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Kong X, Liu P, Wang G, Sun S, Li L. Methods for diagnosing malnutrition in patients with esophageal cancer, and the association with nutritional and inflammatory indices: A cross‑sectional study. Oncol Lett 2025; 29:223. [PMID: 40110582 PMCID: PMC11921283 DOI: 10.3892/ol.2025.14969] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Accepted: 02/14/2025] [Indexed: 03/22/2025] Open
Abstract
Clinically, it is important to diagnose malnutrition for the treatment and prognosis of cancer patients; however, at present, there are no established standards. The present study evaluated the consistency of malnutrition diagnostic tools in association with relevant nutritional and inflammatory markers in patients with advanced esophageal cancer. Specifically, the Patient-Generated Subjective Global Assessment (PG-SGA) and Global Leadership Initiative on Malnutrition (GLIM) tools were assessed. Patients with a new diagnosis of esophageal cancer at Tengzhou Central People's Hospital (Tengzhou, China) between January 2023 and December 2023 were evaluated within 24 h of admission using Nutritional Risk Screening 2002 (NRS2002), GLIM and PG-SGA. Additionally, relevant physical examinations and laboratory data were collected. The malnutrition occurrence rates based on PG-SGA, GLIM and GLIM with NRS2002 screening (NRS2002-GLIM) were 75.01, 51.88 and 41.25%, respectively. The agreement between PG-SGA and GLIM, and between PG-SGA and NRS2002-GLIM diagnoses was weak (κ=0.379, P<0.001; and κ=0.376, P<0.001, respectively). PG-SGA showed a moderate negative correlation with body mass index (BMI) (rs=-0.460), weak positive correlations with age (rs=0.234) and IL-6 (rs=0.249), and very weak negative correlations with albumin (rs=-0.178) and PNI (rs=-0.168). While the indicators correlated with GLIM and PG-SGA were consistent, the strength of correlation varied slightly. Logistic regression analysis of PG-SGA and GLIM indicated that age and BMI were independent risk factors for malnutrition. In addition, PG-SGA also showed that the neutrophil count was an independent risk factor for malnutrition. Overall, patients with esophageal cancer exhibit a high incidence of malnutrition, and different diagnostic methods provide varying results. Malnutrition is closely associated with age, inflammatory markers and BMI, suggesting their potential utility in guiding nutritional interventions for patients with esophageal cancer.
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Affiliation(s)
- Xueyuan Kong
- Department of Oncology, Tengzhou Central People's Hospital, Tengzhou, Zaozhuang, Shandong 277500, P.R. China
| | - Ping Liu
- Department of Oncology, Tengzhou Central People's Hospital, Tengzhou, Zaozhuang, Shandong 277500, P.R. China
| | - Guotian Wang
- Department of Oncology, Tengzhou Central People's Hospital, Tengzhou, Zaozhuang, Shandong 277500, P.R. China
| | - Shiqing Sun
- Department of Oncology, Tengzhou Central People's Hospital, Tengzhou, Zaozhuang, Shandong 277500, P.R. China
| | - Ling Li
- Department of Oncology, Tengzhou Central People's Hospital, Tengzhou, Zaozhuang, Shandong 277500, P.R. China
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Abdul Hafizz AMH, Mohd Mokthar N, Md Zin RR, P. Mongan N, Mamat @ Yusof MN, Kampan NC, Chew KT, Shafiee MN. Insulin-like Growth Factor 1 (IGF1) and Its Isoforms: Insights into the Mechanisms of Endometrial Cancer. Cancers (Basel) 2025; 17:129. [PMID: 39796756 PMCID: PMC11720045 DOI: 10.3390/cancers17010129] [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: 12/04/2024] [Revised: 12/25/2024] [Accepted: 01/01/2025] [Indexed: 01/13/2025] Open
Abstract
Endometrial cancer (EC) is a common gynaecological malignancy associated with metabolic dysfunctions such as obesity, diabetes and insulin resistance, as well as hormonal imbalances, particularly involving oestrogen and progesterone. These factors disrupt normal cellular metabolism, heightening the risk of developing endometrioid EC (EEC), the most prevalent subtype of EC. The insulin-like growth factor-1 (IGF1) pathway, a key regulator of growth, metabolism, and organ function, is implicated in EC progression. Recent research highlights the distinct roles of IGF1 isoforms, including IGF1-Ea, IGF1-Eb, and IGF1-Ec, in promoting tumour growth, metastasis, and hormone signalling interactions, particularly with oestrogen. This review examines the function and clinical significance of IGF-1 isoforms, emphasising their mechanisms in gynaecological physiology and their contributions to EC pathogenesis. Evidence from other cancers further underscores the relevance of IGF1 isoforms in driving tumour behaviours, offering valuable insights into their potential as biomarkers and therapeutic targets. Understanding these mechanisms provides opportunities for novel approaches to the prevention, diagnosis, and treatment of EC, improving patient outcomes and advancing the broader field of hormone-driven cancers.
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Affiliation(s)
| | - Norfilza Mohd Mokthar
- Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
| | - Reena Rahayu Md Zin
- Department of Pathology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
| | - Nigel P. Mongan
- Biodiscovery Institute, Faculty of Medicine and Health Sciences, The University of Nottingham, Sutton Bonington Campus, Loughborough LE12 5RD, UK
| | - Mohd Nazzary Mamat @ Yusof
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
| | - Nirmala Chandralega Kampan
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
| | - Kah Teik Chew
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
| | - Mohamad Nasir Shafiee
- Department of Obstetrics and Gynaecology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Cheras, Kuala Lumpur 56000, Malaysia
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Cacciatore S, Calvani R, Esposito I, Massaro C, Gava G, Picca A, Tosato M, Marzetti E, Landi F. Emerging Targets and Treatments for Sarcopenia: A Narrative Review. Nutrients 2024; 16:3271. [PMID: 39408239 PMCID: PMC11478655 DOI: 10.3390/nu16193271] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 09/23/2024] [Accepted: 09/26/2024] [Indexed: 10/20/2024] Open
Abstract
BACKGROUND Sarcopenia is characterized by the progressive loss of skeletal muscle mass, strength, and function, significantly impacting overall health and quality of life in older adults. This narrative review explores emerging targets and potential treatments for sarcopenia, aiming to provide a comprehensive overview of current and prospective interventions. METHODS The review synthesizes current literature on sarcopenia treatment, focusing on recent advancements in muscle regeneration, mitochondrial function, nutritional strategies, and the muscle-microbiome axis. Additionally, pharmacological and lifestyle interventions targeting anabolic resistance and neuromuscular junction integrity are discussed. RESULTS Resistance training and adequate protein intake remain the cornerstone of sarcopenia management. Emerging strategies include targeting muscle regeneration through myosatellite cell activation, signaling pathways, and chronic inflammation control. Gene editing, stem cell therapy, and microRNA modulation show promise in enhancing muscle repair. Addressing mitochondrial dysfunction through interventions aimed at improving biogenesis, ATP production, and reducing oxidative stress is also highlighted. Nutritional strategies such as leucine supplementation and anti-inflammatory nutrients, along with dietary modifications and probiotics targeting the muscle-microbiome interplay, are discussed as potential treatment options. Hydration and muscle-water balance are emphasized as critical in maintaining muscle health in older adults. CONCLUSIONS A combination of resistance training, nutrition, and emerging therapeutic interventions holds potential to significantly improve muscle function and overall health in the aging population. This review provides a detailed exploration of both established and novel approaches for the prevention and management of sarcopenia, highlighting the need for further research to optimize these strategies.
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Affiliation(s)
- Stefano Cacciatore
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy; (R.C.); (I.E.); (C.M.); (G.G.); (F.L.)
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (A.P.); (M.T.)
| | - Riccardo Calvani
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy; (R.C.); (I.E.); (C.M.); (G.G.); (F.L.)
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (A.P.); (M.T.)
| | - Ilaria Esposito
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy; (R.C.); (I.E.); (C.M.); (G.G.); (F.L.)
| | - Claudia Massaro
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy; (R.C.); (I.E.); (C.M.); (G.G.); (F.L.)
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (A.P.); (M.T.)
| | - Giordana Gava
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy; (R.C.); (I.E.); (C.M.); (G.G.); (F.L.)
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (A.P.); (M.T.)
| | - Anna Picca
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (A.P.); (M.T.)
- Department of Medicine and Surgery, LUM University, Strada Statale 100 Km 18, 70100 Casamassima, Italy
| | - Matteo Tosato
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (A.P.); (M.T.)
| | - Emanuele Marzetti
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy; (R.C.); (I.E.); (C.M.); (G.G.); (F.L.)
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (A.P.); (M.T.)
| | - Francesco Landi
- Department of Geriatrics, Orthopedics and Rheumatology, Università Cattolica del Sacro Cuore, L.go F. Vito 1, 00168 Rome, Italy; (R.C.); (I.E.); (C.M.); (G.G.); (F.L.)
- Fondazione Policlinico Universitario “Agostino Gemelli” IRCCS, L.go A. Gemelli 8, 00168 Rome, Italy; (A.P.); (M.T.)
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Fröhlich AK, Porthun J, Talha KM, Lena A, Hadzibegovic S, Wilkenshoff U, Sonntag F, Nikolski A, Ramer LV, Zeller T, Keller U, Bullinger L, Anker SD, Haverkamp W, von Haehling S, Doehner W, Rauch U, Skurk C, Cleland JGF, Butler J, Coats AJS, Landmesser U, Karakas M, Anker MS. Association of an impaired GH-IGF-I axis with cardiac wasting in patients with advanced cancer. Clin Res Cardiol 2024:10.1007/s00392-024-02400-x. [PMID: 38587563 DOI: 10.1007/s00392-024-02400-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/13/2023] [Accepted: 02/07/2024] [Indexed: 04/09/2024]
Abstract
BACKGROUND Growth hormone (GH) resistance is characterized by high GH levels but low levels of insulin-like growth factor-I (IGF-I) and growth hormone binding protein (GHBP) and, for patients with chronic disease, is associated with the development of cachexia. OBJECTIVES We investigated whether GH resistance is associated with changes in left ventricular (LV) mass (cardiac wasting) in patients with cancer. METHODS We measured plasma IGF-I, GH, and GHBP in 159 women and 148 men with cancer (83% stage III/IV). Patients were grouped by tertile of echocardiographic LVmass/height2 (women, < 50, 50-61, > 61 g/m2; men, < 60, 60-74, > 74 g/m2) and by presence of wasting syndrome with unintentional weight loss (BMI < 24 kg/m2 and weight loss ≥ 5% in the prior 12 months). Repeat echocardiograms were obtained usually within 3-6 months for 85 patients. RESULTS Patients in the lowest LVmass/height2 tertile had higher plasma GH (median (IQR) for 1st, 2nd, and 3rd tertile women, 1.8 (0.9-4.2), 0.8 (0.2-2.2), 0.5 (0.3-1.6) ng/mL, p = 0.029; men, 2.1 (0.8-3.2), 0.6 (0.1-1.7), 0.7 (0.2-1.9) ng/mL, p = 0.003). Among women, lower LVmass was associated with higher plasma IGF-I (68 (48-116), 72 (48-95), 49 (35-76) ng/mL, p = 0.007), whereas such association did not exist for men. Patients with lower LVmass had lower log IGF-I/GH ratio (women, 1.60 ± 0.09, 2.02 ± 0.09, 1.88 ± 0.09, p = 0.004; men, 1.64 ± 0.09, 2.14 ± 0.11, 2.04 ± 0.11, p = 0.002). GHBP was not associated with LVmass. Patients with wasting syndrome with unintentional weight loss had higher plasma GH and GHBP, lower log IGF-I/GH ratio, and similar IGF-I. Overall, GHBP correlated inversely with log IGF-I/GH ratio (women, r = - 0.591, p < 0.001; men, r = - 0.575, p < 0.001). Additionally, higher baseline IGF-I was associated with a decline in LVmass during follow-up (r = - 0.318, p = 0.003). CONCLUSION In advanced cancer, reduced LVmass is associated with increased plasma GH and reduced IGF-I/GH ratio, suggesting increasing GH resistance, especially for patients with wasting syndrome with unintentional weight loss. Higher baseline IGF-I was associated with a decrease in relative LVmass during follow-up.
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Affiliation(s)
- Ann-Kathrin Fröhlich
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
| | - Jan Porthun
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
- Norwegian University of Science and Technology, Campus Gjøvik, Gjøvik, Norway
| | - Khawaja M Talha
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
| | - Alessia Lena
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
| | - Sara Hadzibegovic
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
| | - Ursula Wilkenshoff
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
- Berlin Institute of Health, Charité - University Medicine Berlin, Berlin, Germany
| | - Frederike Sonntag
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
| | - Anja Nikolski
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
| | - Luisa Valentina Ramer
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
| | - Tanja Zeller
- University Center of Cardiovascular Science, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- Clinic for Cardiology, University Heart and Vascular Centre Hamburg, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany
- German Centre for Cardiovascular Research, Partner Site HH/Kiel/HL, Hamburg, Germany
| | - Ulrich Keller
- Department of Hematology, Oncology and Cancer Immunology, Charité - University Medicine Berlin, Campus Benjamin Franklin, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, Berlin, Germany
- Max Delbrück Center, Berlin, Germany
| | - Lars Bullinger
- German Cancer Consortium (DKTK), Partner Site Berlin, a partnership between DKFZ and Charité-Universitätsmedizin Berlin, Berlin, Germany
- Department of Hematology, Oncology, and Tumor Immunology, Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt University Berlin, Berlin, Germany
| | - Stefan D Anker
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology Campus, Virchow Clinic of German Heart Center Charité, Charité - University Medicine Berlin, Berlin, Germany
| | - Wilhelm Haverkamp
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology Campus, Virchow Clinic of German Heart Center Charité, Charité - University Medicine Berlin, Berlin, Germany
| | - Stephan von Haehling
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Göttingen, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany
| | - Wolfram Doehner
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Virchow Clinic, German Heart Center Charité, Berlin, Germany
- Centre for Stroke Research, Berlin, Charité-Universitätsmedizin, Berlin, Germany
| | - Ursula Rauch
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
| | - Carsten Skurk
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
| | - John G F Cleland
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Javed Butler
- Department of Medicine, University of Mississippi Medical Center, Jackson, MS, USA
- Baylor Scott and White Research Institute, Dallas, TX, USA
| | | | - Ulf Landmesser
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany
- Berlin Institute of Health, Charité - University Medicine Berlin, Berlin, Germany
| | - Mahir Karakas
- German Centre for Cardiovascular Research, Partner Site HH/Kiel/HL, Hamburg, Germany
- Department of Intensive Care Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Markus S Anker
- Charité - University Medicine Berlin corporate member of Free University Berlin and Humboldt-University Berlin, Berlin, Germany.
