang National University, Jinju, 52828 South Korea
- Department of Bio & Medical Bigdata (BK4 Program), Gyeongsang National University, Jinju, 52828 South Korea
| |
Collapse
|
10
|
Minibayeva FV, Rassabina AE, Zakirjanova GF, Fedorov NS, Khabibrakhmanova VR, Galeeva EI, Kuznetsova EA, Malomouzh AI, Petrov AM. Protective properties of melanin from lichen Lobaria pulmonaria (L.) HOFFM. In models of oxidative stress in skeletal muscle. Fitoterapia 2024; 177:106127. [PMID: 39019238 DOI: 10.1016/j.fitote.2024.106127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 06/16/2024] [Accepted: 07/13/2024] [Indexed: 07/19/2024]
Abstract
Melanin is a dark pigment from the group of phenolic or indole polymers with inherent biocompatibility and antioxidant capacity. In extremophilic lichen Lobaria pulmonaria, melanin is responsible for protective properties against hostile environments. Herein, the ability of melanin extracted from L. pulmonaria to counteract oxidative stress and related damages was studied in the mouse diaphragm, the main respiratory muscle. Initial in vitro experiments demonstrated ultraviolet (UV)-absorbing, antioxidant and metal chelating activities of melanin. This melanin can form nanoparticles and stabile colloidal system at concentration of 5 μg/ml. Pretreatment of the muscle with melanin (5 μg/ml) markedly reduced UV-induced increase in intracellular and extracellular reactive oxygen species (ROS) as well as antimycin A-mediated enhancement in mitochondrial ROS production accompanied by lipid peroxidation and membrane asymmetry loss. In addition, melanin attenuated suppression of neuromuscular transmission and alterations of contractile responses provoked by hydrogen peroxide. Thus, this study shed the light on the perspectives of the application of a lichen melanin as a protective component for treatment of skeletal muscle disorders, which are accompanied with an increased ROS production.
Collapse
Affiliation(s)
- Farida V Minibayeva
- Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, Box 30, Kazan 420111, Russia.
| | - Anna E Rassabina
- Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, Box 30, Kazan 420111, Russia
| | - Guzalia F Zakirjanova
- Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, Box 30, Kazan 420111, Russia
| | - Nikita S Fedorov
- Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, Box 30, Kazan 420111, Russia
| | - Venera R Khabibrakhmanova
- Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, Box 30, Kazan 420111, Russia
| | - Ekaterina I Galeeva
- Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, Box 30, Kazan 420111, Russia
| | - Eva A Kuznetsova
- Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, Box 30, Kazan 420111, Russia
| | - Artem I Malomouzh
- Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, Box 30, Kazan 420111, Russia; Kazan National Research Technical University, 10, K. Marx St., Kazan 420111, Russia
| | - Alexey M Petrov
- Kazan Institute of Biochemistry and Biophysics, Federal Research Center "Kazan Scientific Center of RAS", 2/31 Lobachevsky Street, Box 30, Kazan 420111, Russia; Institute of Fundamental Medicine and Biology, Kazan (Volga Region) Federal University, 420008 Kazan, Russia; Kazan State Mediсal University, 49 Butlerova Street, Kazan 420012, Russia.
| |
Collapse
|
11
|
Charrier D, Cerullo G, Carpenito R, Vindigni V, Bassetto F, Simoni L, Moro T, Paoli A. Metabolic and Biochemical Effects of Pyrroloquinoline Quinone (PQQ) on Inflammation and Mitochondrial Dysfunction: Potential Health Benefits in Obesity and Future Perspectives. Antioxidants (Basel) 2024; 13:1027. [PMID: 39334686 PMCID: PMC11429417 DOI: 10.3390/antiox13091027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 08/19/2024] [Accepted: 08/22/2024] [Indexed: 09/30/2024] Open
Abstract
Obesity is defined as a complex, systemic disease characterized by excessive and dysfunctional adipose tissue, leading to adverse health effects. This condition is marked by low-grade inflammation, oxidative stress, and metabolic abnormalities, including mitochondrial dysfunction. These factors promote energy dysregulation and impact body composition not only by increasing body fat but also by promoting skeletal muscle mass atrophy. The decline in muscle mass is associated with an increased risk of all-cause mortality in individuals with this disease. The European Food Safety Authority approved pyrroloquinoline quinone (PQQ), a natural compound, as a dietary supplement in 2018. This narrative review aims to provide a comprehensive overview of the potential role of PQQ, based on its anti-inflammatory and antioxidant properties, in addressing dysfunctional adipose tissue metabolism and related disorders.
Collapse
Affiliation(s)
- Davide Charrier
- Department of Biomedical Sciences, University of Padova, 35122 Padua, Italy; (D.C.); (L.S.); (T.M.); (A.P.)
| | - Giuseppe Cerullo
- Department of Biomedical Sciences, University of Padova, 35122 Padua, Italy; (D.C.); (L.S.); (T.M.); (A.P.)
| | - Roberta Carpenito
- Plastic and Reconstructive Surgery Unit, Department of Neurosciences, University of Padua, 35122 Padua, Italy (V.V.); (F.B.)
| | - Vincenzo Vindigni
- Plastic and Reconstructive Surgery Unit, Department of Neurosciences, University of Padua, 35122 Padua, Italy (V.V.); (F.B.)
| | - Franco Bassetto
- Plastic and Reconstructive Surgery Unit, Department of Neurosciences, University of Padua, 35122 Padua, Italy (V.V.); (F.B.)
| | - Luca Simoni
- Department of Biomedical Sciences, University of Padova, 35122 Padua, Italy; (D.C.); (L.S.); (T.M.); (A.P.)
| | - Tatiana Moro
- Department of Biomedical Sciences, University of Padova, 35122 Padua, Italy; (D.C.); (L.S.); (T.M.); (A.P.)
| | - Antonio Paoli
- Department of Biomedical Sciences, University of Padova, 35122 Padua, Italy; (D.C.); (L.S.); (T.M.); (A.P.)
- Research Center for High Performance Sport, UCAM Catholic University of Murcia, 30107 Murcia, Spain
| |
Collapse
|
12
|
Yadav A, Dabur R. Skeletal muscle atrophy after sciatic nerve damage: Mechanistic insights. Eur J Pharmacol 2024; 970:176506. [PMID: 38492879 DOI: 10.1016/j.ejphar.2024.176506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Revised: 03/13/2024] [Accepted: 03/14/2024] [Indexed: 03/18/2024]
Abstract
Sciatic nerve injury leads to molecular events that cause muscular dysfunction advancement in atrophic conditions. Nerve damage renders muscles permanently relaxed which elevates intracellular resting Ca2+ levels. Increased Ca2+ levels are associated with several cellular signaling pathways including AMPK, cGMP, PLC-β, CERB, and calcineurin. Also, multiple enzymes involved in the tricarboxylic acid cycle and oxidative phosphorylation are activated by Ca2+ influx into mitochondria during muscle contraction, to meet increased ATP demand. Nerve damage induces mitophagy and skeletal muscle atrophy through increased sensitivity to Ca2+-induced opening of the permeability transition pore (PTP) in mitochondria attributed to Ca2+, ROS, and AMPK overload in muscle. Activated AMPK interacts negatively with Akt/mTOR is a highly prevalent and well-described central pathway for anabolic processes. Over the decade several reports indicate abnormal behavior of signaling machinery involved in denervation-induced muscle loss but end up with some controversial outcomes. Therefore, understanding how the synthesis and inhibitory stimuli interact with cellular signaling to control muscle mass and morphology may lead to new pharmacological insights toward understanding the underlying mechanism of muscle loss after sciatic nerve damage. Hence, the present review summarizes the existing literature on denervation-induced muscle atrophy to evaluate the regulation and expression of differential regulators during sciatic damage.
Collapse
Affiliation(s)
- Aarti Yadav
- Clinical Biochemistry Laboratory, Department of Biochemistry, Maharshi Dayanand University, Rohtak, 124001, Haryana, India
| | - Rajesh Dabur
- Clinical Biochemistry Laboratory, Department of Biochemistry, Maharshi Dayanand University, Rohtak, 124001, Haryana, India.
| |
Collapse
|
13
|
Shen Y, Zhang C, Dai C, Zhang Y, Wang K, Gao Z, Chen X, Yang X, Sun H, Yao X, Xu L, Liu H. Nutritional Strategies for Muscle Atrophy: Current Evidence and Underlying Mechanisms. Mol Nutr Food Res 2024; 68:e2300347. [PMID: 38712453 DOI: 10.1002/mnfr.202300347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 02/28/2024] [Indexed: 05/08/2024]
Abstract
Skeletal muscle can undergo detrimental changes in various diseases, leading to muscle dysfunction and atrophy, thus severely affecting people's lives. Along with exercise, there is a growing interest in the potential of nutritional support against muscle atrophy. This review provides a brief overview of the molecular mechanisms driving skeletal muscle atrophy and summarizes recent advances in nutritional interventions for preventing and treating muscle atrophy. The nutritional supplements include amino acids and their derivatives (such as leucine, β-hydroxy, β-methylbutyrate, and creatine), various antioxidant supplements (like Coenzyme Q10 and mitoquinone, resveratrol, curcumin, quercetin, Omega 3 fatty acids), minerals (such as magnesium and selenium), and vitamins (such as vitamin B, vitamin C, vitamin D, and vitamin E), as well as probiotics and prebiotics (like Lactobacillus, Bifidobacterium, and 1-kestose). Furthermore, the study discusses the impact of a combined approach involving nutritional support and physical therapy to prevent muscle atrophy, suggests appropriate multi-nutritional and multi-modal interventions based on individual conditions to optimize treatment outcomes, and enhances the recovery of muscle function for patients. By understanding the molecular mechanisms behind skeletal muscle atrophy and implementing appropriate interventions, it is possible to enhance the recovery of muscle function and improve patients' quality of life.
Collapse
Grants
- 81901933 National Natural Science Foundation of China
- 82072160 National Natural Science Foundation of China
- 20KJA310012 Major Natural Science Research Projects in Universities of Jiangsu Province
- BK20202013 Natural Science Foundation of Jiangsu Province, and the Scientific Research Project of The Health Commission of Jiangsu Province
- BK20201209 Natural Science Foundation of Jiangsu Province, and the Scientific Research Project of The Health Commission of Jiangsu Province
- ZDB2020003 Natural Science Foundation of Jiangsu Province, and the Scientific Research Project of The Health Commission of Jiangsu Province
- QingLan Project in Jiangsu Universities
- JC22022037 The Priority Academic Program Development of Jiangsu Higher Education Institutions, and Nantong Science and Technology Program, and Nantong Health Medical Research Center
- MS22022010 The Priority Academic Program Development of Jiangsu Higher Education Institutions, and Nantong Science and Technology Program, and Nantong Health Medical Research Center
- JC12022010 The Priority Academic Program Development of Jiangsu Higher Education Institutions, and Nantong Science and Technology Program, and Nantong Health Medical Research Center
- HS2022003 The Priority Academic Program Development of Jiangsu Higher Education Institutions, and Nantong Science and Technology Program, and Nantong Health Medical Research Center
Collapse
Affiliation(s)
- Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Chen Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Chaolun Dai
- Department of Clinical Medicine, Medical College, Nantong University, Nantong, P. R. China, 226001
| | - Yijie Zhang
- Department of Clinical Medicine, Medical College, Nantong University, Nantong, P. R. China, 226001
| | - Kexin Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Zihui Gao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Xin Chen
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Xiaoming Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Xinlei Yao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Lingchi Xu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Hua Liu
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, Nantong, Jiangsu Province, 226600, P. R. China
| |
Collapse
|
14
|
Son RH, Kim MI, Kim HM, Guo S, Lee DH, Lim GM, Kim SM, Kim JY, Kim CY. Potential of Lycii Radicis Cortex as an Ameliorative Agent for Skeletal Muscle Atrophy. Pharmaceuticals (Basel) 2024; 17:462. [PMID: 38675422 PMCID: PMC11054743 DOI: 10.3390/ph17040462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2024] [Revised: 03/25/2024] [Accepted: 03/28/2024] [Indexed: 04/28/2024] Open
Abstract
Lycii Radicis Cortex (LRC) is a traditional medicine in East Asia with various beneficial effects, including antioxidant, anti-inflammatory, anti-tumor, anti-diabetic, and anti-depressant properties. However, its potential effects on skeletal muscle atrophy have not been studied. In this study, the protective effects of LRC extract (LRCE) on dexamethasone (DEX)-induced muscle atrophy were investigated in C2C12 myotubes and mice. We evaluated the effect of LRCE on improving muscle atrophy using a variety of methods, including immunofluorescence staining, quantitative polymerase chain reaction (qPCR), Western blot, measurements of oxidative stress, apoptosis, ATP levels, and muscle tissue analysis. The results showed that LRCE improved myotube diameter, fusion index, superoxide dismutase (SOD) activity, mitochondrial content, ATP levels, expression of myogenin and myosin heavy chain (MHC), and reduced reactive oxygen species (ROS) production in dexamethasone-induced C2C12 myotubes. LRCE also enhanced protein synthesis and reduced protein degradation in the myotubes. In mice treated with DEX, LRCE restored calf thickness, decreased mRNA levels of muscle-specific RING finger protein 1 (MuRF1) and atrogin-1, and increased insulin-like growth factor 1 (IGF-1) mRNA level. Moreover, LRCE also repaired gastrocnemius muscle atrophy caused by DEX. Although human studies are not available, various preclinical studies have identified potential protective effects of LRCE against muscle atrophy, suggesting that it could be utilized in the prevention and treatment of muscle atrophy.
