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1
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Bordoni B, Escher AR. Fascial Manual Medicine: The Concept of Fascial Continuum. Cureus 2025; 17:e82136. [PMID: 40226146 PMCID: PMC11992952 DOI: 10.7759/cureus.82136] [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] [Accepted: 04/12/2025] [Indexed: 04/15/2025] Open
Abstract
Fascial tissue ubiquitously pervades the body system, becoming the target of many disciplines that use manual techniques for patient treatment. It is a much-debated topic as there is currently no univocal definition among different authors. Due to the non-discontinuity of the fascia, we can speak of a fascial continuum; this principle is the basis of the osteopathic perspective. This vision, which seems banal, is not always applied in manual fascial medicine, where, often, it is conditioned by a reductionist (layers) and mechanistic (compartments) approach, forgetting that the body is not a machine but an organism. This continuity teaches that manual treatment does not only reverberate in the area where the operator's hands rest but creates a series of local and systemic adaptations. This narrative review revises the concept of the fascial continuum by highlighting that fascia is a tissue system (different tissues working in harmony), multi-organ (capable of behaving like an organ), whose macroscopic functional expression (movement) and microscopic (with cellular adaptations) derives from a nanoscopic coherence (electromagnetic behaviors). This means that the body acts as a unit, and makes the manual approach never local but always systemic. The aim of the article is to highlight the fact that the fascial continuum is a single biological entity (solid and fluid), and that manual fascial medicine does not approach a single segment, but the entire person.
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Affiliation(s)
- Bruno Bordoni
- Physical Medicine and Rehabilitation, Foundation Don Carlo Gnocchi, Milan, ITA
| | - Allan R Escher
- Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, USA
- Anesthesiology/Pain Medicine, H. Lee Moffitt Cancer Center and Research Institute, Tampa, USA
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2
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Millward DJ. Post-natal muscle growth and protein turnover: a narrative review of current understanding. Nutr Res Rev 2024; 37:141-168. [PMID: 37395180 DOI: 10.1017/s0954422423000124] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 07/04/2023]
Abstract
A model explaining the dietary-protein-driven post-natal skeletal muscle growth and protein turnover in the rat is updated, and the mechanisms involved are described, in this narrative review. Dietary protein controls both bone length and muscle growth, which are interrelated through mechanotransduction mechanisms with muscle growth induced both from stretching subsequent to bone length growth and from internal work against gravity. This induces satellite cell activation, myogenesis and remodelling of the extracellular matrix, establishing a growth capacity for myofibre length and cross-sectional area. Protein deposition within this capacity is enabled by adequate dietary protein and other key nutrients. After briefly reviewing the experimental animal origins of the growth model, key concepts and processes important for growth are reviewed. These include the growth in number and size of the myonuclear domain, satellite cell activity during post-natal development and the autocrine/paracrine action of IGF-1. Regulatory and signalling pathways reviewed include developmental mechanotransduction, signalling through the insulin/IGF-1-PI3K-Akt and the Ras-MAPK pathways in the myofibre and during mechanotransduction of satellite cells. Likely pathways activated by maximal-intensity muscle contractions are highlighted and the regulation of the capacity for protein synthesis in terms of ribosome assembly and the translational regulation of 5-TOPmRNA classes by mTORC1 and LARP1 are discussed. Evidence for and potential mechanisms by which volume limitation of muscle growth can occur which would limit protein deposition within the myofibre are reviewed. An understanding of how muscle growth is achieved allows better nutritional management of its growth in health and disease.
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Affiliation(s)
- D Joe Millward
- Department of Nutritional Sciences, School of Biosciences & Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford, UK
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3
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Mucha O, Podkalicka P, Żukowska M, Pośpiech E, Dulak J, Łoboda A. miR-378 influences muscle satellite cells and enhances adipogenic potential of fibro-adipogenic progenitors but does not affect muscle regeneration in the glycerol-induced injury model. Sci Rep 2023; 13:13434. [PMID: 37596327 PMCID: PMC10439181 DOI: 10.1038/s41598-023-40729-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2023] [Accepted: 08/16/2023] [Indexed: 08/20/2023] Open
Abstract
Skeletal muscle regeneration relies on the reciprocal interaction between many types of cells. Regenerative capacity may be altered in different disorders. In our study, we investigated whether the deletion of miR-378a (miR-378) affects muscle regeneration. We subjected 6-week-old wild-type (WT) and miR-378 knockout (miR-378-/-) animals to the glycerol-induced muscle injury and performed analyses in various time-points. In miR-378-/- animals, an elevated abundance of muscle satellite cells (mSCs) on day 3 was found. Furthermore, fibro-adipogenic progenitors (FAPs) isolated from the muscle of miR-378-/- mice exhibited enhanced adipogenic potential. At the same time, lack of miR-378 did not affect inflammation, fibrosis, adipose tissue deposition, centrally nucleated fiber count, muscle fiber size, FAP abundance, and muscle contractility at any time point analyzed. To conclude, our study revealed that miR-378 deletion influences the abundance of mSCs and the adipogenic potential of FAPs, but does not affect overall regeneration upon acute, glycerol-induced muscle injury.
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Affiliation(s)
- Olga Mucha
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Kraków, Poland
| | - Paulina Podkalicka
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Kraków, Poland
| | - Monika Żukowska
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Kraków, Poland
| | - Ewelina Pośpiech
- Malopolska Centre of Biotechnology in Krakow, 30-387, Kraków, Poland
| | - Józef Dulak
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Kraków, Poland
| | - Agnieszka Łoboda
- Department of Medical Biotechnology, Faculty of Biochemistry, Biophysics and Biotechnology, Jagiellonian University in Krakow, Gronostajowa 7, 30-387, Kraków, Poland.
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4
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McGlynn ML, Rosales AM, Collins CW, Slivka DR. The independent effects of local heat application on muscle growth program associated mRNA and protein phosphorylation. J Therm Biol 2023; 115:103602. [PMID: 37331320 PMCID: PMC10528064 DOI: 10.1016/j.jtherbio.2023.103602] [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: 03/27/2023] [Revised: 05/10/2023] [Accepted: 05/21/2023] [Indexed: 06/20/2023]
Abstract
The development and maintenance of skeletal muscle is crucial for the support of daily function. Recent evidence suggests that genes coded for proteins associated with the human muscle growth program (myogenic and proteolytic genes) are sensitive to local heat application. Therefore, the purpose of this investigation was to determine the effect of 4 h of local heat application to the vastus lateralis at rest on acute phosphorylation (mTORSer2448, p70-S6K1Thr389, and 4E-BP1Thr47/36) and gene expression changes for proteins associated with the muscle growth program. Intramuscular temperature of the HOT limb was 1.2 ± 0.2 °C higher than CON limb after 4 h of local heating. However, this local heat stimulus did not influence transcription of genes associated with myogenesis (MSTN, p = 0.321; MYF5, p = 0.445; MYF6, p = 0.895; MEF2a, p = 0.809; MYO-G, p = 0.766; MYO-D1, p = 0.118; RPS3, p = 0.321; and RPL-3L, p = 0.577), proteolysis (Atrogin-1, p = 0.573; FOXO3a, p = 0.452; MURF-1, p = 0.284), nor protein phosphorylation (mTORSer2448, p = 0.981; P70-S6K1Thr389, p = 0.583; 4E-BP1Thr37/46, p = 0.238) associated with the muscle growth program. These findings suggest little to no association between the local application of heat, at rest, and the activation of the observed muscle growth program-related markers.
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Affiliation(s)
- Mark L McGlynn
- School of Health and Kinesiology, University of Nebraska at Omaha, Omaha, NE, 68182, USA
| | - Alejandro M Rosales
- School of Integrated Physiology and Athletic Training, University of Montana, Missoula, MT, 59812, USA
| | - Christopher W Collins
- School of Health and Kinesiology, University of Nebraska at Omaha, Omaha, NE, 68182, USA
| | - Dustin R Slivka
- School of Health and Kinesiology, University of Nebraska at Omaha, Omaha, NE, 68182, USA; School of Integrated Physiology and Athletic Training, University of Montana, Missoula, MT, 59812, USA.
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5
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Fu S, Lan Y, Wang G, Bao D, Qin B, Zheng Q, Liu H, Wong VKW. External stimulation: A potential therapeutic strategy for tendon-bone healing. Front Bioeng Biotechnol 2023; 11:1150290. [PMID: 37064229 PMCID: PMC10102526 DOI: 10.3389/fbioe.2023.1150290] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Accepted: 03/23/2023] [Indexed: 04/03/2023] Open
Abstract
Injuries at the tendon-bone interface are very common in the field of sports medicine, and healing at the tendon-bone interface is complex. Injuries to the tendon-bone interface can seriously affect a patient’s quality of life, so it is essential to restore stability and promote healing of the tendon-bone interface. In addition to surgical treatment, the healing of tendons and bones can also be properly combined with extracorporeal stimulation therapy during the recovery process. In this review, we discuss the effects of extracorporeal shock waves (ESWs), low-intensity pulsed ultrasound (LIPUS), and mechanical stress on tendon-bone healing, focusing on the possible mechanisms of action of mechanical stress on tendon-bone healing in terms of transcription factors and biomolecules. The aim is to provide possible therapeutic approaches for subsequent clinical treatment.
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Affiliation(s)
- Shijie Fu
- Faculty of Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China
- Department of Orthopedics, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China
| | - Yujian Lan
- Department of Orthopedics, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Guoyou Wang
- Department of Orthopedics, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Dingsu Bao
- Department of Orthopedics, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Bo Qin
- Department of Orthopedics, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Qiu Zheng
- Department of Orthopedics, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
| | - Huan Liu
- Department of Orthopedics, Affiliated Traditional Chinese Medicine Hospital of Southwest Medical University, Luzhou, Sichuan, China
- *Correspondence: Huan Liu, ; Vincent Kam Wai Wong,
| | - Vincent Kam Wai Wong
- Dr. Neher’s Biophysics Laboratory for Innovative Drug Discovery, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao SAR, China
- *Correspondence: Huan Liu, ; Vincent Kam Wai Wong,
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6
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Secretome from In Vitro Mechanically Loaded Myoblasts Induces Tenocyte Migration, Transition to a Fibroblastic Phenotype and Suppression of Collagen Production. Int J Mol Sci 2021; 22:ijms222313089. [PMID: 34884895 PMCID: PMC8657858 DOI: 10.3390/ijms222313089] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 11/29/2021] [Accepted: 12/01/2021] [Indexed: 11/16/2022] Open
Abstract
It is known that mechanical loading of muscles increases the strength of healing tendon tissue, but the mechanism involved remains elusive. We hypothesized that the secretome from myoblasts in co-culture with tenocytes affects tenocyte migration, cell phenotype, and collagen (Col) production and that the effect is dependent on different types of mechanical loading of myoblasts. To test this, we used an in vitro indirect transwell co-culture system. Myoblasts were mechanically loaded using the FlexCell® Tension system. Tenocyte cell migration, proliferation, apoptosis, collagen production, and several tenocyte markers were measured. The secretome from myoblasts decreased the Col I/III ratio and increased the expression of tenocyte specific markers as compared with tenocytes cultured alone. The secretome from statically loaded myoblasts significantly enhanced tenocyte migration and Col I/III ratio as compared with dynamic loading and controls. In addition, the secretome from statically loaded myoblasts induced tenocytes towards a myofibroblast-like phenotype. Taken together, these results demonstrate that the secretome from statically loaded myoblasts has a profound influence on tenocytes, affecting parameters that are related to the tendon healing process.