- German Centre for Cardiovascular Research (DZHK), Partner Site Berlin, Berlin, Germany.
- Berlin Institute of Health Center for Regenerative Therapies (BCRT), Berlin, Germany.
- Department of Cardiology, Angiology and Intensive Care Medicine Campus Benjamin Franklin, German Heart Center Charité, Hindenburgdamm 30, 12200, Berlin, Germany.
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Chen J, Chen H, Dong X, Hui T, Yan M, Ren D, Zou S, Wang S, Fei E, Zhang W, Lai X. Deficiency of skeletal muscle Agrin contributes to the pathogenesis of age-related sarcopenia in mice. Cell Death Dis 2024; 15:201. [PMID: 38461287 PMCID: PMC10925061 DOI: 10.1038/s41419-024-06581-1] [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: 11/27/2023] [Revised: 02/28/2024] [Accepted: 02/29/2024] [Indexed: 03/11/2024]
Abstract
Sarcopenia, a progressive and prevalent neuromuscular disorder, is characterized by age-related muscle wasting and weakening. Despite its widespread occurrence, the molecular underpinnings of this disease remain poorly understood. Herein, we report that levels of Agrin, an extracellular matrix (ECM) protein critical for neuromuscular formation, were decreased with age in the skeletal muscles of mice. The conditional loss of Agrin in myogenic progenitors and satellite cells (SCs) (Pax7 Cre:: Agrin flox/flox) causes premature muscle aging, manifesting a distinct sarcopenic phenotype in mice. Conversely, the elevation of a miniaturized form of Agrin in skeletal muscle through adenovirus-mediated gene transfer induces enhanced muscle capacity in aged mice. Mechanistic investigations suggest that Agrin-mediated improvement in muscle function occurs through the stimulation of Yap signaling and the concurrent upregulation of dystroglycan expression. Collectively, our findings underscore the pivotal role of Agrin in the aging process of skeletal muscles and propose Agrin as a potential therapeutic target for addressing sarcopenia.
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Affiliation(s)
- Jie Chen
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
- Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Hong Chen
- Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
- School of Life Science, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Xia Dong
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
- Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Tiankun Hui
- Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
- School of Life Science, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Min Yan
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Dongyan Ren
- Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
- School of Life Science, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Suqi Zou
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
- Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Shunqi Wang
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
- Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Erkang Fei
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
- Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Wenhua Zhang
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
- Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China
| | - Xinsheng Lai
- School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China.
- Institute of Biomedical Innovation, Jiangxi Medical College, Nanchang University, Nanchang, 330031, Jiangxi, China.
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Arnhold J. Inflammation-Associated Cytotoxic Agents in Tumorigenesis. Cancers (Basel) 2023; 16:81. [PMID: 38201509 PMCID: PMC10778456 DOI: 10.3390/cancers16010081] [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: 12/03/2023] [Revised: 12/16/2023] [Accepted: 12/20/2023] [Indexed: 01/12/2024] Open
Abstract
Chronic inflammatory processes are related to all stages of tumorigenesis. As inflammation is closely associated with the activation and release of different cytotoxic agents, the interplay between cytotoxic agents and antagonizing principles is highlighted in this review to address the question of how tumor cells overcome the enhanced values of cytotoxic agents in tumors. In tumor cells, the enhanced formation of mitochondrial-derived reactive species and elevated values of iron ions and free heme are antagonized by an overexpression of enzymes and proteins, contributing to the antioxidative defense and maintenance of redox homeostasis. Through these mechanisms, tumor cells can even survive additional stress caused by radio- and chemotherapy. Through the secretion of active agents from tumor cells, immune cells are suppressed in the tumor microenvironment and an enhanced formation of extracellular matrix components is induced. Different oxidant- and protease-based cytotoxic agents are involved in tumor-mediated immunosuppression, tumor growth, tumor cell invasion, and metastasis. Considering the special metabolic conditions in tumors, the main focus here was directed on the disturbed balance between the cytotoxic agents and protective mechanisms in late-stage tumors. This knowledge is mandatory for the implementation of novel anti-cancerous therapeutic approaches.
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Affiliation(s)
- Jürgen Arnhold
- Institute of Medical Physics and Biophysics, Medical Faculty, Leipzig University, Härtelstr. 16-18, 04107 Leipzig, Germany
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7
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Aslam MA, Ma EB, Huh JY. Pathophysiology of sarcopenia: Genetic factors and their interplay with environmental factors. Metabolism 2023; 149:155711. [PMID: 37871831 DOI: 10.1016/j.metabol.2023.155711] [Citation(s) in RCA: 19] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 10/05/2023] [Accepted: 10/17/2023] [Indexed: 10/25/2023]
Abstract
Sarcopenia is a geriatric disorder characterized by a progressive decline in muscle mass and function. This disorder has been associated with a range of adverse health outcomes, including fractures, functional deterioration, and increased mortality. The pathophysiology of sarcopenia is highly complex and multifactorial, involving both genetic and environmental factors as key contributors. This review consolidates current knowledge on the genetic factors influencing the pathogenesis of sarcopenia, particularly focusing on the altered gene expression of structural and metabolic proteins, growth factors, hormones, and inflammatory cytokines. While the influence of environmental factors such as physical inactivity, chronic diseases, smoking, alcohol consumption, and sleep disturbances on sarcopenia is relatively well understood, there is a dearth of studies examining their mechanistic roles. Therefore, this review emphasizes the interplay between genetic and environmental factors, elucidating their cumulative role in exacerbating the progression of sarcopenia beyond their individual effects. The unique contribution of this review lies in synthesizing the latest evidence on the genetic factors and their interaction with environmental factors, aiming to inform the development of novel therapeutic or preventive interventions for sarcopenia.
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Affiliation(s)
- Muhammad Arif Aslam
- College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea
| | - Eun Bi Ma
- College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea
| | - Joo Young Huh
- College of Pharmacy, Chonnam National University, Gwangju, Republic of Korea.
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8
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Fathy Megahed N, Abdel-Kafy ESM, El-Kassas S, Sobhy HM, Hekal SHA, Alagawany M, Manaa EA. Association of insulin receptor substrate 1 ( IRS-1) gene polymorphism with growth and litter-related traits in NMER rabbits. Anim Biotechnol 2023; 34:3749-3756. [PMID: 37310292 DOI: 10.1080/10495398.2023.2219705] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
This study investigated the associations between the c.189G > T polymorphism of the insulin receptor substrate-1 (IRS-1) gene and the growth and litter size-related traits in the Native rabbit in Middle Egypt (NMER). One hundred sixty-two NMER rabbits were genotyped by RFLP-PCR using Sau3AI restriction enzyme and the associations of the reported genotypes with body weights at 5th, 6th, 8th, 10th, and 12th week old, body gain, and daily gain plus, the litter size-related traits were determined. Additionally, the genotypic and allelic frequencies, the effective (Ne) and observed (NA) numbers of alleles, observed (Ho) and expected (He) heterozygosity, Hardy-Weinberg equilibrium (HWE), and the decrease in heterozygosity because of inbreeding (FIS) were calculated. Three genotypes; GG, GT, and TT with 0.65, 0.33, and 0.02 frequencies, respectively which fit HWE were reported. These genotypes displayed a marked low FIS value. Significant associations of the genotypes with the body weights, and gains, except at the 5th week old determined with superiority of the GT genotype compared with the other genotypes. All reported litter size-related traits significantly varied among different genotypes. In summary, the c.189G > T SNP of the IRS-1 gene is an effective genetic marker to improve growth performance and litter size traits of the NMER rabbits.
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Affiliation(s)
- Naglaa Fathy Megahed
- Agricultural Research Center (ARC), Animal Production Research Institute (APRI), Giza, Egypt
| | - El-Sayed M Abdel-Kafy
- Agricultural Research Center (ARC), Animal Production Research Institute (APRI), Giza, Egypt
| | - Seham El-Kassas
- Animal, Poultry and Fish Breeding and Production, Department of Animal Wealth Development, Kafrelsheikh University, Egypt
| | - Hassan Mohamed Sobhy
- Department of Natural Resources faculty of African postgraduate studies, Cairo university, Giza, Egypt
| | | | - Mahmoud Alagawany
- Poultry Department, Faculty of Agriculture, Zagazig University, Zagazig, Egypt
| | - Eman A Manaa
- Animal and Poultry Production, Department of Animal Wealth Development, Faculty of Veterinary Medicine, Benha University, Moshtohor, Toukh, Qalyubia, Egypt
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9
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Ahmadi Hekmatikar A, Nelson A, Petersen A. Highlighting the idea of exerkines in the management of cancer patients with cachexia: novel insights and a critical review. BMC Cancer 2023; 23:889. [PMID: 37730552 PMCID: PMC10512651 DOI: 10.1186/s12885-023-11391-3] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Accepted: 09/10/2023] [Indexed: 09/22/2023] Open
Abstract
BACKGROUND Exerkines are all peptides, metabolites, and nucleic acids released into the bloodstream during and after physical exercise. Exerkines liberated from skeletal muscle (myokines), the heart (cardiokines), liver (hepatokines), white adipose tissue (adipokines), brown adipose tissue (batokines), and neurons (neurokines) may benefit health and wellbeing. Cancer-related cachexia is a highly prevalent disorder characterized by weight loss with specific skeletal muscle and adipose tissue loss. Many studies have sought to provide exercise strategies for managing cachexia, focusing on musculoskeletal tissue changes. Therefore, understanding the responses of musculoskeletal and other tissue exerkines to acute and chronic exercise may provide novel insight and recommendations for physical training to counteract cancer-related cachexia. METHODS For the purpose of conducting this study review, we made efforts to gather relevant studies and thoroughly discuss them to create a comprehensive overview. To achieve this, we conducted searches using appropriate keywords in various databases. Studies that were deemed irrelevant to the current research, not available in English, or lacking full-text access were excluded. Nevertheless, it is important to acknowledge the limited amount of research conducted in this specific field. RESULTS In order to obtain a comprehensive understanding of the findings, we prioritized human studies in order to obtain results that closely align with the scope of the present study. However, in instances where human studies were limited or additional analysis was required to draw more robust conclusions, we also incorporated animal studies. Finally, 295 studies, discussed in this review. CONCLUSION Our understanding of the underlying physiological mechanisms related to the significance of investigating exerkines in cancer cachexia is currently quite basic. Nonetheless, this demonstrated that resistance and aerobic exercise can contribute to the reduction and control of the disease in individuals with cancer cachexia, as well as in survivors, by inducing changes in exerkines.
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Affiliation(s)
- Amirhossein Ahmadi Hekmatikar
- Department of Physical Education & Sport Sciences, Faculty of Humanities, Tarbiat Modares University, Tehran, 14117-13116, Iran
| | - André Nelson
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia
| | - Aaron Petersen
- Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.
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10
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Khatoon B S, Saravanan D, Ganamurali N, Sabarathinam S. A narrative review on the impact of sarcopenic obesity and its psychological consequence in quality of life. Diabetes Metab Syndr 2023; 17:102846. [PMID: 37688926 DOI: 10.1016/j.dsx.2023.102846] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 08/10/2023] [Accepted: 08/18/2023] [Indexed: 09/11/2023]
Abstract
BACKGROUND AND AIM Sarcopenia is a multifactorial metabolic-mediated complication that affects most of the geriatric population physically and mentally. In this study, we intended to study the association between sarcopenia and psychologically related symptoms. Primary objective of the study is to explore the interplay between sarcopenic obesity, psychological consequences and Quality of life in the affected population. The secondary objective is to discuss the diagnostic, treatment approaches and also the role of clinical pharmacist. METHOD The psychology-related complication and sarcopenia association was enumerated in this study based on previous clinical research findings. RESULT The clinical evidence shows a strong correlation between sarcopenia and Mental health and its health consequences and reflection on the quality of life. CONCLUSION Sarcopenia induced mental disturbance has been affirmed in many studies. We believe effective right pharmacological therapy and non-pharmacological therapies with respective lifestyle modification advice could be potential vital factors that can reduce further complications in geriatric populations.