Collapse
Affiliation(s)
- Rak Ho Son
- College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Ansan 15588, Republic of Korea; (R.H.S.); (H.M.K.); (S.G.); (D.H.L.); (G.M.L.)
- R&D Center, Huons Co., Ltd., 55 Hanyangdaehak-ro, Ansan 15588, Republic of Korea;
| | - Myeong Il Kim
- R&D Center, Huons Co., Ltd., 55 Hanyangdaehak-ro, Ansan 15588, Republic of Korea;
| | - Hye Mi Kim
- College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Ansan 15588, Republic of Korea; (R.H.S.); (H.M.K.); (S.G.); (D.H.L.); (G.M.L.)
| | - Shuo Guo
- College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Ansan 15588, Republic of Korea; (R.H.S.); (H.M.K.); (S.G.); (D.H.L.); (G.M.L.)
| | - Do Hyun Lee
- College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Ansan 15588, Republic of Korea; (R.H.S.); (H.M.K.); (S.G.); (D.H.L.); (G.M.L.)
| | - Gyu Min Lim
- College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Ansan 15588, Republic of Korea; (R.H.S.); (H.M.K.); (S.G.); (D.H.L.); (G.M.L.)
| | - Seong-Min Kim
- Medical Device Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 88 Dongnae-ro, Daegu 41061, Republic of Korea;
| | - Jae-Yong Kim
- College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Ansan 15588, Republic of Korea; (R.H.S.); (H.M.K.); (S.G.); (D.H.L.); (G.M.L.)
- R&D Center, Huons Co., Ltd., 55 Hanyangdaehak-ro, Ansan 15588, Republic of Korea;
| | - Chul Young Kim
- College of Pharmacy and Institute of Pharmaceutical Science and Technology, Hanyang University, 55 Hanyangdaehak-ro, Ansan 15588, Republic of Korea; (R.H.S.); (H.M.K.); (S.G.); (D.H.L.); (G.M.L.)
| |
Collapse
|
15
|
Akieda-Asai S, Ma H, Han W, Nagata J, Yamaguchi F, Date Y. Mechanism of muscle atrophy in a normal-weight rat model of type 2 diabetes established by using a soft-pellet diet. Sci Rep 2024; 14:7670. [PMID: 38561446 PMCID: PMC10984920 DOI: 10.1038/s41598-024-57727-2] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Accepted: 03/21/2024] [Indexed: 04/04/2024] Open
Abstract
Dietary factors such as food texture affect feeding behavior and energy metabolism, potentially causing obesity and type 2 diabetes. We previously found that rats fed soft pellets (SPs) were neither hyperphagic nor overweight but demonstrated glucose intolerance, insulin resistance, and hyperplasia of pancreatic β-cells. In the present study, we investigated the mechanism of muscle atrophy in rats that had been fed SPs on a 3-h time-restricted feeding schedule for 24 weeks. As expected, the SP rats were normal weight; however, they developed insulin resistance, glucose intolerance, and fat accumulation. In addition, skeletal muscles of SP rats were histologically atrophic and demonstrated disrupted insulin signaling. Furthermore, we learned that the muscle atrophy of the SP rats developed via the IL-6-STAT3-SOCS3 and ubiquitin-proteasome pathways. Our data show that the dietary habit of consuming soft foods can lead to not only glucose intolerance or insulin resistance but also muscle atrophy.
Collapse
Affiliation(s)
- Sayaka Akieda-Asai
- Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692, Japan.
| | - Hao Ma
- Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692, Japan
| | - Wanxin Han
- Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692, Japan
| | - Junko Nagata
- Department of Sensory and Motor Organs, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan
| | - Fumitake Yamaguchi
- Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692, Japan
- Department of Nursing, Faculty of Medicine, University of Miyazaki, Miyazaki, 889-1692, Japan
| | - Yukari Date
- Frontier Science Research Center, University of Miyazaki, Miyazaki, 889-1692, Japan.
| |
Collapse
|
16
|
Zhang T, Wang J, Wang Y, He L, Lv S, Wang Y, Li W. Wenyang-Tianjing-Jieyu Decoction Improves Depression Rats of Kidney Yang Deficiency Pattern by Regulating T Cell Homeostasis and Inflammation Level. Neuropsychiatr Dis Treat 2024; 20:631-647. [PMID: 38545129 PMCID: PMC10966763 DOI: 10.2147/ndt.s445636] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2023] [Accepted: 03/11/2024] [Indexed: 05/03/2024] Open
Abstract
PURPOSE Chronic inflammation is one of the key mechanisms of depression. Wenyang-Tianjin-Jie Decoction (WTJD) is an effective antidepressant found in the course of diagnosis and treatment, but the mechanism of therapeutic effect is not clear. The study aimed to evaluate the efficacy of WTJD in the kidney yang deficiency (KYD) type of depression rats and reveal its mechanisms. MATERIALS AND METHODS We selected forty 6-week-old male Sprague-Dawley rats for the study. We established a KYD [Phellodendron amurense Rupr (Huangbai) solution oral gavage and 4°C environments; 8 weeks] type of depression (chronic unpredictable mild stimulus; 6 weeks) rat model first. After successful modeling, we used WTJD or fluoxetine on rats for 3 weeks. Then we evaluated the depression and KYD behavior. Finally, we observed the expression of key inflammatory factors and proteins in peripheral blood and hippocampus, and further investigated the immune balance of Th17/Treg and Th1/Th2 cells and the activity of their main regulatory pathways JAK2/STAT3 and TLR4/TRAF6/NF-κB. RESULTS The imbalance of Th17/Treg and Th1/Th2 cells in rats were related to KYD and depressive symptoms. Through this study, we found that WTJD can inhibit the activity of JAK2/STAT3 and TLR4/TRAF6/NF-κB pathways, balance Th17/Treg and Th1/Th2 cell homeostasis, regulate the levels of inflammatory factors in the hippocampus and peripheral blood, and reverse KYD and depression. CONCLUSION This study confirmed that WTJD had a reliable effect on depression rats with KYD, and its mechanism was to regulate the immune homeostasis of hippocampal T cells and related inflammatory factors to improve KYD and depression symptoms in rats.
Collapse
Affiliation(s)
- Tian Zhang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Jiexin Wang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Yi Wang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Linxi He
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Shangbin Lv
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Yiran Wang
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| | - Weihong Li
- Basic Medical College, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China
| |
Collapse
|
17
|
Wan R, Liu S, Feng X, Luo W, Zhang H, Wu Y, Chen S, Shang X. The Revolution of exosomes: From biological functions to therapeutic applications in skeletal muscle diseases. J Orthop Translat 2024; 45:132-139. [PMID: 38544740 PMCID: PMC10966453 DOI: 10.1016/j.jot.2024.01.001] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/01/2023] [Revised: 12/29/2023] [Accepted: 01/08/2024] [Indexed: 11/11/2024] Open
Abstract
Skeletal muscle diseases, a broad category encompassing a myriad of afflictions such as acute muscle injury and muscular dystrophies, pose a significant health burden globally. These conditions often lead to muscle weakness, compromised mobility, and a diminished quality of life. In light of this, innovative and effective therapeutic strategies are fervently sought after. Exosomes, naturally extracellular vesicles with a diameter of 30-150 nm, pervade biological fluids. These microscopic entities harbor a host of biological molecules, including proteins, nucleic acids, and lipids, bearing a significant resemblance to their parent cells. The roles they play in the biological theater are manifold, influencing crucial physiological and pathological processes within the organism. In the context of skeletal muscle diseases, their potential extends beyond these roles, as they present a promising therapeutic target and a vehicle for targeted drug delivery. This potentially paves the way for significant clinical applications. This review aims to elucidate the mechanisms underpinning exosome action, their myriad biological functions, and the strides made in exosome research and application. A comprehensive exploration of the part played by exosomes in skeletal muscle repair and regeneration is undertaken. In addition, we delve into the use of exosomes in the therapeutic landscape of skeletal muscle diseases, providing a valuable reference for a deeper understanding of exosome applications in this realm. The concluding section encapsulates the prospective avenues for exosome research and the promising future they hold, underscoring the tremendous potential these diminutive vesicles possess in the field of skeletal muscle diseases. The Translational Potential of this Article. The comprehensive exploration of exosome's diverse biological functions and translational potential in the context of skeletal muscle diseases presented in this review underscores their promising future as a therapeutic target with significant clinical applications, thus paving the way for innovative and effective therapeutic strategies in this realm.
Collapse
Affiliation(s)
- Renwen Wan
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Shan Liu
- Department of Endocrinology, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xinting Feng
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Wei Luo
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Hanli Zhang
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Yang Wu
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Shiyi Chen
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
| | - Xiliang Shang
- Department of Sports Medicine, Huashan Hospital, Fudan University, Shanghai, 200040, China
| |
Collapse
|
18
|
Jiang H, Liu B, Lin J, Xue T, Han Y, Lu C, Zhou S, Gu Y, Xu F, Shen Y, Xu L, Sun H. MuSCs and IPCs: roles in skeletal muscle homeostasis, aging and injury. Cell Mol Life Sci 2024; 81:67. [PMID: 38289345 PMCID: PMC10828015 DOI: 10.1007/s00018-023-05096-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 12/01/2023] [Accepted: 12/17/2023] [Indexed: 02/01/2024]
Abstract
Skeletal muscle is a highly specialized tissue composed of myofibres that performs crucial functions in movement and metabolism. In response to external stimuli and injuries, a range of stem/progenitor cells, with muscle stem cells or satellite cells (MuSCs) being the predominant cell type, are rapidly activated to repair and regenerate skeletal muscle within weeks. Under normal conditions, MuSCs remain in a quiescent state, but become proliferative and differentiate into new myofibres in response to injury. In addition to MuSCs, some interstitial progenitor cells (IPCs) such as fibro-adipogenic progenitors (FAPs), pericytes, interstitial stem cells expressing PW1 and negative for Pax7 (PICs), muscle side population cells (SPCs), CD133-positive cells and Twist2-positive cells have been identified as playing direct or indirect roles in regenerating muscle tissue. Here, we highlight the heterogeneity, molecular markers, and functional properties of these interstitial progenitor cells, and explore the role of muscle stem/progenitor cells in skeletal muscle homeostasis, aging, and muscle-related diseases. This review provides critical insights for future stem cell therapies aimed at treating muscle-related diseases.