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7
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Ren D, Song J, Liu R, Zeng X, Yan X, Zhang Q, Yuan X. Molecular and Biomechanical Adaptations to Mechanical Stretch in Cultured Myotubes. Front Physiol 2021; 12:689492. [PMID: 34408658 PMCID: PMC8365838 DOI: 10.3389/fphys.2021.689492] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Accepted: 06/29/2021] [Indexed: 11/24/2022] Open
Abstract
Myotubes are mature muscle cells that form the basic structural element of skeletal muscle. When stretching skeletal muscles, myotubes are subjected to passive tension as well. This lead to alterations in myotube cytophysiology, which could be related with muscular biomechanics. During the past decades, much progresses have been made in exploring biomechanical properties of myotubes in vitro. In this review, we integrated the studies focusing on cultured myotubes being mechanically stretched, and classified these studies into several categories: amino acid and glucose uptake, protein turnover, myotube hypertrophy and atrophy, maturation, alignment, secretion of cytokines, cytoskeleton adaption, myotube damage, ion channel activation, and oxidative stress in myotubes. These biomechanical adaptions do not occur independently, but interconnect with each other as part of the systematic mechanoresponse of myotubes. The purpose of this review is to broaden our comprehensions of stretch-induced muscular alterations in cellular and molecular scales, and to point out future challenges and directions in investigating myotube biomechanical manifestations.
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Affiliation(s)
- Dapeng Ren
- Department of Stomatology Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, China.,College of Dentistry, Qingdao University, Qingdao, China
| | - Jing Song
- Department of Stomatology Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ran Liu
- Department of Stomatology Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xuemin Zeng
- Department of Stomatology Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, China.,College of Dentistry, Qingdao University, Qingdao, China
| | - Xiao Yan
- Department of Stomatology Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Qiang Zhang
- Department of Stomatology Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Xiao Yuan
- Department of Stomatology Medical Center, The Affiliated Hospital of Qingdao University, Qingdao, China
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8
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Westman AM, Peirce SM, Christ GJ, Blemker SS. Agent-based model provides insight into the mechanisms behind failed regeneration following volumetric muscle loss injury. PLoS Comput Biol 2021; 17:e1008937. [PMID: 33970905 PMCID: PMC8110270 DOI: 10.1371/journal.pcbi.1008937] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2020] [Accepted: 04/01/2021] [Indexed: 12/22/2022] Open
Abstract
Skeletal muscle possesses a remarkable capacity for repair and regeneration following a variety of injuries. When successful, this highly orchestrated regenerative process requires the contribution of several muscle resident cell populations including satellite stem cells (SSCs), fibroblasts, macrophages and vascular cells. However, volumetric muscle loss injuries (VML) involve simultaneous destruction of multiple tissue components (e.g., as a result of battlefield injuries or vehicular accidents) and are so extensive that they exceed the intrinsic capability for scarless wound healing and result in permanent cosmetic and functional deficits. In this scenario, the regenerative process fails and is dominated by an unproductive inflammatory response and accompanying fibrosis. The failure of current regenerative therapeutics to completely restore functional muscle tissue is not surprising considering the incomplete understanding of the cellular mechanisms that drive the regeneration response in the setting of VML injury. To begin to address this profound knowledge gap, we developed an agent-based model to predict the tissue remodeling response following surgical creation of a VML injury. Once the model was able to recapitulate key aspects of the tissue remodeling response in the absence of repair, we validated the model by simulating the tissue remodeling response to VML injury following implantation of either a decellularized extracellular matrix scaffold or a minced muscle graft. The model suggested that the SSC microenvironment and absence of pro-differentiation SSC signals were the most important aspects of failed muscle regeneration in VML injuries. The major implication of this work is that agent-based models may provide a much-needed predictive tool to optimize the design of new therapies, and thereby, accelerate the clinical translation of regenerative therapeutics for VML injuries.
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Affiliation(s)
- Amanda M. Westman
- Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
| | - Shayn M. Peirce
- Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
- Ophthalmology, University of Virginia, Charlottesville, Virginia, United States of America
| | - George J. Christ
- Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
- Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, United States of America
- * E-mail: (GJC); (SSB)
| | - Silvia S. Blemker
- Biomedical Engineering, University of Virginia, Charlottesville, Virginia, United States of America
- Ophthalmology, University of Virginia, Charlottesville, Virginia, United States of America
- Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia, United States of America
- Mechanical and Aerospace Engineering, University of Virginia, Charlottesville, Virginia, United States of America
- * E-mail: (GJC); (SSB)
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9
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Downregulated miR-204 Promotes Skeletal Muscle Regeneration. BIOMED RESEARCH INTERNATIONAL 2020; 2020:3183296. [PMID: 33282943 PMCID: PMC7685802 DOI: 10.1155/2020/3183296] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/22/2020] [Revised: 09/10/2020] [Accepted: 10/27/2020] [Indexed: 11/27/2022]
Abstract
Skeletal muscle is the most abundant and a highly plastic tissue of the mammals, especially when it comes to regenerate after trauma, but there is limited information about the mechanism of muscle repair and its regeneration. In the present study, we found that miR-204 is downregulated after skeletal muscle injury. In vitro experiments showed that over-expression of miR-204 by transfecting with miR-204 mimics suppressed C2C12 cell proliferation, migration, and blocked subsequent differentiation, whereas inhibition of miR-204 by transfecting with miR-204 inhibitor showed the converse effects. Furthermore, through the dual luciferase reporter system, we demonstrated that miR-204 can target the 3'UTR regions of Pax7, IGF1, and Mef2c and inhibit their expression. Taken together, our results suggest that Pax7, IGF1, and Mef2c are the target genes of miR-204 in the process of myoblasts proliferation, cell migration, and differentiation, respectively, and may contribute to mouse skeletal muscle regeneration. Our results may provide new ideas and references for the skeletal muscle study and may also provide therapeutic strategies of skeletal muscle injury.
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10
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Moustogiannis A, Philippou A, Zevolis E, Taso O, Chatzigeorgiou A, Koutsilieris M. Characterization of Optimal Strain, Frequency and Duration of Mechanical Loading on Skeletal Myotubes' Biological Responses. In Vivo 2020; 34:1779-1788. [PMID: 32606147 PMCID: PMC7439881 DOI: 10.21873/invivo.11972] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 05/15/2020] [Accepted: 05/18/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUND/AIM Mechanical loading of differentiated myoblasts in vitro may mimic loading patterns of skeletal muscle in vivo. However, it is still uncharacterized the loading conditions that can produce the most effective muscle cells' biological responses, in vitro. This study investigated the effects of different loading protocols on the expression of myogenic regulatory factors, anabolic, atrophy and pro-apoptotic factors in skeletal myotubes. MATERIALS AND METHODS C2C12 myoblasts were differentiated and underwent various stretching protocols by altering their elongation, frequency and duration, utilizing an in vitro cell tension system. The loading-induced expression changes of MyoD, Myogenin, MRF4, IGF-1 isoforms, Murf1, Atrogin, Myostatin, Foxo and Fuca were measured by Real Time-PCR. RESULTS Stretching by 2% elongation at 0.25 Hz for 12 h was overall the most effective in inducing beneficial responses. CONCLUSION A low strain, low frequency intermediate duration stretching can most effectively up-regulate myogenic/anabolic factors and down-regulate pro-apoptotic and atrophy genes in myotubes.
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Affiliation(s)
- Athanasios Moustogiannis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastassios Philippou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Evangelos Zevolis
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Orjona Taso
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Michael Koutsilieris
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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11
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Activation of adiponectin receptors has negative impact on muscle mass in C2C12 myotubes and fast-type mouse skeletal muscle. PLoS One 2018; 13:e0205645. [PMID: 30308063 PMCID: PMC6181411 DOI: 10.1371/journal.pone.0205645] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2018] [Accepted: 09/29/2018] [Indexed: 11/19/2022] Open
Abstract
This study investigated the effects of AdipoRon, which is an agonist for adiponectin receptor 1 (AdipoR1) and AdipoR2, on the protein content, myotube diameter, and number of nuclei per myotube of C2C12 cells and skeletal muscle mass in C57BL/6J mice. AdipoRon suppressed the protein content, myotube diameter, and number of nuclei per myotube of C2C12 cells of C2C12 myotubes in a dose-dependent manner. Adiponectin-associated decline of protein content, diameter, and number of nuclei per myotube in C2C12 myotubes was partially rescued by knockdown of AdipoR1 and/or AdipoR2. Phosphorylation level of AMPK showed a trend to be increased by AdipoRon. A significant increase in phosphorylation level of AMPK was observed at 20 μM AdipoRon. Knockdown of AdipoR1 and/or AdipoR2 rescued AdipoRon-associated decrease in protein content of C2C12 myotubes. AdipoRon-associated increase in phosphorylation level of AMPK in C2C12 myotubes was suppressed by knockdown of AdipoR1 and/or AdipoR2. Successive intravenous injections of AdipoRon into mice caused a decrease in the wet weight of plantaris muscle (PLA), but not in soleus muscle (SOL). Mean fiber cross-sectional area of PLA, but not of SOL, was significantly decreased by AdipoRon administration. On the one hand, the expression level of phosphorylated AMPK and ubiquitinated protein in SOL and PLA muscles was upregulated by AdipoRon administration. On the other hand, AdipoRon administration induced no changes in the expression level of puromycin-labeled proteins in both SOL and PLA muscles. Expression level of adiponectin in extensor digitorum longus (EDL) muscle was increased by aging, but not in SOL muscle. Aging had no effect on the expression level of AdipoR1 and AdipoR2 in both muscles. Phosphorylation level of AMPK in EDL was increased by aging, but not SOL muscle. Results from this study suggest that high level of circulating adiponectin may induce skeletal muscle atrophy, especially fast-type muscle.