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Affiliation(s)
- Suhana Khatoon B
- School of Public Health, SRM Institute of Science and Technology Kattankulathur, Chennai, Tamil Nadu, 603203, India.
| | - Divya Saravanan
- School of Public Health, SRM Institute of Science and Technology Kattankulathur, Chennai, Tamil Nadu, 603203, India.
| | - Nila Ganamurali
- Certificate Programme-Analytical Techniques in Herbal Drug Industry, Interdisciplinary Institute of Indian System of Medicine (IIISM), SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India.
| | - Sarvesh Sabarathinam
- Certificate Programme-Analytical Techniques in Herbal Drug Industry, Interdisciplinary Institute of Indian System of Medicine (IIISM), SRM Institute of Science and Technology, Kattankulathur, Chennai, Tamil Nadu, 603203, India; Drug Testing Laboratory, Interdisciplinary Institute of Indian System of Medicine (IIISM), SRM Institute of Science and Technology Kattankulathur, Chennai, Tamil Nadu, 603203, India; Clinical Trial Unit, Metabolic Ward, Interdisciplinary Institute of Indian System of Medicine (IIISM), SRM Institute of Science and Technology Kattankulathur, Chennai, Tamil Nadu, 603203, India.
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11
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Guo J, Qin X, Wang Y, Li X, Wang X, Zhu H, Chen S, Zhao J, Xiao K, Liu Y. Necroptosis Mediates Muscle Protein Degradation in a Cachexia Model of Weanling Pig with Lipopolysaccharide Challenge. Int J Mol Sci 2023; 24:10923. [PMID: 37446099 DOI: 10.3390/ijms241310923] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2023] [Revised: 06/16/2023] [Accepted: 06/19/2023] [Indexed: 07/15/2023] Open
Abstract
Necroptosis, an actively researched form of programmed cell death closely related to the inflammatory response, is important in a variety of disorders and diseases. However, the relationship between necroptosis and muscle protein degradation in cachexia is rarely reported. This study aimed to elucidate whether necroptosis played a crucial role in muscle protein degradation in a cachexia model of weaned piglets induced by lipopolysaccharide (LPS). In Experiment 1, the piglets were intraperitoneally injected with LPS to construct the cachexia model, and sacrificed at different time points after LPS injection (1, 2, 4, 8, 12, and 24 h). In Experiment 2, necrostatin-1 (Nec-1), a necroptosis blocker, was pretreated in piglets before the injection of LPS to inhibit the occurrence of necroptosis. Blood and longissimus dorsi muscle samples were collected for further analysis. In the piglet model with LPS-induced cachexia, the morphological and ultrastructural damage, and the release of pro-inflammatory cytokines including tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and IL-6 were dynamically elicited in longissimus dorsi muscle. Further, protein concentration and protein/DNA ratio were dynamically decreased, and protein degradation signaling pathway, containing serine/threonine kinase (Akt), Forkhead box O (FOXO), muscular atrophy F-box (MAFbx), and muscle ring finger protein 1 (MuRF1), was dynamically activated in piglets after LPS challenge. Moreover, mRNA and protein expression of necroptosis signals including receptor-interacting protein kinase (RIP)1, RIP3, and mixed lineage kinase domain-like pseudokinase (MLKL), were time-independently upregulated. Subsequently, when Nec-1 was used to inhibit necroptosis, the morphological damage, the increase in expression of pro-inflammatory cytokines, the reduction in protein content and protein/DNA ratio, and the activation of the protein degradation signaling pathway were alleviated. These results provide the first evidence that necroptosis mediates muscle protein degradation in cachexia by LPS challenge.
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Affiliation(s)
- Junjie Guo
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Xu Qin
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Yang Wang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Xiangen Li
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Xiuying Wang
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Huiling Zhu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Shaokui Chen
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
| | - Jiangchao Zhao
- Department of Animal Science, Division of Agriculture, University of Arkansas, Fayetteville, AR 72701, USA
| | - Kan Xiao
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
- School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, No. 68 Xuefu South Rd., Wuhan 430023, China
| | - Yulan Liu
- Hubei Key Laboratory of Animal Nutrition and Feed Science, Wuhan Polytechnic University, Wuhan 430023, China
- School of Animal Science and Nutritional Engineering, Wuhan Polytechnic University, No. 68 Xuefu South Rd., Wuhan 430023, China
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12
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Al-Sawaf O, Weiss J, Skrzypski M, Lam JM, Karasaki T, Zambrana F, Kidd AC, Frankell AM, Watkins TBK, Martínez-Ruiz C, Puttick C, Black JRM, Huebner A, Bakir MA, Sokač M, Collins S, Veeriah S, Magno N, Naceur-Lombardelli C, Prymas P, Toncheva A, Ward S, Jayanth N, Salgado R, Bridge CP, Christiani DC, Mak RH, Bay C, Rosenthal M, Sattar N, Welsh P, Liu Y, Perrimon N, Popuri K, Beg MF, McGranahan N, Hackshaw A, Breen DM, O'Rahilly S, Birkbak NJ, Aerts HJWL, Jamal-Hanjani M, Swanton C. Body composition and lung cancer-associated cachexia in TRACERx. Nat Med 2023; 29:846-858. [PMID: 37045997 PMCID: PMC7614477 DOI: 10.1038/s41591-023-02232-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 25.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2022] [Accepted: 01/24/2023] [Indexed: 04/14/2023]
Abstract
Cancer-associated cachexia (CAC) is a major contributor to morbidity and mortality in individuals with non-small cell lung cancer. Key features of CAC include alterations in body composition and body weight. Here, we explore the association between body composition and body weight with survival and delineate potential biological processes and mediators that contribute to the development of CAC. Computed tomography-based body composition analysis of 651 individuals in the TRACERx (TRAcking non-small cell lung Cancer Evolution through therapy (Rx)) study suggested that individuals in the bottom 20th percentile of the distribution of skeletal muscle or adipose tissue area at the time of lung cancer diagnosis, had significantly shorter lung cancer-specific survival and overall survival. This finding was validated in 420 individuals in the independent Boston Lung Cancer Study. Individuals classified as having developed CAC according to one or more features at relapse encompassing loss of adipose or muscle tissue, or body mass index-adjusted weight loss were found to have distinct tumor genomic and transcriptomic profiles compared with individuals who did not develop such features. Primary non-small cell lung cancers from individuals who developed CAC were characterized by enrichment of inflammatory signaling and epithelial-mesenchymal transitional pathways, and differentially expressed genes upregulated in these tumors included cancer-testis antigen MAGEA6 and matrix metalloproteinases, such as ADAMTS3. In an exploratory proteomic analysis of circulating putative mediators of cachexia performed in a subset of 110 individuals from TRACERx, a significant association between circulating GDF15 and loss of body weight, skeletal muscle and adipose tissue was identified at relapse, supporting the potential therapeutic relevance of targeting GDF15 in the management of CAC.
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Affiliation(s)
- Othman Al-Sawaf
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Jakob Weiss
- Artificial Intelligence in Medicine (AIM) Program, Mass General Brigham, Harvard Medical School, Boston, MA, USA
- Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Department of Diagnostic and Interventional Radiology, University Freiburg, Freiburg, Germany
| | - Marcin Skrzypski
- Department of Oncology and Radiotherapy, Medical University of Gdańsk, Gdańsk, Poland
| | - Jie Min Lam
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK
- Department of Oncology, University College London Hospitals, London, UK
| | - Takahiro Karasaki
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | | | - Andrew C Kidd
- Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, UK
| | - Alexander M Frankell
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Thomas B K Watkins
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Carlos Martínez-Ruiz
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Clare Puttick
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - James R M Black
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Ariana Huebner
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Maise Al Bakir
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Mateo Sokač
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
- Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
| | - Susie Collins
- Early Clinical Development, Pfizer UK Ltd, Cambridge, UK
| | - Selvaraju Veeriah
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Neil Magno
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | | | - Paulina Prymas
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Antonia Toncheva
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Sophia Ward
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- Advanced Sequencing Facility, The Francis Crick Institute, London, UK
| | - Nick Jayanth
- Cancer Research UK & UCL Cancer Trials Centre, London, UK
| | - Roberto Salgado
- Department of Pathology, ZAS Hospitals, Antwerp, Belgium
- Division of Research, Peter MacCallum Cancer Centre, Melbourne, Australia
| | | | - David C Christiani
- Department of Medicine, Massachusetts General Hospital/Harvard Medicine School, and Department of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, MA, USA
| | - Raymond H Mak
- Artificial Intelligence in Medicine (AIM) Program, Mass General Brigham, Harvard Medical School, Boston, MA, USA
- Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - Camden Bay
- Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
| | - Michael Rosenthal
- Department of Radiology, Brigham and Women's Hospital and Dana-Farber Cancer Institute, and Harvard Medical School, Boston, MA, USA
| | - Naveed Sattar
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Paul Welsh
- School of Cardiovascular and Metabolic Health, University of Glasgow, Glasgow, UK
| | - Ying Liu
- Department of Genetics, Harvard Medical School, Boston, USA
- Howard Hughes Medical Institute, Harvard Medical School, Boston, USA
| | - Norbert Perrimon
- Department of Genetics, Harvard Medical School, Boston, USA
- Howard Hughes Medical Institute, Harvard Medical School, Boston, USA
| | - Karteek Popuri
- Department of Computer Science, Memorial University of Newfoundland, St. John's, Newfoundland and Labrador, Burnaby, Canada
| | - Mirza Faisal Beg
- School of Engineering Science, Simon Fraser University, Burnaby, British Colombia, Canada
| | - Nicholas McGranahan
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Allan Hackshaw
- Cancer Research UK & UCL Cancer Trials Centre, London, UK
| | - Danna M Breen
- Internal Medicine Research Unit, Pfizer, Cambridge, MA, USA
| | - Stephen O'Rahilly
- Wellcome Trust-MRC Institute of Metabolic Science and NIHR Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK
| | - Nicolai J Birkbak
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Molecular Medicine, Aarhus University Hospital, Aarhus, Denmark
- Bioinformatics Research Centre, Aarhus University, Aarhus, Denmark
| | - Hugo J W L Aerts
- Artificial Intelligence in Medicine (AIM) Program, Mass General Brigham, Harvard Medical School, Boston, MA, USA
- Department of Radiation Oncology, Brigham and Women's Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
- Radiology and Nuclear Medicine, CARIM & GROW, Maastricht University, Maastricht, The Netherlands
| | - Mariam Jamal-Hanjani
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
- Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK.
- Department of Oncology, University College London Hospitals, London, UK.
| | - Charles Swanton
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK.
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK.
- Department of Oncology, University College London Hospitals, London, UK.
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13
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Arnhold J. Host-Derived Cytotoxic Agents in Chronic Inflammation and Disease Progression. Int J Mol Sci 2023; 24:ijms24033016. [PMID: 36769331 PMCID: PMC9918110 DOI: 10.3390/ijms24033016] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 01/20/2023] [Accepted: 02/01/2023] [Indexed: 02/05/2023] Open
Abstract
At inflammatory sites, cytotoxic agents are released and generated from invading immune cells and damaged tissue cells. The further fate of the inflammation highly depends on the presence of antagonizing principles that are able to inactivate these host-derived cytotoxic agents. As long as the affected tissues are well equipped with ready-to-use protective mechanisms, no damage by cytotoxic agents occurs and resolution of inflammation is initiated. However, long-lasting and severe immune responses can be associated with the decline, exhaustion, or inactivation of selected antagonizing principles. Hence, cytotoxic agents are only partially inactivated and contribute to damage of yet-unperturbed cells. Consequently, a chronic inflammatory process results. In this vicious circle of permanent cell destruction, not only novel cytotoxic elements but also novel alarmins and antigens are liberated from affected cells. In severe cases, very low protection leads to organ failure, sepsis, and septic shock. In this review, the major classes of host-derived cytotoxic agents (reactive species, oxidized heme proteins and free heme, transition metal ions, serine proteases, matrix metalloproteases, and pro-inflammatory peptides), their corresponding protective principles, and resulting implications on the pathogenesis of diseases are highlighted.
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Affiliation(s)
- Jürgen Arnhold
- Medical Faculty, Institute of Medical Physics and Biophysics, Leipzig University, Härtelstr. 16-18, 04107 Leipzig, Germany
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14
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Cancer- and cardiac-induced cachexia: same fate through different inflammatory mediators? Inflamm Res 2022; 71:771-783. [PMID: 35680678 DOI: 10.1007/s00011-022-01586-y] [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: 11/17/2021] [Revised: 05/04/2022] [Accepted: 05/09/2022] [Indexed: 11/05/2022] Open
Abstract
BACKGROUND Inflammation is widely recognized as the driving force of cachexia induced by chronic diseases; however, therapies targeting inflammation do not always reverse cachexia. Thus, whether inflammation per se plays an important role in the clinical course of cachectic patients is still a matter of debate. AIMS To give new insights into cachexia's pathogenesis and diagnosis, we performed a comprehensive literature search on the contribution of inflammatory markers to this syndrome, focusing on the noncommunicable diseases cancer and cardiovascular diseases. METHODS A systematic review was performed in PubMed using the keywords ("cancer" OR "cardiac" cachexia AND "human" OR "patient" AND "plasma" or "serum"). A total of 744 studies were retrieved and, from these, 206 were selected for full-text screening. In the end, 98 papers focusing on circulating biomarkers of cachexia were identified, which resulted in a list of 113 different mediators. RESULTS Data collected from the literature highlight the contribution of interleukin-6 (IL-6) and C-reactive protein (CRP) to cachexia, independently of the underlying condition. Despite not being specific, once the diagnosis of cachexia is established, CRP might help to monitor the effectiveness of anti-cachexia therapies. In cardiac diseases, B-type natriuretic peptide (BNP), renin, and obestatin might be putative markers of body wasting, whereas in cancer, growth differentiation factor (GDF) 15, transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) C seem to be better markers of this syndrome. Independently of the circulating mediators, NF-κB and JAK/STAT signaling pathways play a key role in bridging inflammation with muscle wasting; however, therapies targeting these pathways were not proven effective for all cachectic patients. CONCLUSION The critical and integrative analysis performed herein will certainly feed future research focused on the better comprehension of cachexia pathogenesis toward the improvement of its diagnosis and the development of personalized therapies targeting specific cachexia phenotypes.