Collapse
Affiliation(s)
- Haiyan Jiang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Boya Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Junfei Lin
- Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Tong Xue
- Department of Paediatrics, Medical School of Nantong University, Nantong University, Nantong, 226001, People's Republic of China
| | - Yimin Han
- Department of Paediatrics, Medical School of Nantong University, Nantong University, Nantong, 226001, People's Republic of China
| | - Chunfeng Lu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Nantong, 226001, Jiangsu, People's Republic of China
| | - Songlin Zhou
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Yun Gu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Feng Xu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People's Hospital of Nantong City, Nantong, 226001, Jiangsu, People's Republic of China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Lingchi Xu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| |
Collapse
|
19
|
Deng C, Lu C, Wang K, Chang M, Shen Y, Yang X, Sun H, Yao X, Qiu C, Xu F. Celecoxib ameliorates diabetic sarcopenia by inhibiting inflammation, stress response, mitochondrial dysfunction, and subsequent activation of the protein degradation systems. Front Pharmacol 2024; 15:1344276. [PMID: 38313305 PMCID: PMC10834620 DOI: 10.3389/fphar.2024.1344276] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2023] [Accepted: 01/05/2024] [Indexed: 02/06/2024] Open
Abstract
Aim: Diabetic sarcopenia leads to disability and seriously affects the quality of life. Currently, there are no effective therapeutic strategies for diabetic sarcopenia. Our previous studies have shown that inflammation plays a critical role in skeletal muscle atrophy. Interestingly, the connection between chronic inflammation and diabetic complications has been revealed. However, the effects of non-steroidal anti-inflammatory drug celecoxib on diabetic sarcopenia remains unclear. Materials and Methods: The streptozotocin (streptozotocin)-induced diabetic sarcopenia model was established. Rotarod test and grip strength test were used to assess skeletal muscle function. Hematoxylin and eosin and immunofluorescence staining were performed to evaluate inflammatory infiltration and the morphology of motor endplates in skeletal muscles. Succinate dehydrogenase (SDH) staining was used to determine the number of succinate dehydrogenase-positive muscle fibers. Dihydroethidium staining was performed to assess the levels of reactive oxygen species (ROS). Western blot was used to measure the levels of proteins involved in inflammation, oxidative stress, endoplasmic reticulum stress, ubiquitination, and autophagic-lysosomal pathway. Transmission electron microscopy was used to evaluate mitophagy. Results: Celecoxib significantly ameliorated skeletal muscle atrophy, improving skeletal muscle function and preserving motor endplates in diabetic mice. Celecoxib also decreased infiltration of inflammatory cell, reduced the levels of IL-6 and TNF-α, and suppressed the activation of NF-κB, Stat3, and NLRP3 inflammasome pathways in diabetic skeletal muscles. Celecoxib decreased reactive oxygen species levels, downregulated the levels of Nox2 and Nox4, upregulated the levels of GPX1 and Nrf2, and further suppressed endoplasmic reticulum stress by inhibiting the activation of the Perk-EIF-2α-ATF4-Chop in diabetic skeletal muscles. Celecoxib also inhibited the levels of Foxo3a, Fbx32 and MuRF1 in the ubiquitin-proteasome system, as well as the levels of BNIP3, Beclin1, ATG7, and LC3Ⅱ in the autophagic-lysosomal system, and celecoxib protected mitochondria and promoted mitochondrial biogenesis by elevating the levels of SIRT1 and PGC1-α, increased the number of SDH-positive fibers in diabetic skeletal muscles. Conclusion: Celecoxib improved diabetic sarcopenia by inhibiting inflammation, oxidative stress, endoplasmic reticulum stress, and protecting mitochondria, and subsequently suppressing proteolytic systems. Our study provides evidences for the molecular mechanism and treatment of diabetic sarcopenia, and broaden the way for the new use of celecoxib in diabetic sarcopenia.
Collapse
Affiliation(s)
- Chunyan Deng
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Chunfeng Lu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China
| | - Kexin Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Mengyuan Chang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Xiaoming Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Xinlei Yao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, China
| | - Chunjian Qiu
- Department of Endocrinology, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China
| | - Feng Xu
- Department of Endocrinology, Affiliated Hospital 2 of Nantong University and First People’s Hospital of Nantong City, Nantong, China
| |
Collapse
|
20
|
Lin J, Cai Y, Wang J, Liu R, Qiu C, Huang Y, Liu B, Yang X, Zhou S, Shen Y, Wang W, Zhu J. Transcriptome sequencing promotes insights on the molecular mechanism of SKP-SC-EVs mitigating denervation-induced muscle atrophy. Mol Biol Rep 2023; 51:9. [PMID: 38085347 DOI: 10.1007/s11033-023-08952-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2023] [Accepted: 11/09/2023] [Indexed: 12/18/2023]
Abstract
BACKGROUND Complex pathophysiological changes accompany denervation-induced skeletal muscle atrophy, but no effective treatment strategies exist. Our previous study indicated that extracellular vesicles derived from skin-derived precursors-derived Schwann cells (SKP-SC-EVs) can effectively mitigate denervation-induced muscle atrophy. However, the specific molecular mechanism remains unclear. METHODS AND RESULTS In this study, we used bioinformatics methods to scrutinize the impact of SKP-SC-EVs on gene expression in denervation-induced skeletal muscle atrophy. We found that SKP-SC-EVs altered the expression of 358 genes in denervated skeletal muscles. The differentially expressed genes were predominantly participated in biological processes, including cell cycle, inflammation, immunity, and adhesion, and signaling pathways, such as FoxO and PI3K.Using the Molecular Complex Detection (MCODE) plugin, we identified the two clusters with the highest score: cluster 1 comprised 37 genes, and Cluster 2 consisted of 24 genes. Then, fifty hub genes were identified using CytoHubba. The intersection of Hub genes and genes obtained by MCODE showed that all 23 genes related to the cell cycle in Cluster 1 were hub genes, and 5 genes in Cluster 2 were hub genes and associated with inflammation. CONCLUSIONS Overall, the differentially expressed genes in denervated skeletal muscle following SKP-SC-EVs treatment are primarily linked to the cell cycle and inflammation. Consequently, promoting proliferation and inhibiting inflammation may be the critical process in which SKP-SC-EVs delay denervation-induced muscle atrophy. Our findings contribute to a better understanding of the molecular mechanism of SKP-SC-EVs delaying denervation-induced muscle atrophy, offering a promising new avenue for muscle atrophy treatment.
Collapse
Affiliation(s)
- Junfei Lin
- Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Yong Cai
- Department of Neurology, Binhai County People's Hospital, Yancheng, Jiangsu Province, 224500, P. R. China
| | - Jian Wang
- Department of Clinical Laboratory, Nantong Third Hospital Affiliated to Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Ruiqi Liu
- Department of Clinical Medicine, Medical College, Nantong University, Nantong, 226001, Jiangsu Province, P. R. China
| | - Chong Qiu
- Department of Clinical Medicine, Medical College, Nantong University, Nantong, 226001, Jiangsu Province, P. R. China
| | - Yan Huang
- Department of Clinical Medicine, Medical College, Nantong University, Nantong, 226001, Jiangsu Province, P. R. China
| | - Boya Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Xiaoming Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Songlin Zhou
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China.
| | - Wei Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, Jiangsu Province, 226001, P. R. China.
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, P. R. China.
| | - Jianwei Zhu
- Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, P. R. China.
| |
Collapse
|
21
|
Sun J, Zhou H, Chen Z, Zhang H, Cao Y, Yao X, Chen X, Liu B, Gao Z, Shen Y, Qi L, Sun H. Altered m6A RNA methylation governs denervation-induced muscle atrophy by regulating ubiquitin proteasome pathway. J Transl Med 2023; 21:845. [PMID: 37996930 PMCID: PMC10668433 DOI: 10.1186/s12967-023-04694-3] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2023] [Accepted: 11/02/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND Denervation-induced muscle atrophy is complex disease involving multiple biological processes with unknown mechanisms. N6-methyladenosine (m6A) participates in skeletal muscle physiology by regulating multiple levels of RNA metabolism, but its impact on denervation-induced muscle atrophy is still unclear. Here, we aimed to explore the changes, functions, and molecular mechanisms of m6A RNA methylation during denervation-induced muscle atrophy. METHODS During denervation-induced muscle atrophy, the m6A immunoprecipitation sequencing (MeRIP-seq) as well as enzyme-linked immunosorbent assay analysis were used to detect the changes of m6A modified RNAs and the involved biological processes. 3-deazidenosine (Daa) and R-2-hydroxyglutarate (R-2HG) were used to verify the roles of m6A RNA methylation. Through bioinformatics analysis combined with experimental verification, the regulatory roles and mechanisms of m6A RNA methylation had been explored. RESULTS There were many m6A modified RNAs with differences during denervation-induced muscle atrophy, and overall, they were mainly downregulated. After 72 h of denervation, the biological processes involved in the altered mRNA with m6A modification were mainly related to zinc ion binding, ubiquitin protein ligase activity, ATP binding and sequence-specific DNA binding and transcription coactivator activity. Daa reduced overall m6A levels in healthy skeletal muscles, which reduced skeletal muscle mass. On the contrary, the increase in m6A levels mediated by R-2HG alleviated denervation induced muscle atrophy. The m6A RNA methylation regulated skeletal muscle mass through ubiquitin-proteasome pathway. CONCLUSION This study indicated that decrease in m6A RNA methylation was a new symptom of denervation-induced muscle atrophy, and confirmed that targeting m6A alleviated denervation-induced muscle atrophy.
Collapse
Affiliation(s)
- Junjie Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Hai Zhou
- Department of Neurosurgery, Binhai County People's Hospital, Yancheng, 224500, Jiangsu, People's Republic of China
| | - Zehao Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Han Zhang
- Department of Clinical Medicine, Medical College, Nantong University, Nantong, 226001, China
| | - Yanzhe Cao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Xinlei Yao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Xin Chen
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Boya Liu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Zihui Gao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Lei Qi
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Nantong University, Nantong, 226001, Jiangsu, People's Republic of China.
| |
Collapse
|
22
|
Lee HJ, Choi HJ, Lee SA, Baek DH, Heo JB, Song GY, Lee W. Myogenesis Effects of RGX365 to Improve Skeletal Muscle Atrophy. Nutrients 2023; 15:4307. [PMID: 37836590 PMCID: PMC10574276 DOI: 10.3390/nu15194307] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Revised: 10/01/2023] [Accepted: 10/08/2023] [Indexed: 10/15/2023] Open
Abstract
Age-related skeletal muscle atrophy and weakness not only reduce the quality of life of those afflicted, but also worsen the prognosis of underlying diseases. We evaluated the effect of RGX365, a protopanaxatriol-type rare ginsenoside mixture, on improving skeletal muscle atrophy. We investigated the myogenic effect of RGX365 on mouse myoblast cells (C2C12) and dexamethasone (10 µM)-induced atrophy of differentiated C2C12. RGX365-treated myotube diameters and myosin heavy chain (MyHC) expression levels were analyzed using immunofluorescence. We evaluated the myogenic effects of RGX365 in aging sarcopenic mice. RGX365 increased myoblast differentiation and MyHC expression, and attenuated the muscle atrophy-inducing F-box (Atrogin-1) and muscle RING finger 1 (MuRF1) expression. Notably, one month of oral administration of RGX365 to 23-month-old sarcopenic mice improved muscle fiber size and the expression of skeletal muscle regeneration-associated molecules. In conclusion, rare ginsenosides, agonists of steroid receptors, can ameliorate skeletal muscle atrophy during long-term administration.
Collapse
Affiliation(s)
- Hye-Jin Lee
- Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea;
| | - Hui-Ji Choi
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea; (H.-J.C.); (D.H.B.); (J.B.H.)
| | - Sang-Ah Lee
- Faculty of Biotechnology, College of Applied Life Sciences, Jeju National University, Jeju 63243, Republic of Korea;
- Environmental Safety Group, Korea Institute of Science and Technology (KIST) Europe, 66123 Saarbruecken, Germany
| | - Dong Hyuk Baek
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea; (H.-J.C.); (D.H.B.); (J.B.H.)
| | - Jong Beom Heo
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea; (H.-J.C.); (D.H.B.); (J.B.H.)
| | - Gyu Yong Song
- College of Pharmacy, Chungnam National University, Daejeon 34134, Republic of Korea; (H.-J.C.); (D.H.B.); (J.B.H.)