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12
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Prüller J, Mannhardt I, Eschenhagen T, Zammit PS, Figeac N. Satellite cells delivered in their niche efficiently generate functional myotubes in three-dimensional cell culture. PLoS One 2018; 13:e0202574. [PMID: 30222770 PMCID: PMC6141091 DOI: 10.1371/journal.pone.0202574] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2017] [Accepted: 08/05/2018] [Indexed: 12/22/2022] Open
Abstract
Biophysical/biochemical cues from the environment contribute to regulation of the regenerative capacity of resident skeletal muscle stem cells called satellites cells. This can be observed in vitro, where muscle cell behaviour is influenced by the particular culture substrates and whether culture is performed in a 2D or 3D environment, with changes including morphology, nuclear shape and cytoskeletal organization. To create a 3D skeletal muscle model we compared collagen I, Fibrin or PEG-Fibrinogen with different sources of murine and human myogenic cells. To generate tension in the 3D scaffold, biomaterials were polymerised between two flexible silicone posts to mimic tendons. This 3D culture system has multiple advantages including being simple, fast to set up and inexpensive, so providing an accessible tool to investigate myogenesis in a 3D environment. Immortalised human and murine myoblast lines, and primary murine satellite cells showed varying degrees of myogenic differentiation when cultured in these biomaterials, with C2 myoblasts in particular forming large multinucleated myotubes in collagen I or Fibrin. However, murine satellite cells retained in their niche on a muscle fibre and embedded in 3D collagen I or Fibrin gels generated aligned, multinucleated and contractile myotubes.
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Affiliation(s)
- Johanna Prüller
- King's College London, Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, London, England
| | - Ingra Mannhardt
- Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), Hamburg, Germany
| | - Thomas Eschenhagen
- Department of Experimental Pharmacology and Toxicology, University Medical Center Hamburg Eppendorf, Hamburg, Germany.,DZHK (German Centre for Cardiovascular Research), Hamburg, Germany
| | - Peter S Zammit
- King's College London, Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, London, England
| | - Nicolas Figeac
- King's College London, Randall Centre for Cell and Molecular Biophysics, New Hunt's House, Guy's Campus, London, England
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13
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Amer NM, Modesto MJ, Dos Santos CD, Erichsen O, Mascarenhas LPG, Nesi-França S, Marques-Pereira R, De Lacerda L. Resistance exercise alone improves muscle strength in growth hormone deficient males in the transition phase. J Pediatr Endocrinol Metab 2018; 31:887-894. [PMID: 30052519 DOI: 10.1515/jpem-2017-0369] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/09/2017] [Accepted: 05/28/2018] [Indexed: 11/15/2022]
Abstract
Background During the transition phase (TP), patients with growth hormone deficiency (GHD) exhibit decreased muscle strength. Studies assessing the effects of resistance exercise alone on muscle strength in these individuals are scarce. The objective of this study was to evaluate the effects of a program of resistance exercise (PRE) on parameters of muscle strength in subjects in the TP and with childhood-onset GHD treated with recombinant GH (rGH). Methods Sixteen male patients were enrolled and divided into two groups: GHD (n=9) and GH sufficiency (GHS, n=7). Patients with GHD underwent a 12-week PRE followed by another 12-week PRE plus rGH, while GHS patients underwent a 12-week PRE alone. Dynamic knee muscle strength was evaluated using an isokinetic dynamometer. Results Before PRE, there were significant differences between the groups regarding the results of flexor peak torque (FPT) normalized to body weight (BW-FPT) in the dominant (DO, p=0.008) and non-dominant (ND, p=0.01) limbs, and in the agonist/antagonist (A/A) ratio in the DO (p=0.02) and ND (p=0.006) limbs. After PRE in the GHD group, values of FPT and BW-FPT in both limbs increased significantly (p<0.001) and independently of rGH, while the A/A ratio value improved significantly (p<0.001) in the ND limb. Conclusions A short period of PRE alone was sufficient to improve parameters of muscle strength in young male adults with childhood-onset GHD.
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Affiliation(s)
- Nadia Mohamad Amer
- Children and Adolescent Health Post-Graduate Program, Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Marilza J Modesto
- Children and Adolescent Health Post-Graduate Program, Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Cláudia Duarte Dos Santos
- Children and Adolescent Health Post-Graduate Program, Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Oscar Erichsen
- Department of Physiology, Clube Atlético Paranaense, Curitiba, Paraná, Brazil
| | - Luis P G Mascarenhas
- Children and Adolescent Health Post-Graduate Program, Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Suzana Nesi-França
- Pediatric Endocrinology Unit, Department of Pediatrics, Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Rosana Marques-Pereira
- Pediatric Endocrinology Unit, Department of Pediatrics, Federal University of Paraná, Curitiba, Paraná, Brazil
| | - Luiz De Lacerda
- Pediatric Endocrinology Unit, Department of Pediatrics, Federal University of Paraná, Curitiba, Paraná, Brazil
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14
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Torii R, Velliou RI, Hodgson D, Mudera V. Modelling multi-scale cell-tissue interaction of tissue-engineered muscle constructs. J Tissue Eng 2018; 9:2041731418787141. [PMID: 30128109 PMCID: PMC6090492 DOI: 10.1177/2041731418787141] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2018] [Accepted: 06/12/2018] [Indexed: 01/21/2023] Open
Abstract
Expectation on engineered tissue substitute continues to grow, and for an effective development of a functional tissue and to control its quality, cellular mechanoresponse plays a key role. Although the mechanoresponse – in terms of cell–tissue interaction across scales – has been understood better in recent years, there are still technical limitations to quantitatively monitor the processes involved in the development of both native and engineered tissues. Computational (in silico) studies have been utilised to complement the experimental limitations and successfully applied to the prediction of tissue growth. We here review recent activities in the area of combined experimental and computational analyses of tissue growth, especially in the tissue engineering context, and highlight the advantages of such an approach for the future of the tissue engineering, using our own case study of predicting musculoskeletal tissue engineering construct development.
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Affiliation(s)
- Ryo Torii
- Department of Mechanical Engineering, University College London, London, UK
| | | | - David Hodgson
- Centre for Computation, Mathematics and Physics in the Life Sciences and Experimental Biology (COMPLEX), University College London, London, UK.,Clinical Operational Research Unit, Department of Mathematics, University College London, London, UK
| | - Vivek Mudera
- Division of Surgery and Interventional Science, University College London, London, UK
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15
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Virgilio KM, Martin KS, Peirce SM, Blemker SS. Agent-based model illustrates the role of the microenvironment in regeneration in healthy and mdx skeletal muscle. J Appl Physiol (1985) 2018; 125:1424-1439. [PMID: 30070607 DOI: 10.1152/japplphysiol.00379.2018] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease with no effective treatment. Multiple mechanisms are thought to contribute to muscle wasting, including increased susceptibility to contraction-induced damage, chronic inflammation, fibrosis, altered satellite stem cell (SSC) dynamics, and impaired regenerative capacity. The goals of this project were to 1) develop an agent-based model of skeletal muscle that predicts the dynamic regenerative response of muscle cells, fibroblasts, SSCs, and inflammatory cells as a result of contraction-induced injury, 2) calibrate and validate the model parameters based on comparisons with published experimental measurements, and 3) use the model to investigate how changing isolated and combined factors known to be associated with DMD (e.g., altered fibroblast or SSC behaviors) influence muscle regeneration. Our predictions revealed that the percent of injured muscle that recovered 28 days after injury was dependent on the peak SSC counts following injury. In simulations with near-full cross-sectional area recovery (healthy, 4-wk mdx, 3-mo mdx), the SSC counts correlated with the extent of initial injury; however, in simulations with impaired regeneration (9-mo mdx), the peak SSC counts were suppressed relative to initial injury. The differences in SSC counts between these groups were emergent predictions dependent on altered microenvironment factors known to be associated with DMD. Multiple cell types influenced the peak number of SSCs, but no individual parameter predicted the differences in SSC counts. This finding suggests that interventions to target the microenvironment rather than SSCs directly could be an effective method for improving regeneration in impaired muscle. NEW & NOTEWORTHY A computational model predicted that satellite stem cell (SSC) counts are correlated with muscle cross-sectional area (CSA) recovery following injury. In simulations with impaired CSA recovery, SSC counts are suppressed relative to healthy muscle. The suppressed SSC counts were an emergent model prediction, because all simulations had equal initial SSC counts. Fibroblast and anti-inflammatory macrophage counts influenced SSC counts, but no single factor was able to predict the pathological differences in SSC counts that lead to impaired regeneration.
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Affiliation(s)
- Kelley M Virgilio
- Department of Biomedical Engineering, University of Virginia , Charlottesville, Virginia
| | - Kyle S Martin
- Department of Biomedical Engineering, University of Virginia , Charlottesville, Virginia
| | - Shayn M Peirce
- Department of Biomedical Engineering, University of Virginia , Charlottesville, Virginia
| | - Silvia S Blemker
- Department of Biomedical Engineering, University of Virginia , Charlottesville, Virginia.,Department of Orthopaedic Surgery, University of Virginia , Charlottesville, Virginia.,Department of Mechanical and Aerospace Engineering, University of Virginia , Charlottesville, Virginia
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16
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Tang J, He A, Yan H, Jia G, Liu G, Chen X, Cai J, Tian G, Shang H, Zhao H. Damage to the myogenic differentiation of C2C12 cells by heat stress is associated with up-regulation of several selenoproteins. Sci Rep 2018; 8:10601. [PMID: 30006533 PMCID: PMC6045685 DOI: 10.1038/s41598-018-29012-6] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2017] [Accepted: 07/04/2018] [Indexed: 01/05/2023] Open
Abstract
This study was conducted to profile the selenoprotein encoding genes or proteins in mouse C2C12 cells and integrate their roles in the skeletal cell damage induced by heat stress (HS). Cells were cultured at 37.0 °C or 41.5 °C for 4, 6 or 8 days. The mRNA expression of 24 selenoprotein encoding genes and abundance of 5 selenoproteins were investigated. HS suppressed myogenic differentiation and impaired the development of muscle myotubes. HS down-regulated (P < 0.01) mRNA abundance of MYOD and MYOGENIN, and decreased (P < 0.01) MYOGENIN protein expression, HS elevated (P < 0.01) HSP70 and (P < 0.01) the ratio of BCL-2 to BAX at both mRNA and protein level. Meanwhile, HS up-regulated (P < 0.01–0.05) expressions of 18, 11 and 8 selenoprotein encoding genes after 4, 6 and 8 days of hyperthermia, and only down-regulated (P < 0.01) DIO2 after 6 and 8 days of hyperthermia, respectively. Furthermore, HS influenced expression of selenoproteins and up-regulated (P < 0.01–0.05) GPX1, GPX4 and SEPN1 after 6 days of HS. The damage to development of mouse skeletal muscle myotubes by HS accompanied with the up-regulation of both selenoprotein encoding genes and proteins, which suggested a potential protective effect of selenoprotein on hyperthermia associated damage in C2C12 cells.
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Affiliation(s)
- Jiayong Tang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China.,Trace Element Research Center, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Aihua He
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Hui Yan
- Department of Animal Sciences, Purdue University, West Lafayette, IN, 47907, USA
| | - Gang Jia
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Guangmang Liu
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Xiaoling Chen
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Jingyi Cai
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Gang Tian
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Haiying Shang
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China
| | - Hua Zhao
- Animal Nutrition Institute, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China. .,Trace Element Research Center, Sichuan Agricultural University, Chengdu, Sichuan, 611130, China.