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Ahmad SS, Ahmad K, Shaikh S, You HJ, Lee EY, Ali S, Lee EJ, Choi I. Molecular Mechanisms and Current Treatment Options for Cancer Cachexia. Cancers (Basel) 2022; 14:cancers14092107. [PMID: 35565236 PMCID: PMC9105812 DOI: 10.3390/cancers14092107] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Revised: 04/18/2022] [Accepted: 04/22/2022] [Indexed: 02/06/2023] Open
Abstract
Simple Summary The primary characteristics of cancer cachexia are weakness, weight loss, atrophy, fat reduction, and systemic inflammation. Cachexia is strongly associated with cancers involving the lungs, pancreas, esophagus, stomach, and liver, which account for half of all cancer deaths. TGF-β, MSTN, activin, IGF-1/PI3K/AKT, and JAK-STAT signaling pathways are known to underlie muscle atrophy and cachexia. Anamorelin (appetite stimulation), megestrol acetate, eicosapentaenoic acid, phytocannabinoids, targeting MSTN/activin, and molecules targeting proinflammatory cytokines, such as TNF-α and IL-6, are being tested as treatment options for cancer cachexia. Abstract Cancer cachexia is a condition marked by functional, metabolic, and immunological dysfunctions associated with skeletal muscle (SM) atrophy, adipose tissue loss, fat reduction, systemic inflammation, and anorexia. Generally, the condition is caused by a variety of mediators produced by cancer cells and cells in tumor microenvironments. Myostatin and activin signaling, IGF-1/PI3K/AKT signaling, and JAK-STAT signaling are known to play roles in cachexia, and thus, these pathways are considered potential therapeutic targets. This review discusses the current state of knowledge of the molecular mechanisms underlying cachexia and the available therapeutic options and was undertaken to increase understanding of the various factors/pathways/mediators involved and to identify potential treatment options.
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Affiliation(s)
- Syed Sayeed Ahmad
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea; (S.S.A.); (K.A.); (S.S.)
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea;
| | - Khurshid Ahmad
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea; (S.S.A.); (K.A.); (S.S.)
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea;
| | - Sibhghatulla Shaikh
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea; (S.S.A.); (K.A.); (S.S.)
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea;
| | - Hye Jin You
- Tumor Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Gyeonggi-do, Korea; (H.J.Y.); (E.-Y.L.)
- Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, 323, Ilsan-ro, Ilsandong-gu, Goyaan 10408, Gyeonggi-do, Korea
| | - Eun-Young Lee
- Tumor Microenvironment Branch, Division of Cancer Biology, Research Institute, National Cancer Center, 323 Ilsan-ro, Ilsandong-gu, Goyang 10408, Gyeonggi-do, Korea; (H.J.Y.); (E.-Y.L.)
| | - Shahid Ali
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea;
| | - Eun Ju Lee
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea; (S.S.A.); (K.A.); (S.S.)
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea;
- Correspondence: (E.J.L.); (I.C.)
| | - Inho Choi
- Department of Medical Biotechnology, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea; (S.S.A.); (K.A.); (S.S.)
- Research Institute of Cell Culture, Yeungnam University, Gyeongsan 38541, Gyeongsangbuk-do, Korea;
- Correspondence: (E.J.L.); (I.C.)
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16
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Mohanasundaram S, Fernando E. Uremic Sarcopenia. Indian J Nephrol 2022; 32:399-405. [PMID: 36568601 PMCID: PMC9775613 DOI: 10.4103/ijn.ijn_445_21] [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: 10/21/2021] [Revised: 01/18/2022] [Accepted: 01/20/2022] [Indexed: 12/27/2022] Open
Abstract
"Uremic sarcopenia" refers to a progressive decrease in muscle mass, strength, and function despite normal skeletal muscle physiology in patients with chronic kidney disease (CKD). Sarcopenia involves multiple risk factors, comprising immunological changes, hormonal, metabolic acidosis, reduced protein intake, and physical inactivity. All these risk factors, along with complex pathophysiological mechanisms including ubiquitin, insulin/IGF-1, myostatin, and indoxyl sulfate, activate downstream pathways that ultimately increase muscle degradation while reducing muscle regeneration. Uremic sarcopenia not only affects the quality of life but also increases the risk of morbidity and mortality in patients with CKD. Of all the treatment modalities, aerobic and resistance exercise have shown prevention and reduced rate of muscle degeneration. A variety of pharmacological agents have been tried to target different steps in the known pathogenetic pathways, including the use of androgens and anabolic steroids, correction of vitamin D deficiency, use of growth hormone supplementation, and suppression of the ubiquitin pathway. Though some of these techniques have had beneficial results in animal experiments, human trials are still sparse. This review article relates to recent publications that describe the abnormalities in skeletal muscle that primarily leads to muscle wasting and its consequences in patients with CKD.
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Affiliation(s)
- Subashri Mohanasundaram
- Department of Nephrology, Government Stanley Medical College and Hospital, Chennai, Tamil Nadu, India
| | - Edwin Fernando
- Department of Nephrology, Government Stanley Medical College and Hospital, Chennai, Tamil Nadu, India,Address for correspondence: Dr. Edwin Fernando, Department of Nephrology, Government Stanley Medical College and Hospital, Chennai, Tamil Nadu, India. E-mail:
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17
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Adamis D, van Gool WA, Eikelenboom P. Consistent patterns in the inconsistent associations of Insulin-like growth factor 1 (IGF-1), C-Reactive Protein (C-RP) and Interleukin 6 (IL-6) levels with delirium in surgical populations. A systematic review and meta-analysis. Arch Gerontol Geriatr 2021; 97:104518. [PMID: 34536657 DOI: 10.1016/j.archger.2021.104518] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 08/27/2021] [Accepted: 08/31/2021] [Indexed: 12/20/2022]
Abstract
BACKGROUND Biomarkers for delirium could increase diagnostic accuracy and may help to identify pathological pathways. Until now study findings concerning cytokine levels have been inconsistent. AIMS Systematic review and meta-analysis investigating the association between peripheral levels of Insulin-like Growth Factor-1 (IGF-1), C-Reactive Protein (C-RP) and Interleukin-6 (IL-6) and delirium in surgical patients, and to explore if there are distinct/specific patterns that may potentially explain inconsistent results. METHODS PubMed, Scopus, CINAHL, Cochrane, and EMBASE databases were searched. Inclusion criteria were: prospective studies, surgical populations excluding preoperative delirium, available data. The following were collected: type of operation (orthopaedic, abdominal, etc), the timing of operation (acute, elective, both), demographics, number of participants with delirium, time of preoperative blood withdrawal, and preoperative levels of each biomarker. RESULTS Low levels of IGF-1 (n = 7 studies) are significantly associated with post-operative delirium in abdominal surgical samples. High levels of C-RP (n = 9) are associated with delirium in acute orthopaedic and elective abdominal operations. IL-6 (n = 14) is a significant predictor of post-operative delirium in a variety of surgical conditions (elective or acute). DISCUSSION A common pattern exists in the otherwise conflicting reported findings. This similarity may reflect different underling mechanisms and predisposing factors like cachexia and catabolic stages. It seems that delirium in abdominal surgery is triggered by IGF-1 disturbances, while in other surgeries by an inflammatory reaction. CONCLUSIONS Despite the contradictory results concerning the association of IGF-1, C-RP and IL-6 with postoperative delirium, the present meta-analysis shows that there are certain patterns. IL-6 seems a consistent predictor for delirium in surgical samples.
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Affiliation(s)
| | - Willem A van Gool
- Department of Population and Occupational Health, Amsterdam University Medical Center, Amsterdam, the Netherlands.
| | - Piet Eikelenboom
- GGZinGeest, Amsterdam, the Netherlands. Department of Neurology, Academic Medical Center, Amsterdam, the Netherlands
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18
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Huemer MT, Bauer A, Petrera A, Scholz M, Hauck SM, Drey M, Peters A, Thorand B. Proteomic profiling of low muscle and high fat mass: a machine learning approach in the KORA S4/FF4 study. J Cachexia Sarcopenia Muscle 2021; 12:1011-1023. [PMID: 34151535 PMCID: PMC8350207 DOI: 10.1002/jcsm.12733] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Revised: 05/12/2021] [Accepted: 05/21/2021] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The coexistence of low muscle mass and high fat mass, two interrelated conditions strongly associated with declining health status, has been characterized by only a few protein biomarkers. High-throughput proteomics enable concurrent measurement of numerous proteins, facilitating the discovery of potentially new biomarkers. METHODS Data derived from the prospective population-based Cooperative Health Research in the Region of Augsburg S4/FF4 cohort study (median follow-up time: 13.5 years) included 1478 participants (756 men and 722 women) aged 55-74 years in the cross-sectional and 608 participants (315 men and 293 women) in the longitudinal analysis. Appendicular skeletal muscle mass (ASMM) and body fat mass index (BFMI) were determined through bioelectrical impedance analysis at baseline and follow-up. At baseline, 233 plasma proteins were measured using proximity extension assay. We implemented boosting with stability selection to enable false positives-controlled variable selection to identify new protein biomarkers of low muscle mass, high fat mass, and their combination. We evaluated prediction models developed based on group least absolute shrinkage and selection operator (lasso) with 100× bootstrapping by cross-validated area under the curve (AUC) to investigate if proteins increase the prediction accuracy on top of classical risk factors. RESULTS In the cross-sectional analysis, we identified kallikrein-6, C-C motif chemokine 28 (CCL28), and tissue factor pathway inhibitor as previously unknown biomarkers for muscle mass [association with low ASMM: odds ratio (OR) per 1-SD increase in log2 normalized protein expression values (95% confidence interval (CI)): 1.63 (1.37-1.95), 1.31 (1.14-1.51), 1.24 (1.06-1.45), respectively] and serine protease 27 for fat mass [association with high BFMI: OR (95% CI): 0.73 (0.61-0.86)]. CCL28 and metalloproteinase inhibitor 4 (TIMP4) constituted new biomarkers for the combination of low muscle and high fat mass [association with low ASMM combined with high BFMI: OR (95% CI): 1.32 (1.08-1.61), 1.28 (1.03-1.59), respectively]. Including protein biomarkers selected in ≥90% of group lasso bootstrap iterations on top of classical risk factors improved the performance of models predicting low ASMM, high BFMI, and their combination [delta AUC (95% CI): 0.16 (0.13-0.20), 0.22 (0.18-0.25), 0.12 (0.08-0.17), respectively]. In the longitudinal analysis, N-terminal prohormone brain natriuretic peptide (NT-proBNP) was the only protein selected for loss in ASMM and loss in ASMM combined with gain in BFMI over 14 years [OR (95% CI): 1.40 (1.10-1.77), 1.60 (1.15-2.24), respectively]. CONCLUSIONS Proteomic profiling revealed CCL28 and TIMP4 as new biomarkers of low muscle mass combined with high fat mass and NT-proBNP as a key biomarker of loss in muscle mass combined with gain in fat mass. Proteomics enable us to accelerate biomarker discoveries in muscle research.
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Affiliation(s)
- Marie-Theres Huemer
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Alina Bauer
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Agnese Petrera
- Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Markus Scholz
- Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Universität Leipzig, Leipzig, Germany
| | - Stefanie M Hauck
- Research Unit Protein Science, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany
| | - Michael Drey
- Medizinische Klinik und Poliklinik IV, Schwerpunkt Akutgeriatrie, Klinikum der Universität München (LMU), Munich, Germany
| | - Annette Peters
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany.,Chair of Epidemiology, Institute for Medical Information Processing, Biometry and Epidemiology, Medical Faculty, Ludwig-Maximilians-Universität München, Munich, Germany
| | - Barbara Thorand
- Institute of Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health (GmbH), Neuherberg, Germany.,German Center for Diabetes Research (DZD), München-Neuherberg, Germany
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Masi T, Patel BM. Altered glucose metabolism and insulin resistance in cancer-induced cachexia: a sweet poison. Pharmacol Rep 2020; 73:17-30. [PMID: 33141425 DOI: 10.1007/s43440-020-00179-y] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/19/2020] [Accepted: 10/20/2020] [Indexed: 12/12/2022]
Abstract
Cancer cachexia is a wasting disorder characterised by specific skeletal muscle and adipose tissue loss. Cancer cachexia is also driven by inflammation, altered metabolic changes such as increased energy expenditure, elevated plasma glucose, insulin resistance and excess catabolism. In cachexia, host-tumor interaction causes release of the lactate and inflammatory cytokines. Lactate released by tumor cells takes part in hepatic glucose production with the help of gluconeogenic enzymes. Thus, Cori cycle between organs and cancerous cells contributes to increased glucose production and energy expenditure. A high amount of blood glucose leads to increased production of insulin. Overproduction of insulin causes inactivation of PI3K/Akt/m-TOR pathway and finally results in insulin resistance. Insulin is involved in maintaining the vitality of organs and regulate the metabolism of glucose, protein and lipids. Insulin insensitivity decreases the uptake of glucose in the organs and results in loss of skeletal muscles and adipose tissues. However, looking into the complexity of this metabolic syndrome, it is impossible to rely on a single variable to treat patients having cancer cachexia. Hence, it becomes greater a challenge to produce a clinically effective treatment for this metabolic syndrome. Thus, the present paper aims to provide an understanding of pathogenesis and mechanism underlining the altered glucose metabolism and insulin resistance and its contribution to the progression of skeletal muscle wasting and lipolysis, providing future direction of research to develop new pharmacological treatment in cancer cachexia.