- AREZ Co., Ltd., Daejeon 34036, Republic of Korea
| | - Wonhwa Lee
- Department of Chemistry, Sungkyunkwan University, Suwon 16419, Republic of Korea;
| |
Collapse
|
23
|
Zhang H, Qi G, Wang K, Yang J, Shen Y, Yang X, Chen X, Yao X, Gu X, Qi L, Zhou C, Sun H. Oxidative stress: roles in skeletal muscle atrophy. Biochem Pharmacol 2023:115664. [PMID: 37331636 DOI: 10.1016/j.bcp.2023.115664] [Citation(s) in RCA: 82] [Impact Index Per Article: 41.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2023] [Revised: 06/12/2023] [Accepted: 06/13/2023] [Indexed: 06/20/2023]
Abstract
Oxidative stress, inflammation, mitochondrial dysfunction, reduced protein synthesis, and increased proteolysis are all critical factors in the process of muscle atrophy. In particular, oxidative stress is the key factor that triggers skeletal muscle atrophy. It is activated in the early stages of muscle atrophy and can be regulated by various factors. The mechanisms of oxidative stress in the development of muscle atrophy have not been completely elucidated. This review provides an overview of the sources of oxidative stress in skeletal muscle and the correlation of oxidative stress with inflammation, mitochondrial dysfunction, autophagy, protein synthesis, proteolysis, and muscle regeneration in muscle atrophy. Additionally, the role of oxidative stress in skeletal muscle atrophy caused by several pathological conditions, including denervation, unloading, chronic inflammatory diseases (diabetes mellitus, chronic kidney disease, chronic heart failure, and chronic obstructive pulmonary disease), sarcopenia, hereditary neuromuscular diseases (spinal muscular atrophy, amyotrophic lateral sclerosis, and Duchenne muscular dystrophy), and cancer cachexia, have been discussed. Finally, this review proposes the alleviation oxidative stress using antioxidants, Chinese herbal extracts, stem cell and extracellular vesicles as a promising therapeutic strategy for muscle atrophy. This review will aid in the development of novel therapeutic strategies and drugs for muscle atrophy.
Collapse
Affiliation(s)
- Han Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Medical College, Nantong University, Nantong, Jiangsu Province, 226001, PR China
| | - Guangdong Qi
- Department of Endocrinology, Binhai County People's Hospital, Yancheng, Jiangsu Province, 224500, PR China
| | - Kexin Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Medical College, Nantong University, Nantong, Jiangsu Province, 226001, PR China
| | - Jiawen Yang
- Department of Clinical Medicine, Medical College, Nantong University, Nantong 226001, China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Medical College, Nantong University, Nantong, Jiangsu Province, 226001, PR China
| | - Xiaoming Yang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Medical College, Nantong University, Nantong, Jiangsu Province, 226001, PR China
| | - Xin Chen
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, PR China
| | - Xinlei Yao
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Medical College, Nantong University, Nantong, Jiangsu Province, 226001, PR China
| | - Xiaosong Gu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Medical College, Nantong University, Nantong, Jiangsu Province, 226001, PR China
| | - Lei Qi
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, PR China.
| | - Chun Zhou
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province, 226001, PR China.
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Medical College, Nantong University, Nantong, Jiangsu Province, 226001, PR China; Research and Development Center for E-Learning, Ministry of Education, Beijing 100816, PR China.
| |
Collapse
|
24
|
Le H, Rai V, Agrawal DK. Cholesterol: An Important Determinant of Muscle Atrophy in Astronauts. JOURNAL OF BIOTECHNOLOGY AND BIOMEDICINE 2023; 6:67-79. [PMID: 37006714 PMCID: PMC10062007 DOI: 10.26502/jbb.2642-91280072] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/07/2023]
Abstract
Since cholesterol is not routinely measured in astronauts before and after their return from space, there is no data on the role of blood cholesterol level in muscle atrophy and microgravity. Since the first moon landing, aerospace medicine became outdated and has not pushed boundaries like its rocket engineering counterpart. Since the 2019 astronaut twin study, there has yet to be another scientific breakthrough for aerospace medicine. Microgravity-induced muscle atrophy is the most known consequence of spaceflight. Yet, so far, there is no therapeutic solution to prevent it or any real efforts in understanding it on a cellular or molecular level. The most obvious reason to this unprecedented level of research is due to the small cohort of astronauts. With the establishment of private space industries and exponential recruitment of astronauts, there is more reason to push forward spaceflight-related health guidelines and ensure the safety of the brave humans who risk their lives for the progression of mankind. Spaceflight is considered the most challenging job and the failure to prevent injury or harm should be considered reckless negligence by the institutions that actively prevented sophistication of aerospace medicine. In this critical review, role of cholesterol is analyzed across the NASA-established parameters of microgravity-induced muscle atrophy with a focus on potential therapeutic targets for research.
Collapse
Affiliation(s)
- Hoangvi Le
- Department of Translational Research, Western University of Health Sciences, Pomona, California 91766, USA
| | - Vikrant Rai
- Department of Translational Research, Western University of Health Sciences, Pomona, California 91766, USA
| | - Devendra K Agrawal
- Department of Translational Research, Western University of Health Sciences, Pomona, California 91766, USA
| |
Collapse
|
25
|
Wang K, Liu Q, Tang M, Qi G, Qiu C, Huang Y, Yu W, Wang W, Sun H, Ni X, Shen Y, Fang X. Chronic kidney disease-induced muscle atrophy: Molecular mechanisms and promising therapies. Biochem Pharmacol 2023; 208:115407. [PMID: 36596414 DOI: 10.1016/j.bcp.2022.115407] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2022] [Revised: 12/28/2022] [Accepted: 12/28/2022] [Indexed: 01/02/2023]
Abstract
Chronic kidney disease (CKD) is a high-risk chronic catabolic disease due to its high morbidity and mortality. CKD is accompanied by many complications, leading to a poor quality of life, and serious complications may even threaten the life of CKD patients. Muscle atrophy is a common complication of CKD. Muscle atrophy and sarcopenia in CKD patients have complex pathways that are related to multiple mechanisms and related factors. This review not only discusses the mechanisms by which inflammation, oxidative stress, mitochondrial dysfunction promote CKD-induced muscle atrophy but also explores other CKD-related complications, such as metabolic acidosis, vitamin D deficiency, anorexia, and excess angiotensin II, as well as other related factors that play a role in CKD muscle atrophy, such as insulin resistance, hormones, hemodialysis, uremic toxins, intestinal flora imbalance, and miRNA. We highlight potential treatments and drugs that can effectively treat CKD-induced muscle atrophy in terms of complication treatment, nutritional supplementation, physical exercise, and drug intervention, thereby helping to improve the prognosis and quality of life of CKD patients.
Collapse
Affiliation(s)
- Kexin Wang
- Department of Nephrology, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, PR China; Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Qingyuan Liu
- Department of Endocrinology, Binhai County People's Hospital, Yancheng, Jiangsu Province 224500, PR China
| | - Mingyu Tang
- Xinglin College, Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Guangdong Qi
- Department of Endocrinology, Binhai County People's Hospital, Yancheng, Jiangsu Province 224500, PR China
| | - Chong Qiu
- Department of Clinical Medicine, Medical College, Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Yan Huang
- Department of Clinical Medicine, Medical College, Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Weiran Yu
- Department of Clinical Medicine, Medical College, Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Wei Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, PR China; Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, PR China
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, PR China
| | - Xuejun Ni
- Department of Ultrasound Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, PR China.
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, PR China.
| | - Xingxing Fang
- Department of Nephrology, the Second Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, PR China.
| |
Collapse
|
26
|
Kim JY, Kim HM, Kim JH, Guo S, Lee DH, Lim GM, Kim W, Kim CY. Salvia plebeia R.Br. and Rosmarinic Acid Attenuate Dexamethasone-Induced Muscle Atrophy in C2C12 Myotubes. Int J Mol Sci 2023; 24:ijms24031876. [PMID: 36768200 PMCID: PMC9915874 DOI: 10.3390/ijms24031876] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2022] [Revised: 01/13/2023] [Accepted: 01/16/2023] [Indexed: 01/21/2023] Open
Abstract
Skeletal muscle atrophy occurs when protein degradation exceeds protein synthesis and is associated with increased circulating glucocorticoid levels. Salvia plebeia R.Br. (SPR) has been used as herbal remedy for a variety of inflammatory diseases and has various biological actions such as antioxidant and anti-inflammatory activities. However, there are no reports on the effects of SPR and its bioactive components on muscle atrophy. Herein, we investigated the anti-atrophic effect of SPR and rosmarinic acid (RosA), a major compound of SPR, on dexamethasone (DEX)-induced skeletal muscle atrophy in C2C12 myotubes. Myotubes were treated with 10 μM DEX in the presence or absence of SPR or RosA at different concentrations for 24 h and subjected to immunocytochemistry, western blot, and measurements of ROS and ATP levels. SPR and RosA increased viability and inhibited protein degradation in DEX-treated C2C12 myotubes. In addition, RosA promoted the Akt/p70S6K/mTOR pathway and reduced ROS production, and apoptosis. Furthermore, the treatment of RosA significantly recovered SOD activity, autophagy activity, mitochondrial contents, and APT levels in DEX-treated myotubes. These findings suggest that SPR and RosA may provide protective effects against DEX-induced muscle atrophy and have promising potential as a nutraceutical remedy for the treatment of muscle weakness and atrophy.
Collapse
Affiliation(s)
| | | | | | | | | | | | - Wondong Kim
- Correspondence: (W.K.); (C.Y.K.); Tel.: +82-31-400-5817 (W.K.); +82-31-400-5809 (C.Y.K.); Fax: +82-31-400-5958 (C.Y.K.)
| | - Chul Young Kim
- Correspondence: (W.K.); (C.Y.K.); Tel.: +82-31-400-5817 (W.K.); +82-31-400-5809 (C.Y.K.); Fax: +82-31-400-5958 (C.Y.K.)
| |
Collapse
|
27
|
QIU JIAYING, CHANG YAN, LIANG WENPENG, LIN MENGSI, XU HUI, XU WANQING, ZHU QINGWEN, ZHANG HAIBO, ZHANG ZHENYU. Pharmacological effects of denervated muscle atrophy due to metabolic imbalance in different periods. BIOCELL 2023; 47:2351-2359. [DOI: 10.32604/biocell.2023.031043] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/25/2023] [Indexed: 09/11/2024]
|
28
|
Wu Y, Pi D, Zhou S, Wang W, Ye H, Yi Z, Chen Y, Ouyang M. Yiqi Chutan Formula Reverses Cisplatin-Induced Apoptosis and Ferroptosis of Skeletal Muscle by Alleviating Oxidative Stress. Integr Cancer Ther 2023; 22:15347354231172117. [PMID: 37132527 PMCID: PMC10161340 DOI: 10.1177/15347354231172117] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2022] [Revised: 03/24/2023] [Accepted: 04/10/2023] [Indexed: 05/04/2023] Open
Abstract
BACKGROUND Cisplatin is a widely used anticancer drug in clinic, but it has a damaging effect on skeletal muscle cells. Clinical observation showed that Yiqi Chutan formula (YCF) had a alleviating effect on cisplatin toxicity. METHODS In vitro cell model and in vivo animal model were used to observe the damage effect of cisplatin on skeletal muscle cells and verify that YCF reversed cisplatin induced skeletal muscle damage. The levels of oxidative stress, apoptosis and ferroptosis were measured in each group. RESULTS Both in vitro and in vivo studies have confirmed that cisplatin increases the level of oxidative stress in skeletal muscle cells, thus inducing cell apoptosis and ferroptosis. YCF treatment can effectively reverse cisplatin induced oxidative stress in skeletal muscle cells, thereby alleviating cell apoptosis and ferroptosis, and ultimately protecting skeletal muscle. CONCLUSIONS YCF reversed cisplatin-induced apoptosis and ferroptosis of skeletal muscle by alleviating oxidative stress.