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17
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Peviani SM, Guzzoni V, Pinheiro-Dardis CM, Silva YPD, Fioravante ACR, Sagawa AH, Delfino GB, Durigan JLQ, Salvini TF. Regulation of extracellular matrix elements and sarcomerogenesis in response to different periods of passive stretching in the soleus muscle of rats. Sci Rep 2018; 8:9010. [PMID: 29899346 PMCID: PMC5998085 DOI: 10.1038/s41598-018-27239-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2018] [Accepted: 05/21/2018] [Indexed: 01/02/2023] Open
Abstract
Stretching is a common method used to prevent muscle shortening and improve limited mobility. However, the effect of different time periods on stretching-induced adaptation of the extracellular matrix and its regulatory elements have yet to be investigated. We aimed to evaluate the expression of fibrillar collagens, sarcomerogenesis, metalloproteinase (MMP) activity and gene expression of the extracellular matrix (ECM) regulators in the soleus (SOL) muscle of rats submitted to different stretching periods. The soleus muscles were submitted to 10 sets of passive stretching over 10 (St 10d) or 15 days (St 15d) (1 min per set, with 30 seconds' rest between sets). Sarcomerogenesis, muscle cross-sectional area (CSA), and MMP activity and mRNA levels in collagen (type I, III and IV), connective tissue growth factor (CTGF), growth factor-beta (TGF-β), and lysyl oxidase (LOX) were analyzed. Passive stretching over both time periods mitigated COL-I deposition in the SOL muscle of rats. Paradoxically, 10 days of passive stretching induced COL-I and COL-III synthesis, with concomitant upregulation of TGF-β1 and CTGF at a transcriptional level. These responses may be associated with lower LOX mRNA levels in SOL muscles submitted to 10 passive stretching sessions. Moreover, sarcomerogenesis was observed after 15 days of stretching, suggesting that stretching-induced muscle adaptations are time-dependent responses.
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Affiliation(s)
- Sabrina M Peviani
- Department of Physical Therapy, São Carlos Federal University, São Carlos, São Paulo State, Brazil.
| | - Vinicius Guzzoni
- Postdoctoral Fellowship, University of Brasília, Brasília, Federal District, Brazil
| | - Clara M Pinheiro-Dardis
- Department of Physical Therapy, São Carlos Federal University, São Carlos, São Paulo State, Brazil
| | - Yara P da Silva
- Department of Physical Therapy, São Carlos Federal University, São Carlos, São Paulo State, Brazil
| | - Alisson C R Fioravante
- Department of Physical Therapy, São Carlos Federal University, São Carlos, São Paulo State, Brazil
| | - Adriana H Sagawa
- Department of Physical Therapy, São Carlos Federal University, São Carlos, São Paulo State, Brazil
| | - Gabriel B Delfino
- Department of Physical Therapy, São Carlos Federal University, São Carlos, São Paulo State, Brazil
| | - João L Q Durigan
- Graduate Program in Rehabilitation Sciences, University of Brasilia, Brasília, Federal District, Brazil
| | - Tania F Salvini
- Department of Physical Therapy, São Carlos Federal University, São Carlos, São Paulo State, Brazil
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18
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Mersmann F, Bohm S, Arampatzis A. Imbalances in the Development of Muscle and Tendon as Risk Factor for Tendinopathies in Youth Athletes: A Review of Current Evidence and Concepts of Prevention. Front Physiol 2017; 8:987. [PMID: 29249987 PMCID: PMC5717808 DOI: 10.3389/fphys.2017.00987] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2017] [Accepted: 11/17/2017] [Indexed: 01/09/2023] Open
Abstract
Tendons feature the crucial role to transmit the forces exerted by the muscles to the skeleton. Thus, an increase of the force generating capacity of a muscle needs to go in line with a corresponding modulation of the mechanical properties of the associated tendon to avoid potential harm to the integrity of the tendinous tissue. However, as summarized in the present narrative review, muscle and tendon differ with regard to both the time course of adaptation to mechanical loading as well as the responsiveness to certain types of mechanical stimulation. Plyometric loading, for example, seems to be a more potent stimulus for muscle compared to tendon adaptation. In growing athletes, the increased levels of circulating sex hormones might additionally augment an imbalanced development of muscle strength and tendon mechanical properties, which could potentially relate to the increasing incidence of tendon overload injuries that has been indicated for adolescence. In fact, increased tendon stress and strain due to a non-uniform musculotendinous development has been observed recently in adolescent volleyball athletes, a high-risk group for tendinopathy. These findings highlight the importance to deepen the current understanding of the interaction of loading and maturation and demonstrate the need for the development of preventive strategies. Therefore, this review concludes with an evidence-based concept for a specific loading program for increasing tendon stiffness, which could be implemented in the training regimen of young athletes at risk for tendinopathy. This program incorporates five sets of four contractions with an intensity of 85–90% of the isometric voluntary maximum and a movement/contraction duration that provides 3 s of high magnitude tendon strain.
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Affiliation(s)
- Falk Mersmann
- Department of Training and Movement Sciences, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin School of Movement Science, Berlin, Germany
| | - Sebastian Bohm
- Department of Training and Movement Sciences, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin School of Movement Science, Berlin, Germany
| | - Adamantios Arampatzis
- Department of Training and Movement Sciences, Humboldt-Universität zu Berlin, Berlin, Germany.,Berlin School of Movement Science, Berlin, Germany
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19
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Martin KS, Virgilio KM, Peirce SM, Blemker SS. Computational Modeling of Muscle Regeneration and Adaptation to Advance Muscle Tissue Regeneration Strategies. Cells Tissues Organs 2016; 202:250-266. [DOI: 10.1159/000443635] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/22/2015] [Indexed: 11/19/2022] Open
Abstract
Skeletal muscle has an exceptional ability to regenerate and adapt following injury. Tissue engineering approaches (e.g. cell therapy, scaffolds, and pharmaceutics) aimed at enhancing or promoting muscle regeneration from severe injuries are a promising and active field of research. Computational models are beginning to advance the field by providing insight into regeneration mechanisms and therapies. In this paper, we summarize the contributions computational models have made to understanding muscle remodeling and the functional implications thereof. Next, we describe a new agent-based computational model of skeletal muscle inflammation and regeneration following acute muscle injury. Our computational model simulates the recruitment and cellular behaviors of key inflammatory cells (e.g. neutrophils and M1 and M2 macrophages) and their interactions with native muscle cells (muscle fibers, satellite stem cells, and fibroblasts) that result in the clearance of necrotic tissue and muscle fiber regeneration. We demonstrate the ability of the model to track key regeneration metrics during both unencumbered regeneration and in the case of impaired macrophage function. We also use the model to simulate regeneration enhancement when muscle is primed with inflammatory cells prior to injury, which is a putative therapeutic intervention that has not yet been investigated experimentally. Computational modeling of muscle regeneration, pursued in combination with experimental analyses, provides a quantitative framework for evaluating and predicting muscle regeneration and enables the rational design of therapeutic strategies for muscle recovery.
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20
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Sakuma Y, Miyagi M, Inoue G, Ishikawa T, Kamoda H, Yamauchi K, Orita S, Suzuki M, Oikawa Y, Inage K, Kubota G, Sainoh T, Sato J, Takahashi K, Ohtori S. Muscle injury in rats induces upregulation of inflammatory cytokines in injured muscle and calcitonin gene-related peptide in dorsal root ganglia innervating the injured muscle. Muscle Nerve 2016; 54:776-82. [PMID: 26930007 PMCID: PMC5113796 DOI: 10.1002/mus.25092] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2015] [Revised: 02/18/2016] [Accepted: 02/24/2016] [Indexed: 01/26/2023]
Abstract
Introduction: In this study we evaluated the relationships among the behavioral changes after muscle injury, histological changes, changes in inflammatory cytokines in the injured muscle, and changes in the sensory nervous system innervating the muscle in rats. Methods: We established a model of muscle injury in rats using a dropped weight. Behavior was assessed using the CatWalk system. Subsequently, bilateral gastrocnemius muscles and dorsal root ganglia (DRGs) were resected. Muscles were stained with hematoxylin and eosin, and inflammatory cytokines in injured muscles were assayed. DRGs were immunostained for calcitonin gene–related peptide (CGRP). Results: Changes of behavior and upregulation of inflammatory cytokines in injured muscles subsided within 2 days of injury. Repaired tissue was observed 3 weeks after injury. However, upregulation of CGRP in DRG neurons continued for 2 weeks after injury. Conclusion: These findings may explain in part the pathological mechanism of persistent muscle pain. Muscle Nerve54: 776–782, 2016
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Affiliation(s)
- Yoshihiro Sakuma
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan.
| | - Masayuki Miyagi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Gen Inoue
- Department of Orthopaedic Surgery, Kitasato University, School of Medicine, Sagamihara, Japan
| | - Tetsuhiro Ishikawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Hiroto Kamoda
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Kazuyo Yamauchi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Sumihisa Orita
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Miyako Suzuki
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Yasuhiro Oikawa
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Kazuhide Inage
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Go Kubota
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Takeshi Sainoh
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Jun Sato
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Kazuhisa Takahashi
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
| | - Seiji Ohtori
- Department of Orthopaedic Surgery, Graduate School of Medicine, Chiba University, 1-8-1 Inohana, Chuo-ku, Chiba, 260-8670, Japan
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21
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Dumont NA, Bentzinger CF, Sincennes MC, Rudnicki MA. Satellite Cells and Skeletal Muscle Regeneration. Compr Physiol 2016; 5:1027-59. [PMID: 26140708 DOI: 10.1002/cphy.c140068] [Citation(s) in RCA: 492] [Impact Index Per Article: 54.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Skeletal muscles are essential for vital functions such as movement, postural support, breathing, and thermogenesis. Muscle tissue is largely composed of long, postmitotic multinucleated fibers. The life-long maintenance of muscle tissue is mediated by satellite cells, lying in close proximity to the muscle fibers. Muscle satellite cells are a heterogeneous population with a small subset of muscle stem cells, termed satellite stem cells. Under homeostatic conditions all satellite cells are poised for activation by stimuli such as physical trauma or growth signals. After activation, satellite stem cells undergo symmetric divisions to expand their number or asymmetric divisions to give rise to cohorts of committed satellite cells and thus progenitors. Myogenic progenitors proliferate, and eventually differentiate through fusion with each other or to damaged fibers to reconstitute fiber integrity and function. In the recent years, research has begun to unravel the intrinsic and extrinsic mechanisms controlling satellite cell behavior. Nonetheless, an understanding of the complex cellular and molecular interactions of satellite cells with their dynamic microenvironment remains a major challenge, especially in pathological conditions. The goal of this review is to comprehensively summarize the current knowledge on satellite cell characteristics, functions, and behavior in muscle regeneration and in pathological conditions.