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Affiliation(s)
- Tamhida Masi
- Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, 382 481, India
| | - Bhoomika M Patel
- Institute of Pharmacy, Nirma University, Sarkhej-Gandhinagar Highway, Ahmedabad, Gujarat, 382 481, India.
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20
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da Fonseca GWP, Farkas J, Dora E, von Haehling S, Lainscak M. Cancer Cachexia and Related Metabolic Dysfunction. Int J Mol Sci 2020; 21:ijms21072321. [PMID: 32230855 PMCID: PMC7177950 DOI: 10.3390/ijms21072321] [Citation(s) in RCA: 68] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2020] [Revised: 03/20/2020] [Accepted: 03/25/2020] [Indexed: 12/13/2022] Open
Abstract
Cancer cachexia is a complex multifactorial syndrome marked by a continuous depletion of skeletal muscle mass associated, in some cases, with a reduction in fat mass. It is irreversible by nutritional support alone and affects up to 74% of patients with cancer-dependent on the underlying type of cancer-and is associated with physical function impairment, reduced response to cancer-related therapy, and higher mortality. Organs, like muscle, adipose tissue, and liver, play an important role in the progression of cancer cachexia by exacerbating the pro- and anti-inflammatory response initially activated by the tumor and the immune system of the host. Moreover, this metabolic dysfunction is produced by alterations in glucose, lipids, and protein metabolism that, when maintained chronically, may lead to the loss of skeletal muscle and adipose tissue. Although a couple of drugs have yielded positive results in increasing lean body mass with limited impact on physical function, a single therapy has not lead to effective treatment of this condition. Therefore, a multimodal intervention, including pharmacological agents, nutritional support, and physical exercise, may be a reasonable approach for future studies to better understand and prevent the wasting of body compartments in patients with cancer cachexia.
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Affiliation(s)
- Guilherme Wesley Peixoto da Fonseca
- Heart Institute (InCor), University of São Paulo Medical School, São Paulo SP 05403-900, Brazil or
- Department of Cardiology and Pneumology, University Medicine Göttingen (UMG), DE-37075 Goettingen, Germany
| | - Jerneja Farkas
- Research Unit, General Hospital Murska Sobota, SI-9000 Murska Sobota, Slovenia;
- National Institute of Public Health, SI-1000 Ljubljana, Slovenia
- Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
| | - Eva Dora
- Division of Cardiology, General Hospital Murska Sobota, SI-9000 Murska Sobota, Slovenia;
| | - Stephan von Haehling
- Department of Cardiology and Pneumology, University Medicine Göttingen (UMG), DE-37075 Goettingen, Germany
- German Center for Cardiovascular Research (DZHK), partner site Goettingen, DE-37099 Goettingen, Germany
- Correspondence: (S.v.H.); (M.L.); Tel.: +49-551-3920-911 (S.v.H.); +386-251-23-733 (M.L.); Fax: +49-551-3920-918 (S.v.H.); Fax: +386-252-11-007 (M.L.)
| | - Mitja Lainscak
- Faculty of Medicine, University of Ljubljana, SI-1000 Ljubljana, Slovenia
- Division of Cardiology, General Hospital Murska Sobota, SI-9000 Murska Sobota, Slovenia;
- Correspondence: (S.v.H.); (M.L.); Tel.: +49-551-3920-911 (S.v.H.); +386-251-23-733 (M.L.); Fax: +49-551-3920-918 (S.v.H.); Fax: +386-252-11-007 (M.L.)
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21
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Kitamura M, Izawa KP, Yaekura M, Mimura Y, Ikeda Y, Nagashima H, Brubaker PH. Relationship among Activities of Daily Living, Nutritional Status, and 90 Day Readmission in Elderly Patients with Heart Failure. INTERNATIONAL JOURNAL OF ENVIRONMENTAL RESEARCH AND PUBLIC HEALTH 2019; 16:ijerph16245068. [PMID: 31842307 PMCID: PMC6950285 DOI: 10.3390/ijerph16245068] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/14/2019] [Revised: 12/05/2019] [Accepted: 12/10/2019] [Indexed: 12/13/2022]
Abstract
Purpose: This investigation aimed to examine the relationship among activities of daily living (ADL), nutritional status and 90-day hospital readmission in elderly heart failure (HF) patients. Methods: Participants were selected from 634 HF patients consecutively hospitalized at one institution. We investigated patient characteristics, ADL (motor and cognitive items of Functional Independence Measure (FIM)) and nutritional status (Geriatric Nutritional Risk Index (GNRI)). Data were analyzed using unpaired t-test, χ2 test, Cox proportional hazard model, and Kaplan-Meier method. Results: The 169 participants that met inclusion criteria were divided into two groups based on hospital readmission within 90 days of discharge. Body mass index (BMI) (p = 0.03), hemoglobin (p = 0.047), GNRI (p = 0.02) and motor-FIM (p = 0.007) were significantly different between the readmission (n = 31) and non-readmission (n = 138) groups. After Cox proportional hazard model analysis, GNRI (HR: 0.96; p = 0.048) and motor-FIM (HR: 0.97; p = 0.03) scores remained statistically significant. Participants were then classified into four groups based on a previous study’s cut-off values of prognosis for GNRI and motor-FIM. Readmission avoidance rate was significantly lower (p = 0.002) in the group with GNRI <92 and motor FIM <75. Conclusions: This study showed that motor-FIM and GNRI scores for hospitalized elderly HF patients were predictors of readmission within 90 days of discharge.
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Affiliation(s)
- Masahiro Kitamura
- Department of Physical Therapy, Kokura Rehabilitation College, Kitakyushu, Kitakyushu 800-0206, Japan;
- Department of Public Health, Graduate School of Health Sciences, Kobe University, Kobe 654-0142, Japan
- Cardiovascular stroke Renal Project (CRP), Institute, Kobe 654-0142, Japan;
| | - Kazuhiro P. Izawa
- Department of Public Health, Graduate School of Health Sciences, Kobe University, Kobe 654-0142, Japan
- Cardiovascular stroke Renal Project (CRP), Institute, Kobe 654-0142, Japan;
- Faculty of Sport Sciences, Waseda University, Tokorozawa 359-1192, Japan
- Correspondence: ; Tel.: +81-78-796-4566
| | - Masakazu Yaekura
- Department of Rehabilitation, Shinyukuhashi Hospital, Yukuhashi 824-0026, Japan; (M.Y.); (Y.M.); (Y.I.); (H.N.)
| | - Yumi Mimura
- Department of Rehabilitation, Shinyukuhashi Hospital, Yukuhashi 824-0026, Japan; (M.Y.); (Y.M.); (Y.I.); (H.N.)
| | - Yuichi Ikeda
- Department of Rehabilitation, Shinyukuhashi Hospital, Yukuhashi 824-0026, Japan; (M.Y.); (Y.M.); (Y.I.); (H.N.)
| | - Hitomi Nagashima
- Department of Rehabilitation, Shinyukuhashi Hospital, Yukuhashi 824-0026, Japan; (M.Y.); (Y.M.); (Y.I.); (H.N.)
| | - Peter H. Brubaker
- Cardiovascular stroke Renal Project (CRP), Institute, Kobe 654-0142, Japan;
- Department of Health and Exercise Science, Wake Forest University, Winston-Salem, NC 27109, USA
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22
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Jafari‐Vayghan H, Saleh‐Ghadimi S, Maleki V, Moludi J, Alizadeh M. The effects of melatonin on neurohormonal regulation in cardiac cachexia: A mechanistic review. J Cell Biochem 2019; 120:16340-16351. [DOI: 10.1002/jcb.29151] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Revised: 05/15/2019] [Accepted: 05/20/2019] [Indexed: 12/12/2022]
Affiliation(s)
- Hamed Jafari‐Vayghan
- Department of Clinical Nutrition, Faculty of Nutrition and Food Science Tabriz University of Medical Sciences Tabriz Iran
- Nutrition Research Center, Faculty of Nutrition and Food Sciences Tabriz University of Medical Sciences Tabriz Iran
- Student Research Committee Tabriz University of Medical Sciences Tabriz Iran
| | - Sevda Saleh‐Ghadimi
- Student Research Committee Tabriz University of Medical Sciences Tabriz Iran
| | - Vahid Maleki
- Student Research Committee Tabriz University of Medical Sciences Tabriz Iran
| | - Jalal Moludi
- Department of Nutrition, Faculty of Nutrition Sciences and Food Technology Kermanshah University of Medical Sciences Kermanshah Iran
| | - Mohammad Alizadeh
- Department of Clinical Nutrition, Faculty of Nutrition and Food Science Tabriz University of Medical Sciences Tabriz Iran
- Nutrition Research Center, Faculty of Nutrition and Food Sciences Tabriz University of Medical Sciences Tabriz Iran
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23
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Cabrera D, Cabello-Verrugio C, Solís N, San Martín D, Cofré C, Pizarro M, Arab JP, Abrigo J, Campos F, Irigoyen B, Carrasco-Avino G, Bezares K, Riquelme V, Riquelme A, Arrese M, Barrera F. Somatotropic Axis Dysfunction in Non-Alcoholic Fatty Liver Disease: Beneficial Hepatic and Systemic Effects of Hormone Supplementation. Int J Mol Sci 2018; 19:ijms19051339. [PMID: 29724029 PMCID: PMC5983806 DOI: 10.3390/ijms19051339] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 03/30/2018] [Accepted: 04/10/2018] [Indexed: 02/07/2023] Open
Abstract
Background: Somatotropic axis dysfunction associated with non-alcoholic fatty liver disease (NAFLD) has potential multisystemic detrimental effects. Here, we analysed the effects of growth hormone (GH) and insulin-like growth factor-1 (IGF-1) supplementation on liver histology, adipokine profile and muscle function in an NAFLD model. Methods: C57BL/6 mice were fed with a high fat diet (HFD) for 12 weeks and were separated into three groups treated for 4 weeks with: (1) High fat diet (HFD) (n = 10); (2) HFD + GH 9 μg/g/d (n = 10); (3) HFD + IGF-1 0.02 µg/g/d (n = 9). A control group fed a chow diet was included (n = 6). Liver histology, liver triglycerides content, serum alanine aminotransferase (ALT) activity, adiponectin and leptin serum levels, in vivo muscle strength, tetanic force and muscle fibre cross-sectional area (CSA) were measured. Results: HFD + GH and HFD + IGF-1 groups showed significantly lower ALT activity compared to HFD (p < 0.01). Liver triglyceride content in HFD + GH was decreased compared to HFD (p < 0.01). Histologic steatosis score was increased in HFD and HFD + GH group (p < 0.01), whereas HFD + IGF-1 presented no difference compared to the chow group (p = 0.3). HFD + GH group presented lower serum leptin and adiponectin levels compared to HFD. GH and IGF-1 supplementation therapy reverted HFD-induced reduction in muscle strength and CSA (sarcopenia). Conclusions: GH and IGF-1 supplementation induced significant improvement in liver steatosis, aminotransferases and sarcopenia in a diet-induced NAFLD model.
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Affiliation(s)
- Daniel Cabrera
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | | | - Nancy Solís
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Diego San Martín
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Catalina Cofré
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Margarita Pizarro
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Juan Pablo Arab
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Johanna Abrigo
- Faculty of Biological Sciences, Universidad Andrés Bello, Santiago 8320000, Chile.
| | - Fabián Campos
- Faculty of Biological Sciences, Universidad Andrés Bello, Santiago 8320000, Chile.
| | - Betzabé Irigoyen
- Faculty of Biological Sciences, Universidad Andrés Bello, Santiago 8320000, Chile.
| | - Gonzalo Carrasco-Avino
- Departament of Pathotology, Clínica Las Condes, Santiago 8320000, Chile.
- Department of Pathology, Hospital Clínico Universidad de Chile, Santiago 8320000, Chile.
| | - Katiuska Bezares
- Department of Pathology, Hospital Clínico San Juan de Dios, Santiago 8320000, Chile.
| | - Valentina Riquelme
- Faculty of Arts, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Arnoldo Riquelme
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
- Department of Health Sciences, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Marco Arrese
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
- Centro de Envejecimiento y Regeneración (CARE), Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
| | - Francisco Barrera
- Departament of Gastroenterology, School of Medicine, Pontificia Universidad Católica de Chile, Santiago 8320000, Chile.