Collapse
Affiliation(s)
- Yingchao Wu
- Jinan University, Guangzhou, Guangdong, China
| | - Dajin Pi
- Jinan University, Guangzhou, Guangdong, China
| | - Shuyao Zhou
- Guangdong Hanchao Traditional Chinese Medicine Technology Co., Ltd., Guangzhou, Guangdong, China
| | - Wuhong Wang
- Jinan University, Guangzhou, Guangdong, China
| | - Huan Ye
- Jinan University, Guangzhou, Guangdong, China
| | - Zhongjia Yi
- Jinan University, Guangzhou, Guangdong, China
| | - Yiliu Chen
- Jinan University, Guangzhou, Guangdong, China
| | | |
Collapse
|
29
|
Potential Therapeutic Strategies for Skeletal Muscle Atrophy. Antioxidants (Basel) 2022; 12:antiox12010044. [PMID: 36670909 PMCID: PMC9854691 DOI: 10.3390/antiox12010044] [Citation(s) in RCA: 42] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/13/2022] [Accepted: 12/22/2022] [Indexed: 12/28/2022] Open
Abstract
The maintenance of muscle homeostasis is vital for life and health. Skeletal muscle atrophy not only seriously reduces people's quality of life and increases morbidity and mortality, but also causes a huge socioeconomic burden. To date, no effective treatment has been developed for skeletal muscle atrophy owing to an incomplete understanding of its molecular mechanisms. Exercise therapy is the most effective treatment for skeletal muscle atrophy. Unfortunately, it is not suitable for all patients, such as fractured patients and bedridden patients with nerve damage. Therefore, understanding the molecular mechanism of skeletal muscle atrophy is crucial for developing new therapies for skeletal muscle atrophy. In this review, PubMed was systematically screened for articles that appeared in the past 5 years about potential therapeutic strategies for skeletal muscle atrophy. Herein, we summarize the roles of inflammation, oxidative stress, ubiquitin-proteasome system, autophagic-lysosomal pathway, caspases, and calpains in skeletal muscle atrophy and systematically expound the potential drug targets and therapeutic progress against skeletal muscle atrophy. This review focuses on current treatments and strategies for skeletal muscle atrophy, including drug treatment (active substances of traditional Chinese medicine, chemical drugs, antioxidants, enzyme and enzyme inhibitors, hormone drugs, etc.), gene therapy, stem cell and exosome therapy (muscle-derived stem cells, non-myogenic stem cells, and exosomes), cytokine therapy, physical therapy (electroacupuncture, electrical stimulation, optogenetic technology, heat therapy, and low-level laser therapy), nutrition support (protein, essential amino acids, creatine, β-hydroxy-β-methylbutyrate, and vitamin D), and other therapies (biomaterial adjuvant therapy, intestinal microbial regulation, and oxygen supplementation). Considering many treatments have been developed for skeletal muscle atrophy, we propose a combination of proper treatments for individual needs, which may yield better treatment outcomes.
Collapse
|
30
|
Venckunas T, Brazaitis M, Snieckus A, Mickevicius M, Eimantas N, Subocius A, Mickeviciene D, Westerblad H, Kamandulis S. Adding High-Intensity Interval Training to Classical Resistance Training Does Not Impede the Recovery from Inactivity-Induced Leg Muscle Weakness. Antioxidants (Basel) 2022; 12:antiox12010016. [PMID: 36670879 PMCID: PMC9854626 DOI: 10.3390/antiox12010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022] Open
Abstract
Inactivity is known to induce muscle weakness, and chronically increased levels of reactive oxygen species (ROS) are proposed to have a central causative role in this process. Intriguingly, high-intensity interval training (HIIT), which involves bursts of high ROS production, can have positive effects in pathological conditions with chronically increased ROS. Here, young male volunteers were exposed to 3 weeks of unloading of the dominant leg followed by 3 weeks of resistance training without (Ctrl group) or with the addition of all-out cycling HIIT. Changes in muscle thickness were assessed by ultrasonography, and contractile function was studied by measuring the torque during maximal voluntary contractions (MVC). The results show an ~6% decrease in vastus lateralis thickness after the unloading period, which was fully restored after the subsequent training period in both the Ctrl and HIIT groups. MVC torque was decreased by ~11% after the unloading period and recovered fully during the subsequent training period in both groups. All-out cycling performance was improved by the 3 weeks of HIIT. In conclusion, the decline in muscle size and function after 3 weeks of unloading was restored by 3 weeks of resistance training regardless of whether it was combined with HIIT.
Collapse
Affiliation(s)
- Tomas Venckunas
- Institute of Sports Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania
| | - Marius Brazaitis
- Institute of Sports Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania
| | - Audrius Snieckus
- Institute of Sports Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania
- Correspondence:
| | - Mantas Mickevicius
- Institute of Sports Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania
| | - Nerijus Eimantas
- Institute of Sports Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania
| | - Andrejus Subocius
- Institute of Sports Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania
- Kaunas Hospital of the Lithuanian University of Health Sciences, 50161 Kaunas, Lithuania
| | - Dalia Mickeviciene
- Institute of Sports Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania
| | - Håkan Westerblad
- Department of Physiology and Pharmacology, Karolinska Institutet, 171 77 Stockholm, Sweden
| | - Sigitas Kamandulis
- Institute of Sports Science and Innovations, Lithuanian Sports University, 44221 Kaunas, Lithuania
| |
Collapse
|
31
|
Kim JY, Kim HM, Kim JH, Lee JH, Zhang K, Guo S, Lee DH, Gao EM, Son RH, Kim SM, Kim CY. Preventive effects of the butanol fraction of Justicia procumbens L. against dexamethasone-induced muscle atrophy in C2C12 myotubes. Heliyon 2022; 8:e11597. [DOI: 10.1016/j.heliyon.2022.e11597] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/06/2022] [Accepted: 11/10/2022] [Indexed: 11/23/2022] Open
|
32
|
Inflammation: Roles in Skeletal Muscle Atrophy. Antioxidants (Basel) 2022; 11:antiox11091686. [PMID: 36139760 PMCID: PMC9495679 DOI: 10.3390/antiox11091686] [Citation(s) in RCA: 110] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2022] [Revised: 08/25/2022] [Accepted: 08/26/2022] [Indexed: 12/03/2022] Open
Abstract
Various diseases can cause skeletal muscle atrophy, usually accompanied by inflammation, mitochondrial dysfunction, apoptosis, decreased protein synthesis, and enhanced proteolysis. The underlying mechanism of inflammation in skeletal muscle atrophy is extremely complex and has not been fully elucidated, thus hindering the development of effective therapeutic drugs and preventive measures for skeletal muscle atrophy. In this review, we elaborate on protein degradation pathways, including the ubiquitin-proteasome system (UPS), the autophagy-lysosome pathway (ALP), the calpain and caspase pathways, the insulin growth factor 1/Akt protein synthesis pathway, myostatin, and muscle satellite cells, in the process of muscle atrophy. Under an inflammatory environment, various pro-inflammatory cytokines directly act on nuclear factor-κB, p38MAPK, and JAK/STAT pathways through the corresponding receptors, and then are involved in muscle atrophy. Inflammation can also indirectly trigger skeletal muscle atrophy by changing the metabolic state of other tissues or cells. This paper explores the changes in the hypothalamic-pituitary-adrenal axis and fat metabolism under inflammatory conditions as well as their effects on skeletal muscle. Moreover, this paper also reviews various signaling pathways related to muscle atrophy under inflammatory conditions, such as cachexia, sepsis, type 2 diabetes mellitus, obesity, chronic obstructive pulmonary disease, chronic kidney disease, and nerve injury. Finally, this paper summarizes anti-amyotrophic drugs and their therapeutic targets for inflammation in recent years. Overall, inflammation is a key factor causing skeletal muscle atrophy, and anti-inflammation might be an effective strategy for the treatment of skeletal muscle atrophy. Various inflammatory factors and their downstream pathways are considered promising targets for the treatment and prevention of skeletal muscle atrophy.
Collapse
|
33
|
Zhang L, Li M, Wang W, Yu W, Liu H, Wang K, Chang M, Deng C, Ji Y, Shen Y, Qi L, Sun H. Celecoxib alleviates denervation-induced muscle atrophy by suppressing inflammation and oxidative stress and improving microcirculation. Biochem Pharmacol 2022; 203:115186. [PMID: 35882305 DOI: 10.1016/j.bcp.2022.115186] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Revised: 07/16/2022] [Accepted: 07/19/2022] [Indexed: 11/25/2022]
Abstract
The molecular mechanism underlying denervation-induced muscle atrophy is complex and incompletely understood. Our previous results suggested that inflammation may play an important role in the early stages of muscle atrophy. Celecoxib is reported to exert anti-inflammatory effects. Here, we explored the effect of celecoxib on denervation-induced muscle atrophy and sought to identify the mechanism involved. We found that celecoxib treatment significantly increased the wet weight ratio and CSA of the tibialisanteriormuscle. Additionally, celecoxib downregulated the levels of COX-2, inflammatory factors and reduced inflammatory cell infiltration. GO and KEGG pathway enrichment analysis indicated that after 3 days of celecoxib treatment in vivo, the differentially expressed genes (DEGs) were mainly associated with the regulation of immune responses related to complement activation; after 14 days, the DEGs were mainly involved in the regulation of oxidative stress and inflammation-related responses. Celecoxib administration reduced the levels of ROS and oxidative stress-related proteins. Furthermore, we found that celecoxib treatment inhibited the denervation-induced up-regulation of the ubiquitin-proteasome and autophagy-lysosomal systems related proteins; decreased mitophagy in target muscles; and increased levels of MHC. Finally, celecoxib also attenuated microvascular damage in denervated skeletal muscle. Combined, our findings demonstrated that celecoxib inhibits inflammation and oxidative stress in denervated skeletal muscle, thereby suppressing mitophagy and proteolysis, improving blood flow in target muscles, and, ultimately, alleviating denervation-induced muscle atrophy. Our results confirmed that inflammatory responses play a key role in denervation-induced muscle atrophy and highlight a novel strategy for the prevention and treatment of this condition.
Collapse
Affiliation(s)
- Lilei Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, P. R. China
| | - Ming Li
- Department of Laboratory Medicine, Department of Endocrinology, Binhai County People's Hospital affiliated to Kangda College of Nanjing Medical University, Yancheng, Jiangsu Province 224500, P. R. China
| | - Wei Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, P. R. China; Department of Pathology, Affiliated Hospital of Nantong University, Medical School of Nantong University, Nantong 226001, P. R. China
| | - Weiran Yu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, P. R. China
| | - Hua Liu
- Department of Orthopedics, Haian Hospital of Traditional Chinese Medicine, 55 Ninghai Middle Road, Haian, Nantong, Jiangsu Province 226600, P. R. China
| | - Kexin Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, P. R. China
| | - Mengyuan Chang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, P. R. China
| | - Chunyan Deng
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, P. R. China
| | - Yanan Ji
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, P. R. China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, P. R. China.
| | - Lei Qi
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu Province 226001, P. R. China.
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong University, Nantong, Jiangsu Province 226001, P. R. China.
| |
Collapse
|
34
|
IL-6 Deficiency Attenuates Skeletal Muscle Atrophy by Inhibiting Mitochondrial ROS Production through the Upregulation of PGC-1α in Septic Mice. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:9148246. [PMID: 35528525 PMCID: PMC9068301 DOI: 10.1155/2022/9148246] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Revised: 03/13/2022] [Accepted: 03/29/2022] [Indexed: 02/07/2023]
Abstract
Current evidences indicate that both inflammation and oxidative stress contribute to the pathogenesis of sepsis-associated skeletal muscle atrophy. However, the interaction between inflammation and oxidative stress has not been completely understood in sepsis-associated skeletal muscle atrophy. Here in the present study, a murine model of sepsis has been established by cecal ligation and puncture (CLP) with wild-type and interleukin- (IL-) 6 knockout (KO) mice. Our results suggested that IL-6 KO largely attenuated skeletal muscle atrophy as reflected by reduced protein degradation, increased cross-sectional area (CSA) of myofibers, and improved muscle contractile function (all
). In addition, we observed that IL-6 KO promoted the expression of peroxisome proliferator-activated receptor γ coactivator–1alpha (PGC–1α) and inhibited CLP-induced mitochondrial reactive oxygen species (ROS) production in skeletal muscles (all
). However, the knockdown of PGC–1α abolished the protective effects of IL-6 KO in CLP-induced skeletal muscle atrophy and reversed the changes in mitochondrial ROS production (all
). Ex vivo experiments found that exogenous IL-6 inhibited PGC–1α expression, promoted mitochondrial ROS production, and induced proteolysis in C2C12 cells (all
). Together, these results suggested that IL-6 deficiency attenuated skeletal muscle atrophy by inhibiting mitochondrial ROS production through the upregulation of PGC–1α expression in septic mice.