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Affiliation(s)
- Nicolas A Dumont
- Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - C Florian Bentzinger
- Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Nestlé Institute of Health Sciences, EPFL Campus, Lausanne, Switzerland
| | - Marie-Claude Sincennes
- Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Michael A Rudnicki
- Sprott Centre for Stem Cell Research, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Faculty of Medicine, Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
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22
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Goodman CA, Hornberger TA, Robling AG. Bone and skeletal muscle: Key players in mechanotransduction and potential overlapping mechanisms. Bone 2015; 80:24-36. [PMID: 26453495 PMCID: PMC4600534 DOI: 10.1016/j.bone.2015.04.014] [Citation(s) in RCA: 107] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/11/2014] [Revised: 03/18/2015] [Accepted: 04/07/2015] [Indexed: 12/16/2022]
Abstract
The development and maintenance of skeletal muscle and bone mass is critical for movement, health and issues associated with the quality of life. Skeletal muscle and bone mass are regulated by a variety of factors that include changes in mechanical loading. Moreover, bone mass is, in large part, regulated by muscle-derived mechanical forces and thus by changes in muscle mass/strength. A thorough understanding of the cellular mechanism(s) responsible for mechanotransduction in bone and skeletal muscle is essential for the development of effective exercise and pharmaceutical strategies aimed at increasing, and/or preventing the loss of, mass in these tissues. Thus, in this review we will attempt to summarize the current evidence for the major molecular mechanisms involved in mechanotransduction in skeletal muscle and bone. By examining the differences and similarities in mechanotransduction between these two tissues, it is hoped that this review will stimulate new insights and ideas for future research and promote collaboration between bone and muscle biologists.(1).
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Affiliation(s)
- Craig A Goodman
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA; Centre for Chronic Disease Prevention and Management, College of Health and Biomedicine, Victoria University, Melbourne, Australia; Institute of Sport, Exercise and Active Living (ISEAL), Victoria University, Melbourne, VIC, Australia.
| | - Troy A Hornberger
- Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, WI 53706, USA
| | - Alexander G Robling
- Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Roudebush Veterans Affairs Medical Center, Indianapolis, IN 46202, USA; Department of Biomedical Engineering, Indiana University-Purdue University at Indianapolis, Indianapolis, IN 46202, USA
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23
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Martin KS, Blemker SS, Peirce SM. Agent-based computational model investigates muscle-specific responses to disuse-induced atrophy. J Appl Physiol (1985) 2015; 118:1299-309. [PMID: 25722379 DOI: 10.1152/japplphysiol.01150.2014] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Accepted: 02/20/2015] [Indexed: 01/27/2023] Open
Abstract
Skeletal muscle is highly responsive to use. In particular, muscle atrophy attributable to decreased activity is a common problem among the elderly and injured/immobile. However, each muscle does not respond the same way. We developed an agent-based model that generates a tissue-level skeletal muscle response to disuse/immobilization. The model incorporates tissue-specific muscle fiber architecture parameters and simulates changes in muscle fiber size as a result of disuse-induced atrophy that are consistent with published experiments. We created simulations of 49 forelimb and hindlimb muscles of the rat by incorporating eight fiber-type and size parameters to explore how these parameters, which vary widely across muscles, influence sensitivity to disuse-induced atrophy. Of the 49 muscles modeled, the soleus exhibited the greatest atrophy after 14 days of simulated immobilization (51% decrease in fiber size), whereas the extensor digitorum communis atrophied the least (32%). Analysis of these simulations revealed that both fiber-type distribution and fiber-size distribution influence the sensitivity to disuse atrophy even though no single tissue architecture parameter correlated with atrophy rate. Additionally, software agents representing fibroblasts were incorporated into the model to investigate cellular interactions during atrophy. Sensitivity analyses revealed that fibroblast agents have the potential to affect disuse-induced atrophy, albeit with a lesser effect than fiber type and size. In particular, muscle atrophy elevated slightly with increased initial fibroblast population and increased production of TNF-α. Overall, the agent-based model provides a novel framework for investigating both tissue adaptations and cellular interactions in skeletal muscle during atrophy.
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Affiliation(s)
- Kyle S Martin
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia
| | - Silvia S Blemker
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia; Department of Mechanical and Aerospace Engineering, University of Virginia, Charlottesville, Virginia; Department of Orthopaedic Surgery, University of Virginia, Charlottesville, Virginia;
| | - Shayn M Peirce
- Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia; Department of Ophthalmology, University of Virginia, Charlottesville, Virginia; Department of Plastic Surgery, University of Virginia, Charlottesville, Virginia
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Trensz F, Lucien F, Couture V, Söllrald T, Drouin G, Rouleau AJ, Grandbois M, Lacraz G, Grenier G. Increased microenvironment stiffness in damaged myofibers promotes myogenic progenitor cell proliferation. Skelet Muscle 2015; 5:5. [PMID: 25729564 PMCID: PMC4343274 DOI: 10.1186/s13395-015-0030-1] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2014] [Accepted: 01/19/2015] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND The stiffness of the myogenic stem cell microenvironment markedly influences the ability to regenerate tissue. We studied the effect of damaged myofibers on myogenic progenitor cell (MPC) proliferation and determined whether the structural integrity of the microenvironment contributes to phenotypic changes. METHODS Individual myofibers were isolated and cultured for 6 days. During this period, the cytoskeleton of myofibers and transcription factors regulating MPC differentiation were characterized by immunostaining. Atomic Force Microscopy (AFM) was performed to measure stiffness of cultured myofibers. Healthy and damaged myofibers, and their associated MPCs, were studied in skeletal muscle from dystrophic and tenotomy mouse models. MPCs were cultured on stiffness-tunable substrates, and their phenotypes were assessed by immunostaining of myogenic transcription factors. RESULTS We showed that individual myofibers tend to shrink or collapse when cultured ex vivo starting from day 1 and that this is associated with a marked increase in the number of proliferative MPCs (Pax7(+)MyoD(+)). The myofibers collapsed due to a loss of viability as shown by Evans blue dye uptake and the disorganization of their cytoskeletons. Interestingly, collapsed myofibers in mdx skeletal muscles were similar to damaged myofibers in that they lose their viability, have a disorganized cytoskeleton (actin and α-actinin), and display local MPC (MyoD(+)) proliferation at their periphery. In a tenotomy model that causes loss of muscle tension, the cytoskeletal disorganization of myofibers also correlated with the activation/proliferation of MPCs. A deeper analysis of collapsed myofibers revealed that they produce trophic factors that influence MPC proliferation. In addition, collapsed myofibers expressed several genes related to the basal lamina. Immunostaining revealed the presence of fibronectin in the basal lamina and the cytoplasm of damaged myofibers. Lastly, using atomic force microscopy (AFM), we showed that collapsed myofibers exhibit greater stiffness than intact myofibers. Growing MPCs on a 2-kPa polyacrylamide-based substrate, exempt of additional microenvironmental cues, recapitulated proliferation and reduced spontaneous differentiation compared to growth on a 0.5-kPa substrate. CONCLUSIONS Our results support the notion that collapsed or damaged myofibers increase the structural stiffness of the satellite cell microenvironment, which in addition to other cues such as trophic factors and changes in extracellular matrix composition, promotes the proliferation and maintenance of MPCs, required for myofiber repair.
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Affiliation(s)
- Frédéric Trensz
- Research Centre of the Centre Hospitalier de l'Université de Sherbrooke (CRCHUS), Université de Sherbrooke, Sherbrooke, QC Canada
| | - Fabrice Lucien
- Research Centre of the Centre Hospitalier de l'Université de Sherbrooke (CRCHUS), Université de Sherbrooke, Sherbrooke, QC Canada
| | - Vanessa Couture
- Research Centre of the Centre Hospitalier de l'Université de Sherbrooke (CRCHUS), Université de Sherbrooke, Sherbrooke, QC Canada
| | - Thomas Söllrald
- Department of Electrical and Computer Engineering, Faculty of Engineering, Université de Sherbrooke, Sherbrooke, QC Canada
| | - Geneviève Drouin
- Research Centre of the Centre Hospitalier de l'Université de Sherbrooke (CRCHUS), Université de Sherbrooke, Sherbrooke, QC Canada
| | - André-Jean Rouleau
- Research Centre of the Centre Hospitalier de l'Université de Sherbrooke (CRCHUS), Université de Sherbrooke, Sherbrooke, QC Canada
| | - Michel Grandbois
- Research Centre of the Centre Hospitalier de l'Université de Sherbrooke (CRCHUS), Université de Sherbrooke, Sherbrooke, QC Canada ; Department of Pharmacology, Faculty of Medicine, Université de Sherbrooke, Sherbrooke, QC Canada
| | - Gregory Lacraz
- Research Centre of the Centre Hospitalier de l'Université de Sherbrooke (CRCHUS), Université de Sherbrooke, Sherbrooke, QC Canada ; New address: Hubrecht Institute, University Medical Center Utrecht, Utrecht, The Netherlands
| | - Guillaume Grenier
- Research Centre of the Centre Hospitalier de l'Université de Sherbrooke (CRCHUS), Université de Sherbrooke, Sherbrooke, QC Canada ; Department of Orthopedic Surgery, Faculty of Medicine, Université de Sherbrooke, 3001-12th Avenue North, Sherbrooke, J1H 5N4, QC Canada
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Gehlert S, Suhr F, Gutsche K, Willkomm L, Kern J, Jacko D, Knicker A, Schiffer T, Wackerhage H, Bloch W. High force development augments skeletal muscle signalling in resistance exercise modes equalized for time under tension. Pflugers Arch 2014; 467:1343-56. [PMID: 25070178 DOI: 10.1007/s00424-014-1579-y] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2014] [Revised: 07/03/2014] [Accepted: 07/08/2014] [Indexed: 10/25/2022]
Abstract
How force development and time under tension (TUT) during resistance exercise (RE) influence anabolic signalling of skeletal muscle is incompletely understood. We hypothesized that high force development during RE is more important for post-exercise-induced signalling than submaximal and fatiguing RE with lower force development but similar TUT. Twenty-two male subjects (24 ± 6 years, 181 ± 9 cm, 79 ± 2 kg) performed three distinct RE modes in the fed state with equal TUT but distinct force output: (i) maximal eccentric RE (ECC, n = 7) three sets, eight reps, 100% eccentric dynamic force; (ii) standard RE (STD, n = 7), three sets, 10 reps, 75% dynamic force; and (iii) high fatiguing single-set RE (HIT, n = 8), 20 reps, 100% eccentric-concentric force; vastus lateralis biopsies were collected at baseline, 15, 30, 60, 240 min and 24 h after RE, and the signalling of mechanosensitive and mammalian target of rapamycin (mTOR)-related proteins was determined. The phosphorylation levels of pFAK(Tyr397), pJNK(Thr183/Tyr185), pAKT(Thr308/Ser473), pmTOR(Ser2448), p4E-BP1(Thr37/46), p70s6k(Thr389)/(Ser421/Thr424) and pS6(Ser235/236) were significantly higher in ECC than those in STD and HIT at several time points (P < 0.01). pJNK(Thr183/Tyr185) and pS6(Ser235/236) levels were significantly higher in type II myofibres in ECC compared with STD and HIT. HIT exerted throughout the weakest signalling response. We conclude that high force development during acute RE is superior for anabolic skeletal muscle signalling than fatiguing RE with lower force output but similar TUT. Our results suggest that this response is substantially driven by the higher activation of type II myofibres during RE.