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Tieland M, Trouwborst I, Clark BC. Skeletal muscle performance and ageing. J Cachexia Sarcopenia Muscle 2018; 9:3-19. [PMID: 29151281 PMCID: PMC5803609 DOI: 10.1002/jcsm.12238] [Citation(s) in RCA: 493] [Impact Index Per Article: 70.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/18/2017] [Revised: 07/20/2017] [Accepted: 08/05/2017] [Indexed: 02/06/2023] Open
Abstract
The world population is ageing rapidly. As society ages, the incidence of physical limitations is dramatically increasing, which reduces the quality of life and increases healthcare expenditures. In western society, ~30% of the population over 55 years is confronted with moderate or severe physical limitations. These physical limitations increase the risk of falls, institutionalization, co-morbidity, and premature death. An important cause of physical limitations is the age-related loss of skeletal muscle mass, also referred to as sarcopenia. Emerging evidence, however, clearly shows that the decline in skeletal muscle mass is not the sole contributor to the decline in physical performance. For instance, the loss of muscle strength is also a strong contributor to reduced physical performance in the elderly. In addition, there is ample data to suggest that motor coordination, excitation-contraction coupling, skeletal integrity, and other factors related to the nervous, muscular, and skeletal systems are critically important for physical performance in the elderly. To better understand the loss of skeletal muscle performance with ageing, we aim to provide a broad overview on the underlying mechanisms associated with elderly skeletal muscle performance. We start with a system level discussion and continue with a discussion on the influence of lifestyle, biological, and psychosocial factors on elderly skeletal muscle performance. Developing a broad understanding of the many factors affecting elderly skeletal muscle performance has major implications for scientists, clinicians, and health professionals who are developing therapeutic interventions aiming to enhance muscle function and/or prevent mobility and physical limitations and, as such, support healthy ageing.
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Affiliation(s)
- Michael Tieland
- Faculty of Sports and NutritionAmsterdam University of Applied SciencesDr. Meurerlaan 81067 SMAmsterdamthe Netherlands
| | - Inez Trouwborst
- Faculty of Sports and NutritionAmsterdam University of Applied SciencesDr. Meurerlaan 81067 SMAmsterdamthe Netherlands
| | - Brian C. Clark
- Ohio Musculoskeletal and Neurological Institute (OMNI)Ohio University250 Irvine HallAthensOH 45701USA
- Department of Biomedical SciencesOhio UniversityAthensOH 45701USA
- Department of Geriatric MedicineOhio UniversityAthensOH 45701USA
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Gangadharan A, Choi SE, Hassan A, Ayoub NM, Durante G, Balwani S, Kim YH, Pecora A, Goy A, Suh KS. Protein calorie malnutrition, nutritional intervention and personalized cancer care. Oncotarget 2017; 8:24009-24030. [PMID: 28177923 PMCID: PMC5410360 DOI: 10.18632/oncotarget.15103] [Citation(s) in RCA: 58] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2016] [Accepted: 01/23/2017] [Indexed: 12/27/2022] Open
Abstract
Cancer patients often experience weight loss caused by protein calorie malnutrition (PCM) during the course of the disease or treatment. PCM is expressed as severe if the patient has two or more of the following characteristics: obvious significant muscle wasting, loss of subcutaneous fat; nutritional intake of <50% of recommended intake for 2 weeks or more; bedridden or otherwise significantly reduced functional capacity; weight loss of >2% in 1 week, 5% in 1 month, or 7.5% in 3 months. Cancer anorexia-cachexia syndrome (CACS) is a multifactorial condition of advanced PCM associated with underlying illness (in this case cancer) and is characterized by loss of muscle with or without loss of fat mass. Cachexia is defined as weight loss of more than 5% of body weight in 12 months or less in the presence of chronic disease. Hence with a chronic illness on board even a small amount of weight loss can open the door to cachexia. These nutritional challenges can lead to severe morbidity and mortality in cancer patients. In the clinic, the application of personalized medicine and the ability to withstand the toxic effects of anti-cancer therapies can be optimized when the patient is in nutritional homeostasis and is free of anorexia and cachexia. Routine assessment of nutritional status and appropriate intervention are essential components of the effort to alleviate effects of malnutrition on quality of life and survival of patients.
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Affiliation(s)
- Anju Gangadharan
- The Genomics and Biomarkers Program, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Sung Eun Choi
- Department of Family, Nutrition, and Exercise Sciences, Queens College, The City University of New York, Flushing, NY, USA
| | - Ahmed Hassan
- The Genomics and Biomarkers Program, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Nehad M Ayoub
- Department of Clinical Pharmacy, Faculty of Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
| | - Gina Durante
- Department of Clinical Nutrition, Baystate Medical Center, Springfield, MA, USA
| | - Sakshi Balwani
- The Genomics and Biomarkers Program, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Young Hee Kim
- Department of Clinical Nutrition, Baystate Medical Center, Springfield, MA, USA
| | - Andrew Pecora
- Clinical Divisions, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - Andre Goy
- Clinical Divisions, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
| | - K Stephen Suh
- The Genomics and Biomarkers Program, JT Cancer Center, Hackensack University Medical Center, Hackensack Meridian Health, Hackensack, NJ, USA
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Scott JM, Martin DS, Ploutz-Snyder R, Matz T, Caine T, Downs M, Hackney K, Buxton R, Ryder JW, Ploutz-Snyder L. Panoramic ultrasound: a novel and valid tool for monitoring change in muscle mass. J Cachexia Sarcopenia Muscle 2017; 8:475-481. [PMID: 28052593 PMCID: PMC5476852 DOI: 10.1002/jcsm.12172] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/20/2016] [Revised: 09/20/2016] [Accepted: 11/02/2016] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND The strong link between reduced muscle mass and morbidity and mortality highlights the urgent need for simple techniques that can monitor change in skeletal muscle cross-sectional area (CSA). Our objective was to examine the validity of panoramic ultrasound to detect change in quadriceps and gastrocnemius size in comparison with magnetic resonance imaging (MRI) in subjects randomized to 70 days of bed rest (BR) with or without exercise. METHODS Panoramic ultrasound and MRI images of the quadriceps and gastrocnemius muscles were acquired on the right leg of 27 subjects (26 male, 1 female; age: 34.6 ± 7.8 years; body mass: 77.5 ± 10.0 kg; body mass index: 24.2 ± 2.8 kg/m2 ; height: 179.1 ± 6.9 cm) before (BR-6), during (BR3, 7, 11, 15, 22, 29, 36, 53, 69), and after (BR+3, +6, +10) BR. Validity of panoramic ultrasound to detect change in muscle CSA was assessed by Bland-Altman plots, Lin's concordance correlation coefficient (CCC), sensitivity, specificity, positive predictive value, and negative predictive value. RESULTS Six hundred ninety-eight panoramic ultrasound CSA and 698 MRI CSA measurements were assessed. Concordance between ultrasound and MRI was excellent in the quadriceps (CCC: 0.78; P < 0.0001), whereas there was poor concordance in the gastrocnemius (CCC: 0.37; P < 0.0006). Compared with MRI, panoramic ultrasound demonstrated high accuracy in detecting quadriceps atrophy and hypertrophy (sensitivity: 73.7%; specificity: 74.2%) and gastrocnemius atrophy (sensitivity: 83.1%) and low accuracy in detecting gastrocnemius hypertrophy (specificity: 33.0%). CONCLUSIONS Panoramic ultrasound imaging is a valid tool for monitoring quadriceps muscle atrophy and hypertrophy and for detecting gastrocnemius atrophy.
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Saitoh M, Rodrigues Dos Santos M, von Haehling S. Muscle wasting in heart failure : The role of nutrition. Wien Klin Wochenschr 2016; 128:455-465. [PMID: 27761739 DOI: 10.1007/s00508-016-1100-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2016] [Accepted: 09/14/2016] [Indexed: 12/25/2022]
Abstract
Muscle wasting and malnutrition are common complications in patients with advanced heart failure (HF); however, both remain underdiagnosed and undertreated although they both play relevant roles in the progression of HF. The risk of muscle wasting in patients with HF increases in those patients with malnutrition or at risk of malnutrition. Muscle wasting and malnutrition are thought to be positively influenced by adequate therapeutic interventions such as physical activity and nutritional support. Consequently, early detection of malnutrition in patients with HF is recommended. This review discusses muscle wasting and nutritional status, describing the effects of malnutrition on muscle wasting in patients with HF. We review specific issues related to muscle wasting and nutritional status in patients with HF; however, no established strategies currently exist to focus on patients suffering from muscle wasting with malnutrition.
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Affiliation(s)
- Masakazu Saitoh
- Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.
| | - Marcelo Rodrigues Dos Santos
- Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany.,Heart Institute (InCor), University of Sao Paulo Medical School, Sao Paulo, Brazil
| | - Stephan von Haehling
- Innovative Clinical Trials, Department of Cardiology and Pneumology, University Medical Center Göttingen, Robert-Koch-Str. 40, 37075, Göttingen, Germany
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Pan H, Yu H, Ravi V, Li C, Lee AP, Lian MM, Tay BH, Brenner S, Wang J, Yang H, Zhang G, Venkatesh B. The genome of the largest bony fish, ocean sunfish (Mola mola), provides insights into its fast growth rate. Gigascience 2016; 5:36. [PMID: 27609345 PMCID: PMC5016917 DOI: 10.1186/s13742-016-0144-3] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2016] [Accepted: 08/04/2016] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND The ocean sunfish (Mola mola), which can grow up to a length of 2.7 m and weigh 2.3 tons, is the world's largest bony fish. It has an extremely fast growth rate and its endoskeleton is mainly composed of cartilage. Another unique feature of the sunfish is its lack of a caudal fin, which is replaced by a broad and stiff lobe that results in the characteristic truncated appearance of the fish. RESULTS To gain insights into the genomic basis of these phenotypic traits, we sequenced the sunfish genome and performed a comparative analysis with other teleost genomes. Several sunfish genes involved in the growth hormone and insulin-like growth factor 1 (GH/IGF1) axis signalling pathway were found to be under positive selection or accelerated evolution, which might explain its fast growth rate and large body size. A number of genes associated with the extracellular matrix, some of which are involved in the regulation of bone and cartilage development, have also undergone positive selection or accelerated evolution. A comparison of the sunfish genome with that of the pufferfish (fugu), which has a caudal fin, revealed that the sunfish contains more homeobox (Hox) genes although both genomes contain seven Hox clusters. Thus, caudal fin loss in sunfish is not associated with the loss of a specific Hox gene. CONCLUSIONS Our analyses provide insights into the molecular basis of the fast growth rate and large size of the ocean sunfish. The high-quality genome assembly generated in this study should facilitate further studies of this 'natural mutant'.
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Affiliation(s)
- Hailin Pan
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
- China National Genebank, BGI-Shenzhen, Shenzhen, China
| | - Hao Yu
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
- China National Genebank, BGI-Shenzhen, Shenzhen, China
| | - Vydianathan Ravi
- Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, 138673 Singapore
| | - Cai Li
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
- China National Genebank, BGI-Shenzhen, Shenzhen, China
| | - Alison P. Lee
- Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, 138673 Singapore
| | - Michelle M. Lian
- Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, 138673 Singapore
| | - Boon-Hui Tay
- Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, 138673 Singapore
| | - Sydney Brenner
- Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, 138673 Singapore
| | - Jian Wang
- BGI-Shenzhen, Shenzhen, 518083 China
- James D Watson Institute of Genome Sciences, Hangzhou, 310058 China
| | - Huanming Yang
- BGI-Shenzhen, Shenzhen, 518083 China
- James D Watson Institute of Genome Sciences, Hangzhou, 310058 China
| | - Guojie Zhang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, China
- China National Genebank, BGI-Shenzhen, Shenzhen, China
- Centre for Social Evolution, Department of Biology, University of Copenhagen, Copenhagen, Denmark
| | - Byrappa Venkatesh
- Comparative Genomics Laboratory, Institute of Molecular and Cell Biology, A*STAR, Biopolis, Singapore, 138673 Singapore
- Department of Paediatrics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 119228 Singapore
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Alharthi AA. Idiopathic Short Stature in Children: A Hospital Based Study. JOURNAL OF MEDICAL SCIENCES 2016. [DOI: 10.3923/jms.2016.56.61] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
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Loncar G, Springer J, Anker M, Doehner W, Lainscak M. Cardiac cachexia: hic et nunc. J Cachexia Sarcopenia Muscle 2016; 7:246-60. [PMID: 27386168 PMCID: PMC4929818 DOI: 10.1002/jcsm.12118] [Citation(s) in RCA: 100] [Impact Index Per Article: 11.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/21/2016] [Accepted: 03/18/2016] [Indexed: 12/12/2022] Open
Abstract
Cardiac cachexia (CC) is the clinical entity at the end of the chronic natural course of heart failure (HF). Despite the efforts, even the most recent definition of cardiac cachexia has been challenged, more precisely, the addition of new criteria on top of obligatory weight loss. The pathophysiology of CC is complex and multifactorial. A better understanding of pathophysiological pathways in body wasting will contribute to establish potentially novel treatment strategies. The complex biochemical network related with CC and HF pathophysiology underlines that a single biomarker cannot reflect all of the features of the disease. Biomarkers that could pick up the changes in body composition before they convey into clinical manifestations of CC would be of great importance. The development of preventive and therapeutic strategies against cachexia, sarcopenia, and wasting disorders is perceived as an urgent need by healthcare professionals. The treatment of body wasting remains an unresolved challenge to this day. As CC is a multifactorial disorder, it is unlikely that any single agent will be completely effective in treating this condition. Among all investigated therapeutic strategies, aerobic exercise training in HF patients is the most proved to counteract skeletal muscle wasting and is recommended by treatment guidelines for HF.