Collapse
|
35
|
Sun M, Jiao H, Wang X, Li H, Zhou Y, Zhao J, Lin H. The regulating pathway of creatine on muscular protein metabolism depends on the energy state. Am J Physiol Cell Physiol 2022; 322:C1022-C1035. [PMID: 35417269 DOI: 10.1152/ajpcell.00447.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Creatine (Cr) is beneficial for increasing muscle mass and preventing muscle atrophy via involving in energy metabolism through the Cr and phosphocreatine (PCr) system. This study aimed to evaluate the supplemental effect of Cr on protein metabolism under normal and starvation conditions. The primary myoblasts were obtained from the breast muscle of chicks. The mammalian target of rapamycin (mTOR)/P70S6 kinase (P70S6K), ubiquitin proteasome (UP) pathways, and mitochondrial function of myotubes were evaluated at normal or starvation state and with or without glucose supplementation. Under normal condition, Cr supplementation enhanced protein synthesis rate as well as upregulated the total and phosphorylated P70S6K expressions. Cr had little influence on protein catabolism, and mitochondrial function. In a starvation state, however, Cr alleviated myotube atrophy and enhanced protein accretion by inhibiting Atrogin1 and myostatin (MSTN) expression. Furthermore, Cr treatment upregulated the transcriptional coactivators peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) expression, and decreased reactive oxygen species (ROS) accumulation under starvation condition. In the presence of glucose, however, the favorable effect of Cr on protein content and myotube diameter did not occur under starvation condition. The present result indicates that at normal state, Cr stimulated protein synthesis via the mTOR/P70S6K pathway. In a starvation state, Cr mainly take a favorable effect on protein accumulation via suppression of UP pathway and mediated mitochondrial function mainly by serving as an energy supplier. The result highlights the potential clinical application for the modulation of muscle mass under different nutritional conditions.
Collapse
Affiliation(s)
- Mingfa Sun
- Department of Animal Science, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, China
| | - Hongchao Jiao
- Department of Animal Science, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, China
| | - Xiaojuan Wang
- Department of Animal Science, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, China
| | - Haifang Li
- College of Life Sciences, Shandong Agricultural University, Taian City, Shandong Province, China
| | - Yunlei Zhou
- College of Chemistry and Material Science, Shandong Agricultural University, Taian City, Shandong Province, China
| | - Jingpeng Zhao
- Department of Animal Science, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, China
| | - Hai Lin
- Department of Animal Science, Shandong Agricultural University, Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Taian City, Shandong Province, China
| |
Collapse
|
36
|
Kushwaha AD, Saraswat D. A Nanocurcumin and Pyrroloquinoline Quinone Formulation Prevents Hypobaric Hypoxia-Induced Skeletal Muscle Atrophy by Modulating NF-κB Signaling Pathway. High Alt Med Biol 2022; 23:249-263. [PMID: 35384739 DOI: 10.1089/ham.2021.0127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Kushwaha, Asha D., and Deepika Saraswat. A nanocurcumin and pyrroloquinoline quinone formulation prevents hypobaric hypoxia-induced skeletal muscle atrophy by modulating NF-κB signaling pathway. High Alt Med Biol 00:000-000, 2022. Background: Hypobaric hypoxia (HH)-induced deleterious skeletal muscle damage depends on exposure time and availability of oxygen at cellular level, which eventually can limit human work performance at high altitude (HA). Despite the advancements made in pharmacological (performance enhancer, antioxidants) and nonpharmacological therapeutics (acclimatization strategies), only partial success has been achieved in improving physical performance at HA. A distinctive combination of nanocurcumin (NC) and pyrroloquinoline quinone (PQQ) has been formulated (named NCF [nanocurcumin formulation], Indian patent No. 302877) in our laboratory, and has proven very promising in improving cardiomyocyte adaptation to chronic HH. We hypothesized that NCF might improve skeletal muscle adaptation and could be a performance enhancer at HA. Material and Methods: Adult Sprague-Dawley rats (220 ± 10 g) were divided into five groups (n = 6/group): normoxia vehicle control, hypoxia vehicle control, hypoxia NCF, hypoxia NC, and hypoxia PQQ. All the animals (except those in normoxia) were exposed to simulated HH in a chamber at temperature 22°C ± 2°C, humidity 50% ± 5%, altitude 25,000 ft for 1, 3, or 7 days. After completion of the stipulated exposure time, gastrocnemius and soleus muscles were excised from animals for further analysis. Results: Greater lengths of hypoxic exposure caused progressively increased muscle ring finger-1 (MuRF-1; p < 0.01) expression and calpain activation (0.56 ± 0.05 vs. 0.13 ± 0.02 and 0.44 ± 0.03 vs. 0.12 ± 0.021) by day 7, respectively in the gastrocnemius and soleus muscles. Myosin heavy chain type I (slow oxidative) fibers significantly (p > 0.01) decreased in gastrocnemius (>50%) and soleus (>46%) muscles by the seventh day of exposure. NCF supplementation showed (p ≤ 0.05) tremendous improvement in skeletal muscle acclimatization through effective alleviation of oxidative damage, and changes in calpain activity and atrophic markers at HA compared with hypoxia control or treatment alone with NC/PQQ. Conclusion: Thus, NCF-mediated anti-oxidative, anti-inflammatory effects lead to decreased proteolysis resulting in mitigated skeletal muscle atrophy under HH.
Collapse
Affiliation(s)
- Asha D Kushwaha
- Experimental Biology Division, Defense Institute of Physiology and Allied Sciences, Defense Research and Development Organization, Delhi, India
| | - Deepika Saraswat
- Experimental Biology Division, Defense Institute of Physiology and Allied Sciences, Defense Research and Development Organization, Delhi, India
| |
Collapse
|
37
|
Biogenesis and Function of Extracellular Vesicles in Pathophysiological Processes Skeletal Muscle Atrophy. Biochem Pharmacol 2022; 198:114954. [DOI: 10.1016/j.bcp.2022.114954] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 02/08/2022] [Accepted: 02/08/2022] [Indexed: 12/13/2022]
|
38
|
Antioxidant Activity of Valeriana fauriei Protects against Dexamethasone-Induced Muscle Atrophy. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:3645431. [PMID: 35069972 PMCID: PMC8769843 DOI: 10.1155/2022/3645431] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Revised: 12/01/2021] [Accepted: 12/15/2021] [Indexed: 12/28/2022]
Abstract
Skeletal muscle atrophy is defined as wasting or loss of muscle. Although glucocorticoids (GCs) are well-known anti-inflammatory drugs, their long-term or high-dose use induces skeletal muscle atrophy. Valeriana fauriei (VF) is used to treat restlessness, anxiety, and sleep disorders; however, its effects on skeletal muscle health have not been investigated. This study investigated whether Valeriana fauriei could ameliorate muscle atrophy. We induced muscle atrophy in vitro and in vivo, by treatment with dexamethasone (DEX), a synthetic GC. In DEX-induced myotube atrophy, Valeriana fauriei treatment increased the fusion index and decreased the expression of muscle atrophic genes such as muscle atrophy F-box (MAFbx/Atrogin-1) and muscle RING-finger protein 1 (MuRF1). In DEX-treated mice with muscle atrophy, Valeriana fauriei supplementation increased the ability to exercise, muscle weight, and cross-sectional area, whereas it inhibited myosin heavy chain isoform transition and the expression of muscle atrophy biomarkers. Valeriana fauriei treatment led to via the downregulation of muscle atrophic genes via inhibition of GC receptor translocation. Valeriana fauriei was also found to act as a reactive oxygen species (ROS) scavenger. Didrovaltrate (DI), an iridoid compound from Valeriana fauriei, was found to downregulate atrophic genes and decrease ROS in the DEX-induced myotube atrophy. Consolidated, our results indicate that Valeriana fauriei prevents DEX-induced muscle atrophy by inhibiting GC receptor translocation. Further, Valeriana fauriei acts as a ROS scavenger, and its functional compound is didrovaltrate. We suggest that Valeriana fauriei and its functional compound didrovaltrate possess therapeutic potentials against muscle atrophy.
Collapse
|
39
|
SKP-SC-EVs Mitigate Denervated Muscle Atrophy by Inhibiting Oxidative Stress and Inflammation and Improving Microcirculation. Antioxidants (Basel) 2021; 11:antiox11010066. [PMID: 35052570 PMCID: PMC8772917 DOI: 10.3390/antiox11010066] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2021] [Revised: 12/22/2021] [Accepted: 12/25/2021] [Indexed: 12/23/2022] Open
Abstract
Denervated muscle atrophy is a common clinical disease that has no effective treatments. Our previous studies have found that oxidative stress and inflammation play an important role in the process of denervated muscle atrophy. Extracellular vesicles derived from skin precursor-derived Schwann cells (SKP-SC-EVs) contain a large amount of antioxidants and anti-inflammatory factors. This study explored whether SKP-SC-EVs alleviate denervated muscle atrophy by inhibiting oxidative stress and inflammation. In vitro studies have found that SKP-SC-EVs can be internalized and caught by myoblasts to promote the proliferation and differentiation of myoblasts. Nutrient deprivation can cause myotube atrophy, accompanied by oxidative stress and inflammation. However, SKP-SC-EVs can inhibit oxidative stress and inflammation caused by nutritional deprivation and subsequently relieve myotube atrophy. Moreover, there is a remarkable dose-effect relationship. In vivo studies have found that SKP-SC-EVs can significantly inhibit a denervation-induced decrease in the wet weight ratio and myofiber cross-sectional area of target muscles. Furthermore, SKP-SC-EVs can dramatically inhibit highly expressed Muscle RING Finger 1 and Muscle Atrophy F-box in target muscles under denervation and reduce the degradation of the myotube heavy chain. SKP-SC-EVs may reduce mitochondrial vacuolar degeneration and autophagy in denervated muscles by inhibiting autophagy-related proteins (i.e., PINK1, BNIP3, LC3B, and ATG7). Moreover, SKP-SC-EVs may improve microvessels and blood perfusion in denervated skeletal muscles by enhancing the proliferation of vascular endothelial cells. SKP-SC-EVs can also significantly inhibit the production of reactive oxygen species (ROS) in target muscles after denervation, which indicates that SKP-SC-EVs elicit their role by upregulating Nrf2 and downregulating ROS production-related factors (Nox2 and Nox4). In addition, SKP-SC-EVs can significantly reduce the levels of interleukin 1β, interleukin-6, and tumor necrosis factor α in target muscles. To conclude, SKP-SC-EVs may alleviate the decrease of target muscle blood perfusion and passivate the activities of ubiquitin-proteasome and autophagy-lysosome systems by inhibiting oxidative stress and inflammatory response, then reduce skeletal muscle atrophy caused by denervation. This study not only enriches the molecular regulation mechanism of denervated muscle atrophy, but also provides a scientific basis for SKP-SC-EVs as a protective drug to prevent and treat muscle atrophy.
Collapse
|
40
|
Liu Q, Deng J, Qiu Y, Gao J, Li J, Guan L, Lee H, Zhou Q, Xiao J. Non-coding RNA basis of muscle atrophy. MOLECULAR THERAPY. NUCLEIC ACIDS 2021; 26:1066-1078. [PMID: 34786211 PMCID: PMC8569427 DOI: 10.1016/j.omtn.2021.10.010] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Muscle atrophy is a common complication of many chronic diseases including heart failure, cancer cachexia, aging, etc. Unhealthy habits and usage of hormones such as dexamethasone can also lead to muscle atrophy. However, the underlying mechanisms of muscle atrophy are not completely understood. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long ncRNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in muscle atrophy. This review mainly discusses the regulation of ncRNAs in muscle atrophy induced by various factors such as heart failure, cancer cachexia, aging, chronic obstructive pulmonary disease (COPD), peripheral nerve injury (PNI), chronic kidney disease (CKD), unhealthy habits, and usage of hormones; highlights the findings of ncRNAs as common regulators in multiple types of muscle atrophy; and summarizes current therapies and underlying mechanisms for muscle atrophy. This review will deepen the understanding of skeletal muscle biology and provide new strategies and insights into gene therapy for muscle atrophy.