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Affiliation(s)
- Sebastian Gehlert
- Institute of Cardiology and Sports Medicine, Department of Molecular and Cellular Sport Medicine, German Sport University Cologne, Am Sportpark Müngersdorf 6, 50933, Cologne, Germany,
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Matsumoto Y, Nakano J, Oga S, Kataoka H, Honda Y, Sakamoto J, Okita M. The non-thermal effects of pulsed ultrasound irradiation on the development of disuse muscle atrophy in rat gastrocnemius muscle. ULTRASOUND IN MEDICINE & BIOLOGY 2014; 40:1578-1586. [PMID: 24613643 DOI: 10.1016/j.ultrasmedbio.2013.12.031] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/11/2013] [Revised: 12/10/2013] [Accepted: 12/31/2013] [Indexed: 06/03/2023]
Abstract
This study examined the effects of therapeutic pulsed ultrasound (US) on the development of disuse muscle atrophy in rat gastrocnemius muscle. Male Wistar rats were randomly distributed into control, immobilization (Im), sham US, and US groups. In the Im, sham US and US groups, the bilateral ankle joints of each rat were immobilized in full plantar flexion with a plaster cast for a 4-wk period. The pulsed US (frequency, 1 MHz; intensity, 1.0 W/cm(2); pulsed mode 1:4; 15 min) was irradiated to the gastrocnemius muscle in the US group over a 4-wk immobilization period. The pulsed US irradiation delivered only non-thermal effects to the muscle. In conjunction with US irradiation, 5-bromo-2'-deoxyuridine (BrdU) was injected subcutaneously to label the nuclei of proliferating satellite cells 1 h before each pulsed US irradiation. Immobilization resulted in significant decreases in the mean diameters of type I, IIA and IIB muscle fibers of the gastrocnemius muscle in the Im, sham US and US groups compared with the control group. However, the degrees of muscle fiber atrophy for all types were significantly lower in the US group compared with the Im and sham US groups. Although the number of capillaries and the concentrations of insulin-like growth factor and basic fibroblast growth factor did not change in the muscle, the number of BrdU-positive nuclei in the muscle was significantly increased by pulsed US irradiation in the US group. The results of this study suggest that pulsed US irradiation inhibits the development of disuse muscle atrophy partly via activation of satellite cells.
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Affiliation(s)
- Yoko Matsumoto
- Department of Rehabilitation, Saiseikai Nagasaki Hospital, Nagasaki, Japan
| | - Jiro Nakano
- Unit of Physical and Occupational Therapy, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan.
| | - Satoshi Oga
- Department of Rehabilitation, Saiseikai Nagasaki Hospital, Nagasaki, Japan
| | - Hideki Kataoka
- Department of Rehabilitation, Nagasaki Memorial Hospital, Nagasaki, Japan; Department of Locomotive Rehabilitation Science, Unit of Rehabilitation Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Yuichiro Honda
- Department of Locomotive Rehabilitation Science, Unit of Rehabilitation Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Junya Sakamoto
- Department of Rehabilitation, Nagasaki University Hospital, Nagasaki, Japan
| | - Minoru Okita
- Department of Locomotive Rehabilitation Science, Unit of Rehabilitation Sciences, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
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Use of flow, electrical, and mechanical stimulation to promote engineering of striated muscles. Ann Biomed Eng 2013; 42:1391-405. [PMID: 24366526 DOI: 10.1007/s10439-013-0966-4] [Citation(s) in RCA: 76] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2013] [Accepted: 12/18/2013] [Indexed: 12/12/2022]
Abstract
The field of tissue engineering involves design of high-fidelity tissue substitutes for predictive experimental assays in vitro and cell-based regenerative therapies in vivo. Design of striated muscle tissues, such as cardiac and skeletal muscle, has been particularly challenging due to a high metabolic demand and complex cellular organization and electromechanical function of the native tissues. Successful engineering of highly functional striated muscles may thus require creation of biomimetic culture conditions involving medium perfusion, electrical and mechanical stimulation. When optimized, these external cues are expected to synergistically and dynamically activate important intracellular signaling pathways leading to accelerated muscle growth and development. This review will discuss the use of different types of tissue culture bioreactors aimed at providing conditions for enhanced structural and functional maturation of engineered striated muscles.
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Goto A, Ohno Y, Ikuta A, Suzuki M, Ohira T, Egawa T, Sugiura T, Yoshioka T, Ohira Y, Goto K. Up-regulation of adiponectin expression in antigravitational soleus muscle in response to unloading followed by reloading, and functional overloading in mice. PLoS One 2013; 8:e81929. [PMID: 24324732 PMCID: PMC3855747 DOI: 10.1371/journal.pone.0081929] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2013] [Accepted: 10/28/2013] [Indexed: 12/28/2022] Open
Abstract
The purpose of this study was to investigate the expression level of adiponectin and its related molecules in hypertrophied and atrophied skeletal muscle in mice. The expression was also evaluated in C2C12 myoblasts and myotubes. Both mRNA and protein expression of adiponectin, mRNA expression of adiponectin receptor (AdipoR) 1 and AdipoR2, and protein expression of adaptor protein containing pleckstrin homology domain, phosphotyrosine binding domain, and leucine zipper motif 1 (APPL1) were observed in C2C12 myoblasts. The expression levels of these molecules in myotubes were higher than those in myoblasts. The expression of adiponectin-related molecules in soleus muscle was observed at mRNA (adiponectin, AdipoR1, AdipoR2) and protein (adiponectin, APPL1) levels. The protein expression levels of adiponectin and APPL1 were up-regulated by 3 weeks of functional overloading. Down-regulation of AdipoR1 mRNA, but not AdipoR2 mRNA, was observed in atrophied soleus muscle. The expression of adiponectin protein, AdipoR1 mRNA, and APPL1 protein was up-regulated during regrowth of unloading-associated atrophied soleus muscle. Mechanical loading, which could increase skeletal muscle mass, might be a useful stimulus for the up-regulations of adiponectin and its related molecules in skeletal muscle.
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Affiliation(s)
- Ayumi Goto
- Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University, Aichi, Japan
| | - Yoshitaka Ohno
- Laboratory of Physiology, School of Health Sciences, Toyohashi SOZO University, Aichi, Japan
| | - Akihiro Ikuta
- Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University, Aichi, Japan
| | - Miho Suzuki
- Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University, Aichi, Japan
| | - Tomotaka Ohira
- Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University, Aichi, Japan
| | - Tatsuro Egawa
- Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University, Aichi, Japan
- Research Fellow of the Japan Society for the Promotion of Science, Tokyo, Japan
| | - Takao Sugiura
- Department of Exercise and Health Sciences, Yamaguchi University, Yamaguchi, Japan
| | | | | | - Katsumasa Goto
- Department of Physiology, Graduate School of Health Sciences, Toyohashi SOZO University, Aichi, Japan
- Laboratory of Physiology, School of Health Sciences, Toyohashi SOZO University, Aichi, Japan
- * E-mail:
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Park JH, Ushida T, Akimoto T. Control of cell differentiation by mechanical stress. JOURNAL OF PHYSICAL FITNESS AND SPORTS MEDICINE 2013. [DOI: 10.7600/jpfsm.2.49] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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The role of mTORC1 in regulating protein synthesis and skeletal muscle mass in response to various mechanical stimuli. Rev Physiol Biochem Pharmacol 2013; 166:43-95. [PMID: 24442322 DOI: 10.1007/112_2013_17] [Citation(s) in RCA: 95] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Skeletal muscle plays a fundamental role in mobility, disease prevention, and quality of life. Skeletal muscle mass is, in part, determined by the rates of protein synthesis, and mechanical loading is a major regulator of protein synthesis and skeletal muscle mass. The mammalian/mechanistic target of rapamycin (mTOR), found in the multi-protein complex, mTORC1, is proposed to play an essential role in the regulation of protein synthesis and skeletal muscle mass. The purpose of this review is to examine the function of mTORC1 in relation to protein synthesis and cell growth, the current evidence from rodent and human studies for the activation of mTORC1 signaling by different types of mechanical stimuli, whether mTORC1 signaling is necessary for changes in protein synthesis and skeletal muscle mass that occur in response to different types of mechanical stimuli, and the proposed molecular signaling mechanisms that may be responsible for the mechanical activation of mTORC1 signaling.
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32
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Gerber C, Meyer DC, Von Rechenberg B, Hoppeler H, Frigg R, Farshad M. Rotator cuff muscles lose responsiveness to anabolic steroids after tendon tear and musculotendinous retraction: an experimental study in sheep. Am J Sports Med 2012; 40:2454-61. [PMID: 23024152 DOI: 10.1177/0363546512460646] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/31/2023]
Abstract
BACKGROUND Long-standing rotator cuff tendon tearing is associated with retraction, loss of work capacity, irreversible fatty infiltration, and atrophy of the rotator cuff muscles. Although continuous musculotendinous relengthening can experimentally restore muscular architecture, restoration of atrophy and fatty infiltration is hitherto impossible. HYPOTHESIS Continuous relengthening with pharmacological stimulation of muscle growth using an anabolic steroid or insulin-like growth factor (IGF) can reverse atrophy and fatty infiltration as well as improve the work capacity of chronically retracted rotator cuff muscles in sheep. STUDY DESIGN Controlled laboratory study. METHODS Sixteen weeks after tenotomy of the infraspinatus (ISP) tendon, atrophy and fatty infiltration had developed in the retracted ISP muscle. The musculotendinous unit was continuously relengthened in 14 sheep during 6 weeks: Four sheep were treated without pharmacological stimulation, 4 with intramuscular administration of an anabolic steroid, and 6 with IGF before final repair and rehabilitation (12 weeks). Changes were documented by intraoperative measurements of muscle work capacity, histology, and computed tomography/magnetic resonance imaging. RESULTS Musculotendinous relengthening by continuous traction resulted in gains of length ranging from 0.7 cm in the IGF group to 1.3 cm in the control group. Fatty infiltration progressed in all groups, and the muscle's cross-sectional area ranged from 71% to 74% of the contralateral side at sacrifice and did not show any differences between groups in weight, volume, histological composition, or work capability of the muscle. The contralateral muscles in the anabolic steroid group, however, showed significantly higher (mean ± standard deviation) muscle work capacity of 10 ± 0.9 N·m than the contralateral muscles of the control group (6.8 ± 2.4 N·m) (P < .05). This was accompanied by an increased mean muscle fiber area as well as by an unusual gain in the animals' weight after injection of the anabolic steroid. CONCLUSION Subcutaneous continuous relengthening of a chronically retracted musculotendinous unit is feasible and advances the retracted musculotendinous junction toward its original position. This does not change the muscle work capacity. Whereas anabolic steroids have been shown to be effective in preventing classic degenerative muscle changes after tendon tears, neither an anabolic steroid nor IGF contributes to regeneration of the muscle once degenerative changes are established. CLINICAL RELEVANCE The findings demonstrate that muscle cells lose reactiveness to an anabolic steroid and IGF once retraction has led to fatty infiltration and atrophy of the muscle. Retraction of the muscle after tendon tears must be avoided by early repair, particularly in an athlete, as no regeneration can be achieved by mechanical or pharmacological means at this time.