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Affiliation(s)
- Goran Loncar
- Department of Cardiology Clinical Hospital Zvezdara Belgrade Serbia; School of Medicine University of Belgrade Belgrade Serbia
| | - Jochen Springer
- Innovative Clinical Trials, Department of Cardiology and Pneumology University Medical Center Göttingen (UMG) Göttingen Germany
| | - Markus Anker
- Department of Cardiology Charité - Universitätsmedizin Berlin Germany
| | - Wolfram Doehner
- Center for Stroke Research Berlin Charité Universitätsmedizin Berlin Germany
| | - Mitja Lainscak
- Department of Cardiology and Department of Research and Education General Hospital Celje Celje Slovenia; Faculty of Medicine University of Ljubljana Ljubljana Slovenia
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Identification of neutrophil-derived proteases and angiotensin II as biomarkers of cancer cachexia. Br J Cancer 2016; 114:680-7. [PMID: 26954714 PMCID: PMC4800302 DOI: 10.1038/bjc.2016.3] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2015] [Revised: 11/01/2015] [Accepted: 12/16/2015] [Indexed: 12/20/2022] Open
Abstract
Background: Cachexia is a metabolic disorder characterised by muscle wasting, diminished response to anti-cancer treatments and poor quality of life. Our objective was to identify blood-based biomarkers of cachexia in advanced cancer patients. Hence, we characterised the plasma cytokine and blood cell mRNA profiles of patients grouped in three cohorts: patients with cachexia, pre-cachexia (no cachexia but high CRP levels: ⩾5 mg l−1) and no cachexia (no cachexia and CRP: <5 mg l−1). Methods: A total of 122 newly diagnosed cancer patients with seven cancer types were studied prior to their initial therapy. Plasma levels of 22 cytokines were quantified using the bio-plex technology. mRNAs isolated from whole blood and expression profiles were determined by the chip array technology and Ingenuity Pathway Analysis (IPA) software. Results: In comparison with non-cachectic individuals, both pre-cachectic and cachectic patients showed an increase (⩾1.5-folds) in mRNA expression of neutrophil-derived proteases (NDPs) and significantly elevated angiotensin II (Ang II) (P=0.005 and P=0.02, respectively), TGFβ1 (P=0.042 and P<0.0001, respectively) and CRP (both P<0.0001) in the plasma. Moreover, cachectic patients displayed a significant increase in IL-6 (P=0.005), IL-8 (P=0.001) and absolute neutrophil counts (P=0.007). Conclusions: Ang II, TGFβ1, CRP and NDP are blood biomarkers for cancer cachexia. These findings contribute to early diagnosis and prevention of cachexia.
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Growth Hormone Protects the Intestine Preserving Radiotherapy Efficacy on Tumors: A Short-Term Study. PLoS One 2015; 10:e0144537. [PMID: 26670463 PMCID: PMC4682900 DOI: 10.1371/journal.pone.0144537] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2015] [Accepted: 11/19/2015] [Indexed: 02/06/2023] Open
Abstract
The efficacy of radiotherapy on tumors is hampered by its devastating adverse effects on healthy tissue, particularly that of the gastrointestinal tract. These effects cause acute symptoms that are so disruptive to patients that they can lead to interruption of the radiotherapy program. These adverse effects could limit the intensity of radiation received by the patient, resulting in a sublethal dose to the tumor, thus increasing the risk of tumor resistance. The lack of an effective treatment to protect the bowel during radiation therapy to allow higher radiation doses that are lethal to the tumor has become a barrier to implementing effective therapy. In this study, we present a comparative analysis of both intestinal and tumor tissue in regard to the efficacy and the preventive impact of a short-term growth hormone (GH) treatment in tumor-bearing rats as a protective agent during radiotherapy. Our data show that the exogenous administration of GH improved intestinal recovery after radiation treatment while preserving the therapeutic effect against the tumor. GH significantly increased proliferation in the irradiated intestine but not in the irradiated tumors, as assessed by Positron Emission Tomography and the proliferative markers Ki67, cyclin D3, and Proliferating Cell Nuclear Antigen. This proliferative effect was consistent with a significant increase in irradiated intestinal villi and crypt length. Furthermore, GH significantly decreased caspase-3 activity in the intestine, whereas GH did not produce this effect in the irradiated tumors. In conclusion, short-term GH treatment protects the bowel, inducing proliferation while reducing apoptosis in healthy intestinal tissue and preserving radiotherapy efficacy on tumors.
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Cardiac cachexia: hic et nunc: "hic et nunc" - here and now. Int J Cardiol 2015; 201:e1-12. [PMID: 26545926 DOI: 10.1016/j.ijcard.2015.10.115] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/12/2015] [Accepted: 10/13/2015] [Indexed: 02/07/2023]
Abstract
Cardiac cachexia (CC) is the clinical entity at the end of chronic natural course of heart failure (HF). Despite the efforts, even the most recent definition of cardiac cachexia has been challenged, more precisely the addition of new criteria on top of obligatory weight loss. The pathophysiology of CC is complex and multifactorial. Better understanding of pathophysiological pathways in body wasting will contribute to establish potentially novel treatment strategies. The complex biochemical network related with CC and HF pathophysiology underlines that a single biomarker cannot reflect all of the features of the disease. Biomarkers that could pick-up the changes in body composition before they convey into clinical manifestations of CC would be of great importance. The development of preventive and therapeutic strategies against cachexia, sarcopenia and wasting disorders is perceived as an urgent need by healthcare professionals. The treatment of body wasting remains an unresolved challenge to this day. As CC is a multifactorial disorder, it is unlikely that any single agent will be completely effective in treating this condition. Among all investigated therapeutic strategies, aerobic exercise training in HF patients is the most proved to counteract skeletal muscle wasting and is recommended by treatment guidelines for HF.
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A hypothesis for a possible synergy between ghrelin and exercise in patients with cachexia: Biochemical and physiological bases. Med Hypotheses 2015; 85:927-33. [PMID: 26404870 DOI: 10.1016/j.mehy.2015.09.008] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2014] [Revised: 09/07/2015] [Accepted: 09/07/2015] [Indexed: 12/15/2022]
Abstract
This article reviews the biochemical and physiological observations underpinning the synergism between ghrelin and ghrelin agonists with exercise, especially progressive resistance training that has been shown to increase muscle mass. The synergy of ghrelin agonists and physical exercise could be beneficial in conditions where muscle wasting is present, such as that found in patients with advanced cancer. The principal mechanism that controls muscle anabolism following the activation of the ghrelin receptor in the central nervous system involves the release of growth hormone/insulin-like growth factor-1 (GH/IGF-1). GH/IGF-1 axis has a dual pathway of action on muscle growth: (a) a direct action on muscle, bone and fat tissue and (b) an indirect action via the production of both muscle-restricted mIGF-1 and anti-cachectic cytokines. Progressive resistance training is a potent inducer of the secretion the muscle-restricted IGF-1 (mIGF-1) that enhances protein synthesis, increases lean body mass and eventually leads to the improvement of muscle strength. Thus, the combination of ghrelin administration with progressive resistance training may serve to circumvent ghrelin resistance and further reduce muscle wasting, which are commonly associated with cachexia.
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Stenvinkel P, Carrero JJ, von Walden F, Ikizler TA, Nader GA. Muscle wasting in end-stage renal disease promulgates premature death: established, emerging and potential novel treatment strategies. Nephrol Dial Transplant 2015; 31:1070-7. [PMID: 25910496 DOI: 10.1093/ndt/gfv122] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 03/27/2015] [Indexed: 12/15/2022] Open
Abstract
Muscle wasting (or sarcopenia) is a common feature of the uremic phenotype and predisposes this vulnerable patient population to increased risk of comorbid complications, poor quality of life, frailty and premature death. The old age of dialysis patients is in addition a likely contributor to loss of muscle mass. As recent evidence suggests that assessment of muscle strength (i.e. function) is a better predictor of outcome and comorbidities than muscle mass, this opens new screening, assessment and therapeutic opportunities. Among established treatment strategies, the benefit of resistance exercise and endurance training are increasingly recognized among nephrologists as being effective and should be promoted in sedentary chronic kidney disease patients. Testosterone and growth hormone replacement appear as the most promising among emerging treatments strategies for muscle wasting. As treatment of muscle wasting is difficult and seldom successful in this often old, frail, sedentary and exercise-hesitant patient group, novel treatment strategies are urgently needed. In this review, we summarize recent studies on stimulation of mitochondrial biogenesis, myogenic stem (satellite) cells and manipulation of transforming growth factor family members, all of which hold promise for more effective therapies to target muscle mass loss and function in the future.
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Affiliation(s)
- Peter Stenvinkel
- Department of Renal Medicine, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Juan Jesus Carrero
- Department of Renal Medicine, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Ferdinand von Walden
- Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | - T Alp Ikizler
- Division of Nephrology, Vanderbilt University Medical Center, Nashville, USA
| | - Gustavo A Nader
- Department of Kinesiology, The Pennsylvania State University, University Park, USA
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Growth Hormone Deficiency and Lysinuric Protein Intolerance: Case Report and Review of the Literature. JIMD Rep 2015; 19:35-41. [PMID: 25614305 DOI: 10.1007/8904_2014_362] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Revised: 08/19/2014] [Accepted: 09/03/2014] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Lysinuric protein intolerance (LPI; MIM# 222700) is a rare metabolic disorder caused by a defective cationic amino acids (CAA) membrane transport leading to decreased circulating plasma CAA levels and resulting in dysfunction of the urea cycle. Short stature is commonly observed in children with LPI and has been associated with protein malnutrition. A correlation between LPI and growth hormone deficiency (GHD) has also been postulated because of the known interaction between the AA arginine, ornithine, and lysine and growth hormone (GH) secretion. Our report describes a case of GHD in an LPI patient, who has not presented a significant increase in growth velocity with recombinant-human GH (rhGH) therapy, suggesting some possible pathogenic mechanisms of growth failure. CASE PRESENTATION The proband was a 6-year-old boy, diagnosed as suffering from LPI, erythrophagocytosis (HP) in bone marrow, and short stature. Two GH provocative tests revealed GHD. The patient started rhGH therapy and a controlled-protein diet initially with supplementation of oral arginine and then of citrulline. At 3-year follow-up, no significant increase in growth velocity and in insulin-like growth factor-1 (IGF-1) levels was observed. Inadequate nutrition and low plasmatic levels of arginine, ornithine, lysine, and HP may have contributed to his poor growth. CONCLUSION Our case suggests that growth failure in patients with GHD and LPI treated with rhGH could have a complex and multifactorial pathogenesis. Persistently low plasmatic levels of lysine, arginine, and ornithine, associated with dietary protein and caloric restriction and systemic inflammation, could determine a defect in coupling GH to IGF-1 production explaining why GH replacement therapy is not able to significantly improve growth impairment. We hypothesize that a better understanding of growth failure pathophysiology in these patients could lead to the development of more rational strategies to treat short stature in patients with LPI.
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Trobec K, Palus S, Tschirner A, von Haehling S, Doehner W, Lainscak M, Anker SD, Springer J. Rosiglitazone reduces body wasting and improves survival in a rat model of cancer cachexia. Nutrition 2014; 30:1069-75. [DOI: 10.1016/j.nut.2013.12.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2013] [Revised: 12/05/2013] [Accepted: 12/05/2013] [Indexed: 12/25/2022]
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Biomarkers for cardiac cachexia: Reality or utopia. Clin Chim Acta 2014; 436:323-8. [DOI: 10.1016/j.cca.2014.06.022] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2014] [Revised: 06/18/2014] [Accepted: 06/21/2014] [Indexed: 11/21/2022]
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Cichello SA, Weisinger RS, Schuijers J, Jois M. 1-Sarcosine-angiotensin II infusion effects on food intake, weight loss, energy expenditure, and skeletal muscle UCP3 gene expression in a rat model. J Cachexia Sarcopenia Muscle 2014; 5:239-46. [PMID: 24614996 PMCID: PMC4159489 DOI: 10.1007/s13539-014-0133-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2013] [Accepted: 01/27/2014] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND There are a myriad of proteins responsible for modulation of expenditure of energy. Angiotensin II (Ang II) is a vital component of renin-angiotensin system that affects blood pressure and also linked to both cachexia and obesity via fat and muscle metabolism. Previous research suggests that the direct action of Ang II is on the brain, via angiotensin II type 1 receptor protein, affecting food intake and energy expenditure. The objective of the study is to investigate the effect of 1-sarcosine (SAR)-Ang II infusion on energy expenditure and metabolism in a rat model of congestive heart failure cachexia. METHODS Adult female rats of the Sprague Dawley strain (n = 33) were used (11 pair-fed control, 12 ad libitum and 10, 1-sarcosine-angiotensin II-infused rats). Body weight, faecal excretion, feed intake (in grams), water intake (in milliliters) and urine excreted were recorded daily. The measurements were recorded in three different periods (4 days prior to surgery, "pre-infusion"; day of surgery and 5 days postsurgery, "infusion period"; days 7 to 14, "recovery" period). Different analytical methods were used to measure energy expenditure per period, uncoupling protein 3 mRNA expression, crude protein and adipose tissue body composition. RESULTS During the infusion period, the SAR-Ang II group experienced rapid weight loss (p < 0.05) in comparison to the ad libitum and pair-fed groups. The SAR-Ang II group displayed lower (p < 0.05) body fat content (in percent) than the controls. There was also increased (p < 0.05) uncoupling protein 3 (UCP3) mRNA expression in the SAR-Ang II group and pair-fed group when compared to the controls. CONCLUSION In summary, the results suggest that SAR-Ang II infusion impairs appetite and decreases body weight by wasting predominantly adipose tissue, which may be due to elevated energy expenditure via mitochondrial uncoupling (UCP3 protein activity).