Collapse
Affiliation(s)
- Qi Liu
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Jiali Deng
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Yan Qiu
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Juan Gao
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Jin Li
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Longfei Guan
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing 101149, China
| | - Hangil Lee
- Department of Neurosurgery, Wayne State University School of Medicine, Detroit, MI 48201, USA
| | - Qiulian Zhou
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| | - Junjie Xiao
- Institute of Geriatrics (Shanghai University), Affiliated Nantong Hospital of Shanghai University (The Sixth People's Hospital of Nantong), School of Medicine, Shanghai University, Nantong 226011, China.,Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, Shanghai Engineering Research Center of Organ Repair, School of Life Science, Shanghai University, Shanghai 200444, China
| |
Collapse
|
41
|
Swim training affects Akt signaling and ameliorates loss of skeletal muscle mass in a mouse model of amyotrophic lateral sclerosis. Sci Rep 2021; 11:20899. [PMID: 34686697 PMCID: PMC8536703 DOI: 10.1038/s41598-021-00319-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Accepted: 10/11/2021] [Indexed: 12/01/2022] Open
Abstract
We tested the hypothesis that swim training reverses the impairment of Akt/FOXO3a signaling, ameliorating muscle atrophy in ALS mice. Transgenic male mice B6SJL-Tg (SOD1G93A) 1Gur/J were used as the ALS model (n = 35), with wild-type B6SJL (WT) mice as controls (n = 7). ALS mice were analyzed before ALS onset, at ALS onset, and at terminal ALS. Levels of insulin/Akt signaling pathway proteins were determined, and the body and tibialis anterior muscle mass and plasma creatine kinase. Significantly increased levels of FOXO3a in ALS groups (from about 13 to 21-fold) compared to WT mice were observed. MuRF1 levels in the ONSET untrained group (12.0 ± 1.7 AU) were significantly higher than in WT mice (1.12 ± 0.2 AU) and in the BEFORE ALS group (3.7 ± 0.9 AU). This was associated with body mass and skeletal muscle mass reduction. Swim training significantly ameliorated the reduction of skeletal muscle mass in both TERMINAL groups (p < 0.001) and partially reversed changes in the levels of Akt signaling pathway proteins. These findings shed light on the swimming-induced attenuation of skeletal muscle atrophy in ALS with possible practical implications for anti-cachexia approaches.
Collapse
|
42
|
Sun H, Sun J, Li M, Qian L, Zhang L, Huang Z, Shen Y, Law BYK, Liu L, Gu X. Transcriptome Analysis of Immune Receptor Activation and Energy Metabolism Reduction as the Underlying Mechanisms in Interleukin-6-Induced Skeletal Muscle Atrophy. Front Immunol 2021; 12:730070. [PMID: 34552592 PMCID: PMC8450567 DOI: 10.3389/fimmu.2021.730070] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2021] [Accepted: 08/17/2021] [Indexed: 12/30/2022] Open
Abstract
Background Inflammation may trigger skeletal muscle atrophy induced by cancer cachexia. As a pro-inflammatory factor, interleukin-6 may cause skeletal muscle atrophy, but the underlying molecular mechanisms have not been explored. Methods In this experimental study, we used adult male ICR mice, weighing 25 ± 2 g, and the continuous infusion of interleukin-6 into the tibialis anterior muscle to construct a skeletal muscle atrophy model (experimental group). A control group received a saline infusion. RNA-sequencing was used to analyze the differentially expressed genes in tissue samples after one and three days. Gene Ontology and the Kyoto Encyclopedia of Genes and Genomes analysis were applied to define the function of these genes, and protein-protein interaction analysis was performed to identify potential transcription factors. Fluorescence microscopy was used to determine the muscle fiber cross-sectional area after 14 days. Results Continuous infusion of interleukin-6 for 14 days caused significant muscle atrophy. RNA-sequencing found 359 differentially expressed genes in the 1- and 3-day tissue samples and 1748 differentially expressed genes only in the 3-day samples. Functional analysis showed that the differentially expressed genes found in both the 1- and 3-day samples were associated with immune receptor activation, whereas the differentially expressed genes found only in the 3-day sample were associated with reduced energy metabolism. The expression of multiple genes in the oxidative phosphorylation and tricarboxylic acid cycle pathways was down-regulated. Furthermore, differentially expressed transcription factors were identified, and their interaction with interleukin-6 and the differentially expressed genes was predicted, which indicated that STAT3, NF-κB, TP53 and MyoG may play an important role in the process of interleukin-6-induced muscle atrophy. Conclusions This study found that interleukin-6 caused skeletal muscle atrophy through immune receptor activation and a reduction of the energy metabolism. Several transcription factors downstream of IL-6 have the potential to become new regulators of skeletal muscle atrophy. This study not only enriches the molecular regulation mechanism of muscle atrophy, but also provides a potential target for targeted therapy of muscle atrophy.
Collapse
Affiliation(s)
- Hualin Sun
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, Macau, SAR China
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, National Medical Products Administration Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong, China
| | - Junjie Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, National Medical Products Administration Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong, China
| | - Ming Li
- Department of Laboratory Medicine, Binhai County People’s Hospital Affiliated to Kangda College of Nanjing Medical University, Yancheng, China
| | - Lei Qian
- Department of Laboratory Medicine, Binhai County People’s Hospital Affiliated to Kangda College of Nanjing Medical University, Yancheng, China
| | - Lilei Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, National Medical Products Administration Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong, China
| | - Ziwei Huang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, National Medical Products Administration Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong, China
- Division of Sports Medicine and Adult Reconstructive Surgery, Department of Emergency, Department of Orthopedic Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, National Medical Products Administration Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong, China
| | - Betty Yuen-Kwan Law
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, Macau, SAR China
| | - Liang Liu
- State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Macau, Macau, SAR China
| | - Xiaosong Gu
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Co-Innovation Center of Neuroregeneration, Nantong University, National Medical Products Administration Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Nantong, China
| |
Collapse
|
43
|
Tsukamoto T, Tsujii M, Odake K, Iino T, Nakamura T, Matsumine A, Sudo A. Febuxostat reduces muscle wasting in tumor-bearing mice with LM8 osteosarcoma cells via inhibition of reactive oxygen species generation. Free Radic Res 2021; 55:810-820. [PMID: 34278932 DOI: 10.1080/10715762.2021.1947502] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
Cachexic condition due to malignant tumors has been a challenging problem. The aim of this study is to analyze effects of febuxostat on both in vitro and in vivo models of the wasting of skeletal muscles, due to LM8 osteosarcoma cells. C2C12 myotubes were incubated in the conditioned medium of LM8. Febuxostat was added at a concentration of 3 µM and 30 µM, and ROS, diameter of myotubes, and expression of atrogin-1 were analyzed. Furthermore, an in vivo study was performed by subcutaneous injection of LM8 on C3H mice. Febuxostat was administered in the drinking water at 5 µg/ml, and 25 µg/ml. In addition, tumor-bearing mice without febuxostat (group TB) and control mice (group C) were established. At 4 weeks, body weight, wet weights of the gastrocnemius muscles, XO activity, 8-OHdG, and expression of TNF-α and IL-6 were evaluated. ROS generation, atrophy of myotubes, and upregulation of atrogin-1 were clearly observed in C2C12 myotubes following incubation in the conditioned medium. These pathological conditions were significantly inhibited by febuxostat administration. Furthermore, mice in group TB showed significant loss of body weight and muscle weight in which XO activity, 8-OHdG, and expression of IL-6 were significantly increased compared to those in group C. Febuxostat administration not only significantly improved the body weight and muscleweight, but also reduced markers of oxidative stress and pro-inflammatory cytokines. Febuxostat did not show anti-tumor effects. Febuxostat, which is clinically used for treatment of hyperuricemia, is effective against the wasting of the skeletal muscles induced by LM8 osteosarcoma cells.
Collapse
Affiliation(s)
- Tadashi Tsukamoto
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| | - Masaya Tsujii
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| | - Kazuya Odake
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| | - Takahiro Iino
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| | - Tomoki Nakamura
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| | - Akihiko Matsumine
- Department of Orthopaedic Surgery, Fukui University Faculty of Medical Science, Eiheiji-Cho, Japan
| | - Akihiro Sudo
- Department of Orthopaedic Surgery, Mie university Graduate School of Medicine, Tsu, Japan
| |
Collapse
|
44
|
Seo H, Lee SH, Park Y, Lee HS, Hong JS, Lim CY, Kim DH, Park SS, Suh HJ, Hong KB. (-)-Epicatechin-Enriched Extract from Camellia sinensis Improves Regulation of Muscle Mass and Function: Results from a Randomized Controlled Trial. Antioxidants (Basel) 2021; 10:1026. [PMID: 34202133 PMCID: PMC8300738 DOI: 10.3390/antiox10071026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 12/14/2022] Open
Abstract
Loss of skeletal muscle mass and function with age represents an important source of frailty and functional decline in the elderly. Antioxidants from botanical extracts have been shown to enhance the development, mass, and strength of skeletal muscle by influencing age-related cellular and molecular processes. Tannase-treated green tea extract contains high levels of the antioxidants (-)-epicatechin (EC) and gallic acid that may have therapeutic benefits for age-related muscle decline. The aim of this study was to investigate the effect of tannase-treated green tea extract on various muscle-related parameters, without concomitant exercise, in a single-center, randomized, double-blind, placebo-controlled study. Administration of tannase-treated green tea extract (600 mg/day) for 12 weeks significantly increased isokinetic flexor muscle and handgrip strength in the treatment group compared with those in the placebo (control) group. In addition, the control group showed a significant decrease in arm muscle mass after 12 weeks, whereas no significant change was observed in the treatment group. Blood serum levels of follistatin, myostatin, high-sensitivity C-reactive protein (hs-CRP), interleukin (IL)-6, IL-8, insulin-like growth factor-1 (IGF-1), and cortisol were analyzed, and the decrease in myostatin resulting from the administration of tannase-treated green tea extract was found to be related to the change in muscle mass and strength. In summary, oral administration of tannase-treated green tea extract containing antioxidants without concomitant exercise can improve muscle mass and strength and may have therapeutic benefits in age-related muscle function decline.
Collapse
Affiliation(s)
- Hyeyeong Seo
- Department of Integrated Biomedical and Life Science, Graduate School, Korea University, Seoul 02841, Korea;
| | - Seok-Hee Lee
- Department of Food Science and Biotechnology, Dongguk University, Goyang 10326, Korea; (S.-H.L.); (Y.P.)
| | - Yooheon Park
- Department of Food Science and Biotechnology, Dongguk University, Goyang 10326, Korea; (S.-H.L.); (Y.P.)
| | - Hee-Seok Lee
- Department of Food Science and Technology, Chung-Ang University, Anseong 17546, Korea;
| | - Jeong Sup Hong
- Animal Center and Preclinical Evaluation Research Institute, Yonam College, Cheonan 31005, Korea;
| | - Cho Young Lim
- R&D Center, BTC Corporation, Ansan 15588, Korea; (C.Y.L.); (D.H.K.)
| | - Dong Hyeon Kim
- R&D Center, BTC Corporation, Ansan 15588, Korea; (C.Y.L.); (D.H.K.)
| | - Sung-Soo Park
- Department of Food Science and Nutrition, Jeju National University, Jeju 63243, Korea;
| | - Hyung Joo Suh
- Department of Integrated Biomedical and Life Science, Graduate School, Korea University, Seoul 02841, Korea;
- Transdisciplinary Major in Learning Health Systems, Department of Healthcare Sciences, Graduate School, Korea University, Seoul 02841, Korea
| | - Ki-Bae Hong
- Department of Food Science and Nutrition, Jeju National University, Jeju 63243, Korea;
| |
Collapse
|
45
|
Downing K, Prisby R, Varanasi V, Zhou J, Pan Z, Brotto M. Old and new biomarkers for volumetric muscle loss. Curr Opin Pharmacol 2021; 59:61-69. [PMID: 34146835 DOI: 10.1016/j.coph.2021.05.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2021] [Revised: 05/04/2021] [Accepted: 05/05/2021] [Indexed: 12/21/2022]
Abstract
Volumetric muscle loss (VML) impacts skeletal muscles and causes damage to associated tissues such as blood vessels and other structural tissues. Despite progress in the VML field, current preclinical approaches are often ineffective at restoring muscle volume. Additional research is paramount to develop strategies that improve muscle mass and function, while restoring supporting tissues. We highlight mechanisms that govern normal muscle function that are also key players for VML, including intracellular calcium signaling/homeostasis, mitochondria signaling (calcium, reactiove oxidative species (ROS)/oxidative stress), and angiogenesis. We propose an integration of these processes within the context of emerging biomaterials that provide structural support for muscle regeneration. We posit that new biomarkers (i.e. myokines and lipid signaling mediators) may serve as sentinels of early muscle injury and regeneration. We conclude that as new ideas, approaches, and models come together, new treatments will emerge to allow the full rebuilding of skeletal muscles and functional recovery of skeletal muscles after VML.