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Schachter TN, Shen T, Liu Y, Schneider MF. Kinetics of nuclear-cytoplasmic translocation of Foxo1 and Foxo3A in adult skeletal muscle fibers. Am J Physiol Cell Physiol 2012; 303:C977-90. [PMID: 22932683 DOI: 10.1152/ajpcell.00027.2012] [Citation(s) in RCA: 32] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
In skeletal muscle, the transcription factors Foxo1 and Foxo3A control expression of proteins that mediate muscle atrophy, making the nuclear concentration and nuclear-cytoplasmic movements of Foxo1 and Foxo3A of therapeutic interest in conditions of muscle wasting. Here, we use Foxo-GFP fusion proteins adenovirally expressed in cultured adult mouse skeletal muscle fibers to characterize the time course of nuclear efflux of Foxo1-GFP in response to activation of the insulin-like growth factor-1 (IGF-1)/phosphatidylinositol-3-kinase (PI3K)/Akt pathway to determine the time course of nuclear influx of Foxo1-GFP during inhibition of this pathway and to show that Akt mediates the efflux of nuclear Foxo1-GFP induced by IGF-1. Localization of endogenous Foxo1 in muscle fibers, as determined via immunocytochemistry, is consistent with that of Foxo1-GFP. Inhibition of the nuclear export carrier chromosome region maintenance 1 by leptomycin B (LMB) traps Foxo1 in the nucleus and results in a relatively rapid rate of Foxo1 nuclear accumulation, consistent with a high rate of nuclear-cytoplasmic shuttling of Foxo1 under control conditions before LMB application, with near balance of unidirectional influx and efflux. Expressed Foxo3A-GFP shuttles ∼20-fold more slowly than Foxo1-GFP. Our approach allows quantitative kinetic characterization of Foxo1 and Foxo3A nuclear-cytoplasmic movements in living muscle fibers under various experimental conditions.
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Affiliation(s)
- Tova Neustadt Schachter
- Dept. of Biochemistry and Molecular Biology, Univ. of Maryland School of Medicine, 108 North Greene St., Baltimore MD 21201-1503, USA.
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DO MKQ, Suzuki T, Gerelt B, Sato Y, Mizunoya W, Nakamura M, Ikeuchi Y, Anderson JE, Tatsumi R. Time-coordinated prevalence of extracellular HGF, FGF2 and TGF-β3 in crush-injured skeletal muscle. Anim Sci J 2012; 83:712-7. [PMID: 23035711 DOI: 10.1111/j.1740-0929.2012.01057.x] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2012] [Accepted: 06/12/2012] [Indexed: 12/22/2022]
Abstract
Successful regeneration and remodeling of neuromuscular junctions are critical for restoring functional capacities and properties of skeletal muscle after damage, and axon-guidance molecules may be involved in the signaling that regulates such restoration. Recently, we found that early-differentiated satellite cells up-regulate a secreted neural chemorepellent Sema3A upon in vivo muscle-crush injury. The study also revealed that Sema3A expression is up-regulated in primary satellite-cell cultures in response to hepatocyte growth factor (HGF) and basic fibroblast growth factor (FGF2) and is prevented by transforming growth factor (TGF)-β2, 3. In order to verify the physiological significance of this regulation in vitro, the present study was designed to estimate the time-course of extracellular HGF, FGF2 and TGF-β3 concentrations after crush-injury of Gastrocnemius muscle in the rat lower hind-limb, using a combination of a non-homogenization/non-spin extraction of extracellular wound fluids and enhanced chemiluminescence-Western blotting analyses. Results clearly demonstrated that active HGF and FGF2 are prevalent in 2-8 days post-crush, whereas active TGF-β3 increases after 12 days, providing a better understanding of the time-coordinated levels of HGF, FGF2 and TGF-β3 that drive regulation of Sema3A expression during regenerative intramuscular moto-neuritogenesis.
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Affiliation(s)
- Mai-Khoi Q DO
- Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture
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Wernbom M, Paulsen G, Nilsen TS, Hisdal J, Raastad T. Sarcolemmal permeability and muscle damage as hypertrophic stimuli in blood flow restricted resistance exercise (Reply to Loenneke and Abe). Eur J Appl Physiol 2012. [DOI: 10.1007/s00421-012-2309-9] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Abstract
Multiple cellular and molecular processes are rapidly activated following skeletal muscle damage to restore normal muscle structure and function. These processes typically involve an inflammatory response and potentially the consequent occurrence of secondary damage before their resolution and the completion of muscle repair or regeneration. The overall outcome of the inflammatory process is potentially divergent, with the induction of prolonged inflammation and further muscle damage, or its active termination and the promotion of muscle repair and regeneration. The final, detrimental, or beneficial effect of the inflammatory response on muscle repair is influenced by specific interactions between inflammatory and muscle cell-derived cytokines that act as positive and/or negative regulators to coordinate local and systemic inflammatory-related events and modulate muscle repair process. A crucial balance between proinflammatory and anti-inflammatory cytokines appears to attenuate an excessive inflammatory reaction, prevent the development of muscle fibrosis, and adequately promote the regenerative process. In this review, we address the interactive cytokine responses following muscle damage, in the context of induction and progression, or resolution of muscle inflammation and the promotion of muscle repair.
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Do MKQ, Sato Y, Shimizu N, Suzuki T, Shono JI, Mizunoya W, Nakamura M, Ikeuchi Y, Anderson JE, Tatsumi R. Growth factor regulation of neural chemorepellent Sema3A expression in satellite cell cultures. Am J Physiol Cell Physiol 2011; 301:C1270-9. [DOI: 10.1152/ajpcell.00257.2011] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Successful regeneration and remodeling of the intramuscular motoneuron network and neuromuscular connections are critical for restoring skeletal muscle function and physiological properties. The regulatory signals of such coordination remain unclear, although axon-guidance molecules may be involved. Recently, satellite cells, resident myogenic stem cells positioned beneath the basal lamina and at high density at the myoneural junction regions of mature fibers, were shown to upregulate a secreted neural chemorepellent semaphorin 3A (Sema3A) in response to in vivo muscle-crush injury. The initial report on that expression centered on the observation that hepatocyte growth factor (HGF), an essential cue in muscle fiber growth and regeneration, remarkably upregulates Sema3A expression in early differentiated satellite cells in vitro [Tatsumi et al., Am J Physiol Cell Physiol 297: C238–C252, 2009]. Here, we address regulatory effects of basic fibroblast growth factor (FGF2) and transforming growth factor (TGF)-βs on Sema3A expression in satellite cell cultures. When treated with FGF2, Sema3A message and protein were upregulated as revealed by reverse transcription-polymerase chain reaction and immunochemical studies. Sema3A upregulation by FGF2 was dose dependent with a maximum (8- to 1-fold relative to the control) at 2.5 ng/ml (150 pM) and occurred exclusively at the early differentiation stage. The response was highly comparable in dose response and timing to effects of HGF treatment, without any additive or synergistic effect from treatment with a combination of both potent upregulators. In contrast, TGF-β2 and -β3 potently decreased basal Sema3A expression; the maximum effect was at very low concentrations (40 and 8 pM, respectively) and completely cancelled the activities of FGF2 and HGF to upregulate Sema3A. These results therefore encourage the prospect that a time-coordinated increase in HGF, FGF2, and TGF-β ligands and their receptors promotes a programmed strategy for Sema3A expression that guarantees successful intramuscular motor reinnervation by delaying sprouting and reattachment of motoneuron terminals onto damaged muscle fibers early in regeneration pending restoration of muscle fiber contractile integrity.
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Affiliation(s)
- Mai-Khoi Q. Do
- Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture,
| | - Yusuke Sato
- Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture,
| | - Naomi Shimizu
- Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture,
| | - Takahiro Suzuki
- Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture,
| | - Jun-ichi Shono
- Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture,
| | - Wataru Mizunoya
- Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture,
| | - Mako Nakamura
- Faculty of Agriculture, Kyushu University, Fukuoka, Japan; and
| | - Yoshihide Ikeuchi
- Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture,
| | - Judy E. Anderson
- Department of Biological Sciences, Faculty of Science, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Ryuichi Tatsumi
- Department of Animal and Marine Bioresource Sciences, Graduate School of Agriculture,
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Watabe H, Furuhama T, Tani-Ishii N, Mikuni-Takagaki Y. Mechanotransduction activates α₅β₁ integrin and PI3K/Akt signaling pathways in mandibular osteoblasts. Exp Cell Res 2011; 317:2642-9. [PMID: 21824471 DOI: 10.1016/j.yexcr.2011.07.015] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Revised: 07/14/2011] [Accepted: 07/16/2011] [Indexed: 10/17/2022]
Abstract
It is unclear how bone cells at different sites detect mechanical loading and how site-specific mechanotransduction affects bone homeostasis. To differentiate the anabolic mechanical responses of mandibular cells from those of calvarial and long bone cells, we isolated osteoblasts from C57B6J mouse bones, cultured them for 1week, and subjected them to therapeutic low intensity pulsed ultrasound (LIPUS). While the expression of the marker proteins of osteoblasts and osteocytes such as alkaline phosphatase and FGF23, as well as Wnt1 and β-catenin, was equally upregulated, the expression of mandibular osteoblast messages related to bone remodeling and apoptosis differed from that of messages of other osteoblasts, in that the messages encoding the pro-remodeling protein RANKL and the anti-apoptotic protein Bcl-2 were markedly upregulated from the very low baseline levels. Blockage of the PI3K and α(5)β(1) integrin pathways showed that the mandibular osteoblast required mechanotransduction downstream of α(5)β(1) integrin to upregulate expression of the proteins β-catenin, p-Akt, Bcl-2, and RANKL. Mandibular osteoblasts thus must be mechanically loaded to preserve their capability to promote remodeling and to insure osteoblast survival, both of which maintain intact mandibular bone tissue. In contrast, calvarial Bcl-2 is fully expressed, together with ILK and phosphorylated mTOR, in the absence of LIPUS. The antibody blocking α(5)β(1) integrin suppressed both the baseline expression of all calvarial proteins examined and the LIPUS-induced expression of all mandibular proteins examined. These findings indicate that the cellular environment, in addition to the tridermic origin, determines site-specific bone homeostasis through the remodeling and survival of osteoblastic cells. Differentiated cells of the osteoblastic lineage at different sites transmit signals through transmembrane integrins such as α(5)β(1) integrin in mandibular osteoblasts, whose signaling may play a major role in controlling bone homeostasis.