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Affiliation(s)
- S A Cichello
- School of Life Sciences, La Trobe University, Bundoora, VIC, 3086, Australia,
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Palus S, von Haehling S, Springer J. Muscle wasting: an overview of recent developments in basic research. J Cachexia Sarcopenia Muscle 2014; 5:193-8. [PMID: 25163459 PMCID: PMC4159486 DOI: 10.1007/s13539-014-0157-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/06/2014] [Accepted: 08/07/2014] [Indexed: 02/06/2023] Open
Abstract
The syndrome of cachexia, i.e., involuntary weight loss in patients with underlying diseases, sarcopenia, i.e., loss of muscle mass due to aging, and general muscle atrophy from disuse and/or prolonged bed rest have received more attention over the last decades. All lead to a higher morbidity and mortality in patients, and therefore, they represent a major socio-economic burden for the society today. This mini-review looks at recent developments in basic research that are relevant to the loss of skeletal muscle. It aims to cover the most significant publication of last 3 years on the causes and effects of muscle wasting, new targets for therapy development, and potential biomarkers for assessing skeletal muscle mass. The targets include the following: (1) E-3 ligases TRIM32, SOCS1, and SOCS3 by involving the elongin BC ubiquitin-ligase, Cbl-b, culling 7, Fbxo40, MG53 (TRIM72), and the mitochondrial Mul1; (2) the kinase MST1; and (3) the G-protein Gαi2. D(3)-creatine has the potential to be used as a novel biomarker that allows to monitor actual change in skeletal muscle mass over time. In conclusion, significant development efforts are being made by academic groups as well as numerous pharmaceutical companies to identify new target and biomarker muscles, as muscle wasting represents a great medical need, but no therapies have been approved in the last decades.
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Affiliation(s)
- Sandra Palus
- Department of Innovative Clinical Trials, University Medical Centre Göttingen, Göttingen, Germany
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Zhang GW, Jia W, Chen SY, Jia XB, Wang J, Lai SJ. Association between the IRS1 and FTO genes regulates body weight in rabbits. Gene 2014; 548:75-80. [DOI: 10.1016/j.gene.2014.07.011] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2014] [Revised: 06/29/2014] [Accepted: 07/07/2014] [Indexed: 11/27/2022]
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Palus S, von Haehling S, Springer J. Muscle wasting: an overview of recent developments in basic research. Int J Cardiol 2014; 176:640-4. [PMID: 25205489 DOI: 10.1016/j.ijcard.2014.08.086] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2014] [Accepted: 08/15/2014] [Indexed: 12/25/2022]
Abstract
The syndrome of cachexia, i.e. involuntary weight loss in patients with underlying diseases, sarcopenia, i.e. loss of muscle mass due to ageing, and general muscle atrophy from disuse and/or prolonged bed rest have received more attention over the last decades. All lead to a higher morbidity and mortality in patients and therefore, they represent a major socio-economic burden for the society today. This mini-review looks at recent developments in basic research that are relevant to the loss of skeletal muscle. It aims to cover the most significant publication of last three years on the causes and effects of muscle wasting, new targets for therapy development and potential biomarkers for assessing skeletal muscle mass. The targets include 1) E-3 ligases: TRIM32, SOCS1 and SOCS3 by involving the elongin BC ubiquitin-ligase, Cbl-b, culling 7, Fbxo40, MG53 (TRIM72) and the mitochondrial Mul1, 2) the kinase MST1 and 3) the G-protein Gαi2. D(3)-creatine has the potential to be used as a novel biomarker that allows to monitor actual change in skeletal muscle mass over time. In conclusion, significant development efforts are being made by academic groups as well as numerous pharmaceutical companies to identify new targets and biomarkers muscle, as muscle wasting represents a great medical need, but no therapies have been approved in the last decades.
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Affiliation(s)
- Sandra Palus
- Department of Innovative Clinical Trials, University Medical Centre Göttingen, Göttingen, Germany
| | - Stephan von Haehling
- Department of Innovative Clinical Trials, University Medical Centre Göttingen, Göttingen, Germany
| | - Jochen Springer
- Department of Innovative Clinical Trials, University Medical Centre Göttingen, Göttingen, Germany; Department of Cardiology and Pneumology, University Medical Centre Göttingen, Göttingen, Germany.
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Mueller TC, Burmeister MA, Bachmann J, Martignoni ME. Cachexia and pancreatic cancer: Are there treatment options? World J Gastroenterol 2014; 20:9361-9373. [PMID: 25071331 PMCID: PMC4110568 DOI: 10.3748/wjg.v20.i28.9361] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/14/2014] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
Cachexia is frequently described in patients with pancreatic ductal adenocarcinoma (PDAC) and is associated with reduced survival and quality of life. Unfortunately, the therapeutic options of this multi-factorial and complex syndrome are limited. This is due to the fact that, despite extensive preclinical and clinical research, the underlying pathological mechanisms leading to PDAC-associated cachexia are still not fully understood. Furthermore, there is still a lack of consensus on the definition of cachexia, which complicates the standardization of diagnosis and treatment as well as the analysis of the current literature. In order to provide an efficient therapy for cachexia, an early and reliable diagnosis and consistent monitoring is required, which can be challenging especially in obese patients. Although many substances have been tested in clinical and preclinical settings, so far none of them have been proven to have a long-term effect in ameliorating cancer-associated cachexia. However, recent studies have demonstrated that multidimensional therapeutic modalities are able to alleviate pancreatic cancer-associated cachexia and ultimately improve patients’ outcome. In this current review, we propose a stepwise and pragmatic approach to facilitate and standardize the treatment of cachexia in pancreatic cancer patients. This strategy consists of nutritional, dietary, pharmacological, physical and psychological methods.
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Obata F, Kuranaga E, Tomioka K, Ming M, Takeishi A, Chen CH, Soga T, Miura M. Necrosis-driven systemic immune response alters SAM metabolism through the FOXO-GNMT axis. Cell Rep 2014; 7:821-33. [PMID: 24746817 DOI: 10.1016/j.celrep.2014.03.046] [Citation(s) in RCA: 59] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2013] [Revised: 02/25/2014] [Accepted: 03/18/2014] [Indexed: 01/27/2023] Open
Abstract
Sterile inflammation triggered by endogenous factors is thought to contribute to the pathogenesis of acute and chronic inflammatory diseases. Here, we demonstrate that apoptosis-deficient mutants spontaneously develop a necrosis-driven systemic immune response in Drosophila and provide an in vivo model for studying the organismal response to sterile inflammation. Metabolomic analysis of hemolymph from apoptosis-deficient mutants revealed increased sarcosine and reduced S-adenosyl-methionine (SAM) levels due to glycine N-methyltransferase (Gnmt) upregulation. We showed that Gnmt was elevated in response to Toll activation induced by the local necrosis of wing epidermal cells. Necrosis-driven inflammatory conditions induced dFoxO hyperactivation, leading to an energy-wasting phenotype. Gnmt was cell-autonomously upregulated by dFoxO in the fat body as a possible rheostat for controlling energy loss, which functioned during fasting as well as inflammatory conditions. We propose that the dFoxO-Gnmt axis is essential for the maintenance of organismal SAM metabolism and energy homeostasis.
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Affiliation(s)
- Fumiaki Obata
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan
| | - Erina Kuranaga
- Laboratory for Histogenetic Dynamics, RIKEN CDB, Kobe 650-0047, Japan
| | - Katsura Tomioka
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Ming Ming
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Asuka Takeishi
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Chun-Hong Chen
- National Health Research Institutes, Zhunan, Miaoli County 35053, Taiwan
| | - Tomoyoshi Soga
- Institute for Advanced Biosciences, Keio University, Tsuruoka, Yamagata 997-0052, Japan
| | - Masayuki Miura
- Department of Genetics, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Bunkyo-ku, Tokyo 113-0033, Japan; CREST, Japan Science and Technology Agency, Chiyoda-ku, Tokyo 102-0075, Japan.
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Anker MS, von Haehling S, Springer J, Banach M, Anker SD. Highlights of mechanistic and therapeutic cachexia and sarcopenia research 2010 to 2012 and their relevance for cardiology. Arch Med Sci 2013; 9:166-71. [PMID: 23515589 PMCID: PMC3598129 DOI: 10.5114/aoms.2013.33356] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/03/2012] [Revised: 11/05/2012] [Accepted: 11/06/2012] [Indexed: 02/07/2023] Open
Abstract
Sarcopenia and cachexia are significant medical problems with a high disease-related burden in cardiovascular illness. Muscle wasting and weight loss are very frequent particularly in chronic heart failure and they relate to poor prognosis. Although clinically largely underestimated, the fields of cachexia and sarcopenia are of great relevance to cardiologists. In cachexia and sarcopenia a significant number of research publications related to basic science questions of muscle wasting and lipolysis were published between 2010 and 2012. Recently, the two processes of muscle wasting and lipolysis were found to be closely linked. Treatment research in pre-clinical models involves studies on a number of different therapeutic entities, including ghrelin, selective androgen receptor modulators (SARMs), as well as drugs targeting myostatin or melanocortin-4. In the human setting, studies using enobosarm (a SARM) and anamorelin (ghrelin) are in phase III. The last 3 years have seen significant efforts to define the field using consensus statements. In the future, these definitions should also be considered for guidelines and treatment trials in cardiovascular medicine. The current review aims to summarize important information and development in the fields of muscle wasting, sarcopenia and cachexia, focusing on findings in cardiovascular research, in order for cardiologists to have a better understanding of the progress in this still insufficiently known field.
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Affiliation(s)
- Markus S. Anker
- Center for Clinical and Basic Research, IRCCS San Raffaele, Rome, Italy
| | - Stephan von Haehling
- Applied Cachexia Research, Department of Cardiology, Charité, Campus Virchow-Klinikum, Berlin, Germany
| | - Jochen Springer
- Applied Cachexia Research, Center for Cardiovascular Research, Charité, Campus Mitte, Berlin, Germany
| | - Maciej Banach
- Department of Hypertension, Medical University of Lodz, Poland
| | - Stefan D. Anker
- Center for Clinical and Basic Research, IRCCS San Raffaele, Rome, Italy
- Applied Cachexia Research, Department of Cardiology, Charité, Campus Virchow-Klinikum, Berlin, Germany
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Anker MS, von Haehling S, Springer J, Banach M, Anker SD. Highlights of the mechanistic and therapeutic cachexia and sarcopenia research 2010 to 2012 and their relevance for cardiology. Int J Cardiol 2013; 162:73-6. [DOI: 10.1016/j.ijcard.2012.10.018] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Accepted: 10/20/2012] [Indexed: 12/25/2022]
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Steinman J, DeBoer MD. Treatment of cachexia: melanocortin and ghrelin interventions. VITAMINS AND HORMONES 2013; 92:197-242. [PMID: 23601426 DOI: 10.1016/b978-0-12-410473-0.00008-8] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Cachexia is a condition typified by wasting of fat and LBM caused by anorexia and further endocrinological modulation of energy stores. Diseases known to cause cachectic symptoms include cancer, chronic kidney disease, and chronic heart failure; these conditions are associated with increased levels of proinflammatory cytokines and increased resting energy expenditure. Early studies have suggested the central melanocortin system as one of the main mediators of the symptoms of cachexia. Pharmacological and genetic antagonism of these pathways attenuates cachectic symptoms in laboratory models; effects have yet to be studied in humans. In addition, ghrelin, an endogenous orexigenic hormone with receptors on melanocortinergic neurons, has been shown to ameliorate symptoms of cachexia, at least in part, by an increase in appetite via melanocortin modulation, in addition to its anticatabolic and anti-inflammatory effects. These effects of ghrelin have been confirmed in multiple types of cachexia in both laboratory and human studies, suggesting a positive future for cachexia treatments.
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Affiliation(s)
- Jeremy Steinman
- Division of Pediatric Endocrinology, Department of Pediatrics, P.O. Box 800386, University of Virginia, Charlottesville, Virginia, USA
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Macciò A, Madeddu C, Mantovani G. Current pharmacotherapy options for cancer anorexia and cachexia. Expert Opin Pharmacother 2012; 13:2453-2472. [PMID: 23072481 DOI: 10.1517/14656566.2012.734297] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
INTRODUCTION Anorexia and cachexia syndrome represents a complex clinical picture that occurs in the late stage of several chronic inflammatory diseases, including cancer. Unless counteracted cancer-related anorexia and cachexia syndrome affects quality of life (QL) and survival. However, to date a standard effective treatment is lacking. AREAS COVERED The aim of this review is to describe the current pharmacological approaches for anorexia and cachexia syndrome, focusing on cancer-related syndrome. The several pharmacological agents tested so far are discussed, distinguishing them in unproven drugs, effective drugs, and drugs under investigation. Moreover, a section is devoted to the promising use of nutritional supplements and nutraceuticals. The emerging role of a multitargeted combined treatment approach is exhaustively reviewed. EXPERT OPINION Considering the complex clinical picture and the multifactorial pathogenesis of anorexia and cachexia syndrome, we believe that its clinical management requires a multidisciplinary and multipharmacological approach. In our opinion the anorexia and cachexia syndrome treatment should include drugs that target the following conditions: inflammatory status, oxidative stress, nutritional disorders, muscle catabolism, anemia, immunosuppression, and fatigue. The multidimensional therapies for anorexia and cachexia syndrome should ideally be introduced within a context of the "best supportive care," which includes optimal symptom management and careful psychosocial counseling.
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Affiliation(s)
- Antonio Macciò
- Sirai Hospital, Department of Obstetrics and Gynecology, Carbonia, Italy.
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Lainscak M, Anker SD, von Haehling S. No train, no gain: does this apply to heart failure with preserved ejection fraction? Int J Cardiol 2012; 162:69-70. [PMID: 23121915 DOI: 10.1016/j.ijcard.2012.10.020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2012] [Accepted: 10/17/2012] [Indexed: 10/27/2022]
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