Collapse
Affiliation(s)
- Kerrie Downing
- Bone-Muscle Collaborative Sciences, College of Nursing & Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA
| | - Rhonda Prisby
- Bone-Muscle Collaborative Sciences, College of Nursing & Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA
| | - Venu Varanasi
- Bone-Muscle Collaborative Sciences, College of Nursing & Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA
| | - Jingsong Zhou
- Bone-Muscle Collaborative Sciences, College of Nursing & Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA
| | - Zui Pan
- Bone-Muscle Collaborative Sciences, College of Nursing & Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA.
| | - Marco Brotto
- Bone-Muscle Collaborative Sciences, College of Nursing & Health Innovation, The University of Texas at Arlington, Arlington, TX 76010, USA.
| |
Collapse
|
46
|
Qiu J, Wu L, Chang Y, Sun H, Sun J. Alternative splicing transitions associate with emerging atrophy phenotype during denervation-induced skeletal muscle atrophy. J Cell Physiol 2021; 236:4496-4514. [PMID: 33319931 DOI: 10.1002/jcp.30167] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 10/23/2020] [Accepted: 11/05/2020] [Indexed: 12/25/2022]
Abstract
Alternative splicing (AS) presents a key posttranscriptional regulatory mechanism associated with numerous physiological processes. However, little is known about its role in skeletal muscle atrophy. In this study, we used a rat model of denervated skeletal muscle atrophy and performed RNA-sequencing to analyze transcriptome profiling of tibialis anterior muscle at multiple time points following denervation. We found that AS is a novel mechanism involving muscle atrophy, which is independent changes at the transcript level. Bioinformatics analysis further revealed that AS transitions are associated with the appearance of the atrophic phenotype. Moreover, we found that the inclusion of multiple highly conserved exons of Obscn markedly increased at 3 days after denervation. In addition, we confirmed that this newly transcript inhibited C2C12 cell proliferation and exacerbated myotube atrophy. Finally, our study revealed that a large number of RNA-binding proteins were upregulated when the atrophy phenotype appeared. Our data emphasize the importance of AS in this process.
Collapse
Affiliation(s)
- Jiaying Qiu
- Department of Prenatal Screening and Diagnosis Center, Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Affiliated Maternity and Child Health Care Hospital of Nantong University, Nantong University, Nantong, Jiangsu, China
| | - Liucheng Wu
- Laboratory Animal Center, Nantong University, Nantong, China
| | - Yan Chang
- School of Life Sciences, Nantong University, Nantong, Jiangsu, China
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China
| | - Junjie Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, Jiangsu, China
| |
Collapse
|
47
|
Triolo M, Hood DA. Manifestations of Age on Autophagy, Mitophagy and Lysosomes in Skeletal Muscle. Cells 2021; 10:cells10051054. [PMID: 33946883 PMCID: PMC8146406 DOI: 10.3390/cells10051054] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 04/24/2021] [Accepted: 04/27/2021] [Indexed: 01/18/2023] Open
Abstract
Sarcopenia is the loss of both muscle mass and function with age. Although the molecular underpinnings of sarcopenia are not fully understood, numerous pathways are implicated, including autophagy, in which defective cargo is selectively identified and degraded at the lysosome. The specific tagging and degradation of mitochondria is termed mitophagy, a process important for the maintenance of an organelle pool that functions efficiently in energy production and with relatively low reactive oxygen species production. Emerging data, yet insufficient, have implicated various steps in this pathway as potential contributors to the aging muscle atrophy phenotype. Included in this is the lysosome, the end-stage organelle possessing a host of proteolytic and degradative enzymes, and a function devoted to the hydrolysis and breakdown of defective molecular complexes and organelles. This review provides a summary of our current understanding of how the autophagy-lysosome system is regulated in aging muscle, highlighting specific areas where knowledge gaps exist. Characterization of the autophagy pathway with a particular focus on the lysosome will undoubtedly pave the way for the development of novel therapeutic strategies to combat age-related muscle loss.
Collapse
Affiliation(s)
- Matthew Triolo
- Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada;
- School of Kinesiology and Health Science, York University, Toronto, ON M3J 1P3, Canada
| | - David A. Hood
- Muscle Health Research Centre, York University, Toronto, ON M3J 1P3, Canada;
- School of Kinesiology and Health Science, York University, Toronto, ON M3J 1P3, Canada
- Correspondence: ; Tel.: +(416)-736-2100 (ext. 66640)
| |
Collapse
|
48
|
Chen X, Li M, Chen B, Wang W, Zhang L, Ji Y, Chen Z, Ni X, Shen Y, Sun H. Transcriptome sequencing and analysis reveals the molecular mechanism of skeletal muscle atrophy induced by denervation. ANNALS OF TRANSLATIONAL MEDICINE 2021; 9:697. [PMID: 33987395 PMCID: PMC8106053 DOI: 10.21037/atm-21-1230] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Background The molecular mechanism of denervated muscle atrophy is very complex and has not been elucidated to date. In this study, we aimed to use transcriptome sequencing technology to systematically analyze the molecular mechanism of denervated muscle atrophy in order to eventually develop effective strategies or drugs to prevent muscle atrophy. Methods Transcriptome sequencing technology was used to analyze the differentially expressed genes (DEGs) in denervated skeletal muscles. Unsupervised hierarchical clustering of DEGs was performed. Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to analyze the DEGs. Results Results showed that 2,749 transcripts were up-regulated, and 2,941 transcripts were down-regulated in denervated tibialis anterior (TA) muscles after 14 days of denervation. The up-regulated expressed genes were analyzed through GO and the results demonstrated that biological processes of the up-regulated expressed genes included apoptotic process, cellular response to DNA damage stimulus, aging, and protein ubiquitination; the cellular component of the up-regulated expressed genes included cytoplasm, cytoskeleton, and nucleus; and the molecular function of the up-regulated expressed genes included ubiquitin-protein transferase activity and hydrolase activity. The KEGG pathway of the up-regulated expressed genes included ubiquitin mediated proteolysis, Fc gamma R-mediated phagocytosis, and transforming growth factor-beta (TGF-β) signaling pathway. The biological processes of the down-regulated expressed genes included angiogenesis, tricarboxylic acid cycle, adenosine triphosphate (ATP) biosynthetic process, muscle contraction, gluconeogenesis; the cellular component of the down-regulated expressed genes included mitochondrion, cytoskeleton, and myofibril; and the molecular function of the down-regulated expressed genes included nicotinamide adenine dinucleotide plus hydrogen (NADH) dehydrogenase (ubiquinone) activity, proton-transporting ATP synthase activity, ATP binding, electron carrier activity, cytochrome-c oxidase activity, and oxidoreductase activity. The KEGG pathway of the down-regulated expressed genes included oxidative phosphorylation, tricarboxylic acid cycle, glycolysis/gluconeogenesis, and the PI3K-Akt signaling pathway. Conclusions A huge number of DEGs were identified in TA muscles after denervation. The up-regulated expressed genes mainly involve in proteolysis, apoptosis, and ageing. The down-regulated expressed genes mainly involve in energy metabolism, angiogenesis, and protein synthesis. This study further enriched the molecular mechanism of denervation-induced muscle atrophy.
Collapse
Affiliation(s)
- Xin Chen
- Department of Neurology, Affiliated Hospital of Nantong University, Nantong, China
| | - Ming Li
- Department of Laboratory, People's Hospital of Binhai County, Yancheng, China
| | - Bairong Chen
- Department of Medical Laboratory, School of Public Health, Nantong University, Nantong, China
| | - Wei Wang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Lilei Zhang
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Yanan Ji
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Zehao Chen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Xuejun Ni
- Department of Ultrasound, Affiliated Hospital of Nantong University, Nantong, China
| | - Yuntian Shen
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| | - Hualin Sun
- Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, NMPA Key Laboratory for Research and Evaluation of Tissue Engineering Technology Products, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, China
| |
Collapse
|
49
|
A transition to degeneration triggered by oxidative stress in degenerative disorders. Mol Psychiatry 2021; 26:736-746. [PMID: 33159186 PMCID: PMC7914161 DOI: 10.1038/s41380-020-00943-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/08/2020] [Revised: 10/15/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022]
Abstract
Although the activities of many signaling pathways are dysregulated during the progression of neurodegenerative and muscle degeneration disorders, the precise sequence of cellular events leading to degeneration has not been fully elucidated. Two kinases of particular interest, the growth-promoting Tor kinase and the energy sensor AMPK, appear to show reciprocal changes in activity during degeneration, with increased Tor activity and decreased AMPK activity reported. These changes in activity have been predicted to cause degeneration by attenuating autophagy, leading to the accumulation of unfolded protein aggregates and dysfunctional mitochondria, the consequent increased production of reactive oxygen species (ROS), and ultimately oxidative damage. Here we propose that this increased ROS production not only causes oxidative damage but also ultimately induces an oxidative stress response that reactivates the redox-sensitive AMPK and activates the redox-sensitive stress kinase JNK. Activation of these kinases reactivates autophagy. Because at this late stage, cells have become filled with dysfunctional mitochondria and protein aggregates, which are autophagy targets, this autophagy reactivation induces degeneration. The mechanism proposed here emphasizes that the process of degeneration is dynamic, that dysregulated signaling pathways change over time and can transition from deleterious to beneficial and vice versa as degeneration progresses.
Collapse
|
50
|
Peris-Moreno D, Cussonneau L, Combaret L, Polge C, Taillandier D. Ubiquitin Ligases at the Heart of Skeletal Muscle Atrophy Control. Molecules 2021; 26:molecules26020407. [PMID: 33466753 PMCID: PMC7829870 DOI: 10.3390/molecules26020407] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 01/08/2021] [Accepted: 01/10/2021] [Indexed: 02/07/2023] Open
Abstract
Skeletal muscle loss is a detrimental side-effect of numerous chronic diseases that dramatically increases mortality and morbidity. The alteration of protein homeostasis is generally due to increased protein breakdown while, protein synthesis may also be down-regulated. The ubiquitin proteasome system (UPS) is a master regulator of skeletal muscle that impacts muscle contractile properties and metabolism through multiple levers like signaling pathways, contractile apparatus degradation, etc. Among the different actors of the UPS, the E3 ubiquitin ligases specifically target key proteins for either degradation or activity modulation, thus controlling both pro-anabolic or pro-catabolic factors. The atrogenes MuRF1/TRIM63 and MAFbx/Atrogin-1 encode for key E3 ligases that target contractile proteins and key actors of protein synthesis respectively. However, several other E3 ligases are involved upstream in the atrophy program, from signal transduction control to modulation of energy balance. Controlling E3 ligases activity is thus a tempting approach for preserving muscle mass. While indirect modulation of E3 ligases may prove beneficial in some situations of muscle atrophy, some drugs directly inhibiting their activity have started to appear. This review summarizes the main signaling pathways involved in muscle atrophy and the E3 ligases implicated, but also the molecules potentially usable for future therapies.
Collapse
|