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Affiliation(s)
- H Watabe
- Department of Oral Medicine, Kanagawa Dental College, Japan
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Saygili E, Pekassa M, Saygili E, Rackauskas G, Hommes D, Noor-Ebad F, Gemein C, Zink MDH, Schwinger RHG, Weis J, Marx N, Schauerte P, Rana OR. Mechanical stretch of sympathetic neurons induces VEGF expression via a NGF and CNTF signaling pathway. Biochem Biophys Res Commun 2011; 410:62-7. [PMID: 21640078 DOI: 10.1016/j.bbrc.2011.05.105] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 05/17/2011] [Indexed: 10/18/2022]
Abstract
Mechanical stretch has been shown to increase vascular endothelial growth factor (VEGF) expression in cultured myocytes. Sympathetic neurons (SN) also possess the ability to express and secrete VEGF, which is mediated by the NGF/TrkA signaling pathway. Recently, we demonstrated that SN respond to stretch with an upregulation of nerve growth factor (NGF) and ciliary neurotrophic factor (CNTF). Whether stretch increases neuronal VEGF expression still remains to be clarified. Therefore, SN from the superior cervical ganglia of neonatal Sprangue Dawley rats were exposed to a gradual increase of stretch from 3% up to 13% within 3days (3%, 7% and 13%). Under these conditions, the expression and secretion of VEGF was analyzed. Mechanical stretch significantly increased VEGF mRNA and protein expression (mRNA: control=1 vs. stretch=3.1; n=3/protein: control=1 vs. stretch=2.7; n=3). ELISA experiments to asses VEGF content in the cell culture supernatant showed a time and dose dependency in VEGF increment due to stretch. NGF and CNTF neutralization decreased stretch-induced VEGF augmentation in a significant manner. This response was mediated in part by TrkA receptor activation. The stretch-induced VEGF upregulation was accompanied by an increase in HIF-1α expression. KDR levels remained unchanged under conditions of stretch, but showed a significant increase due to NGF neutralization. In summary, SN respond to stretch with an upregulation of VEGF, which is mediated by the NGF/CNTF and TrkA signaling pathway paralleled by HIF-1α expression. NGF signaling seems to play an important role in regulating neuronal KDR expression.
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Affiliation(s)
- Erol Saygili
- Department of Cardiology, University RWTH Aachen, Aachen, Germany.
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Mohamad NI, Nosaka K, Cronin J. Maximizing Hypertrophy: Possible Contribution of Stretching in the Interset Rest Period. Strength Cond J 2011. [DOI: 10.1519/ssc.0b013e3181fe7164] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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Tatsumi R. Mechano-biology of skeletal muscle hypertrophy and regeneration: possible mechanism of stretch-induced activation of resident myogenic stem cells. Anim Sci J 2010; 81:11-20. [PMID: 20163667 DOI: 10.1111/j.1740-0929.2009.00712.x] [Citation(s) in RCA: 93] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
In undamaged postnatal muscle fibers with normal contraction and relaxation activities, quiescent satellite cells of resident myogenic stem cells are interposed between the overlying external lamina and the sarcolemma of a subjacent mature muscle fiber. When muscle is injured, exercised, overused or mechanically stretched, these cells are activated to enter the cell proliferation cycle, divide, differentiate, and fuse with the adjacent muscle fiber, and are responsible for regeneration and work-induced hypertrophy of muscle fibers. Therefore, a mechanism must exist to translate mechanical changes in muscle tissue into chemical signals that can activate satellite cells. Recent studies of satellite cells or single muscle fibers in culture and in vivo demonstrated the essential role of hepatocyte growth factor (HGF) and nitric oxide (NO) radical in the activation pathway. These experiments have also reported that mechanically stretching satellite cells or living skeletal muscles triggers the activation by rapid release of HGF from its extracellular tethering and the subsequent presentation to the receptor c-met. HGF release has been shown to rely on calcium-calmodulin formation and NO radical production in satellite cells and/or muscle fibers in response to the mechanical perturbation, and depend on the subsequent up-regulation of matrix metalloproteinase (MMP) activity. These results indicate that the activation mechanism is a cascade of events including calcium ion influx, calcium-calmodulin formation, NO synthase activation, NO radical production, MMP activation, HGF release and binding to c-met. Better understanding of 'mechano-biology' on the satellite cell activation is essential for designing procedures that could enhance muscle growth and repair activities in meat-animal agriculture and also in neuromuscular disease and aging in humans.
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Affiliation(s)
- Ryuichi Tatsumi
- Department of Bioscience and Biotechnology, Graduate School of Agriculture, Kyushu University, Higashi, Fukuoka, Japan.
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Hanke N, Kubis HP, Scheibe RJ, Berthold-Losleben M, Hüsing O, Meissner JD, Gros G. Passive mechanical forces upregulate the fast myosin heavy chain IId/x via integrin and p38 MAP kinase activation in a primary muscle cell culture. Am J Physiol Cell Physiol 2010; 298:C910-20. [PMID: 20071689 DOI: 10.1152/ajpcell.00265.2009] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
We have studied the mechanism by which a previously described primary muscle culture growing on microcarriers predominantly expresses fast myosin heavy chain (MHC) IId/x. We have measured MHC IId/x mRNA and protein levels, mRNA of MHC I and markers of muscle metabolism, insulin-like growth factor (IGF)-1 and mechano-growth factor (MGF) transcripts, indicators of the activation of the Akt-mammalian target of rapamycin (mTOR) axis, the p38-, ERK1/2-, and JNK-mitogen-activated protein kinase (MAP) kinase pathways, and of protein phosphatase PP2A, and we have assessed the involvement of integrin. By placing the culture flasks on a rotary shaker, we induce a continuous motion of the culture medium in which the carrier-myotube aggregates are suspended. This motion exerts passive forces on the myotubes that are decisive for the predominance of MHC II expression. These forces act via integrin, which transduces the mechanical signal into activation of PP2A and of p38 MAP-Kinase. The latter presumably is directly responsible for a drastic upregulation of MHC IId/x, whereas MHC I and metabolic markers remain unaffected. At the same time, despite an elevated level of IGF-1 transcription under passive forces, the IGF-1 receptor-Akt-mTOR axis is switched off as evident from the lack of an effect of inhibition of the IGF-1 receptor and from the PP2A-mediated low degree of phosphorylation of Akt and 4E-BP1. Similarly, the ERK1/2- and JNK-MAP kinase pathways are repressed. We conclude that passive stretch exerted on the myotubes by the rotary fluid motion induces a rather selective upregulation of fast MHC II, which goes along with a mild muscle hypertrophy as judged from the amount of protein per cell and is caused by p38 MAP kinase activity elevated via integrin sensing. The direct link between passive stretch and MHC II expression constitutes a novel mechanism, which is expected to become effective physiologically under passive stretch and eccentric contractions of skeletal muscles.
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Affiliation(s)
- Nina Hanke
- Zentrum Physiologie, Vegetative Physiologie, Medizinische Hochschule Hannover, 30625 Hannover, Germany
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Sasai N, Agata N, Inoue-Miyazu M, Kawakami K, Kobayashi K, Sokabe M, Hayakawa K. Involvement of PI3K/Akt/TOR pathway in stretch-induced hypertrophy of myotubes. Muscle Nerve 2010; 41:100-6. [DOI: 10.1002/mus.21473] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Quaglino A, Salierno M, Pellegrotti J, Rubinstein N, Kordon EC. Mechanical strain induces involution-associated events in mammary epithelial cells. BMC Cell Biol 2009; 10:55. [PMID: 19615079 PMCID: PMC2721828 DOI: 10.1186/1471-2121-10-55] [Citation(s) in RCA: 33] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2009] [Accepted: 07/17/2009] [Indexed: 12/04/2022] Open
Abstract
Background Shortly after weaning, a complex multi-step process that leads to massive epithelial apoptosis is triggered by tissue local factors in the mouse mammary gland. Several reports have demonstrated the relevance of mechanical stress to induce adaptive responses in different cell types. Interestingly, these signaling pathways also participate in mammary gland involution. Then, it has been suggested that cell stretching caused by milk accumulation after weaning might be the first stimulus that initiates the complete remodeling of the mammary gland. However, no previous report has demonstrated the impact of mechanical stress on mammary cell physiology. To address this issue, we have designed a new practical device that allowed us to evaluate the effects of radial stretching on mammary epithelial cells in culture. Results We have designed and built a new device to analyze the biological consequences of applying mechanical stress to cells cultured on flexible silicone membranes. Subsequently, a geometrical model that predicted the percentage of radial strain applied to the elastic substrate was developed. By microscopic image analysis, the adjustment of these calculations to the actual strain exerted on the attached cells was verified. The studies described herein were all performed in the HC11 non-tumorigenic mammary epithelial cell line, which was originated from a pregnant BALB/c mouse. In these cells, as previously observed in other tissue types, mechanical stress induced ERK1/2 phosphorylation and c-Fos mRNA and protein expression. In addition, we found that mammary cell stretching triggered involution associated cellular events as Leukemia Inhibitory Factor (LIF) expression induction, STAT3 activation and AKT phosphorylation inhibition. Conclusion Here, we show for the first time, that mechanical strain is able to induce weaning-associated events in cultured mammary epithelial cells. These results were obtained using a new practical and affordable device specifically designed for such a purpose. We believe that our results indicate the relevance of mechanical stress among the early post-lactation events that lead to mammary gland involution.
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Affiliation(s)
- Ana Quaglino
- Departamento de Química Biológica e Instituto de Fisiología, Biología Molecular y Neurociencias-CONICET, Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Argentina.
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Wahl P, Brixius K, Bloch W. Exercise‐induced stem cell activation and its implication for cardiovascular and skeletal muscle regeneration. MINIM INVASIV THER 2009; 17:91-9. [DOI: 10.1080/13645700801969816] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
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Morioka S, Goto K, Kojima A, Naito T, Matsuba Y, Akema T, Fujiya H, Sugiura T, Ohira Y, Beppu M, Aoki H, Yoshioka T. Functional overloading facilitates the regeneration of injured soleus muscles in mice. J Physiol Sci 2009; 58:397-404. [PMID: 18845057 DOI: 10.2170/physiolsci.rp004008] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2008] [Accepted: 09/22/2008] [Indexed: 11/05/2022]
Abstract
The effect of functional overloading on the regenerating process of injured skeletal muscle was investigated in 10-week-old male mice (C57BL/6J). Functional overloading on soleus of both hindlimbs was performed by cutting the distal tendons of plantaris and gastrocnemius muscles for 2 weeks before cardiotoxin (CTX) injection as the preconditioning and also during 10 weeks of recovery. To activate the necrosis-regeneration cycle, 0.1 ml of 10-microM CTX was injected into soleus muscle. The mean values of absolute muscle weight and the percentage of Pax7-positive nuclei in soleus were increased by the preconditioning. These values, as well as total muscle protein content, in the group with CTX injection plus overloading were larger than in the group with CTX injection alone. Fibers with central nucleus were noted in the group with CTX injection with or without overloading. The rate of disappearance of fibers having central nucleus during recovery was stimulated by overloading. Histological analyses revealed that the regeneration of injured soleus muscle with overloading proceeded more rapidly than the muscle without overloading. These results, in combination with previous lines of evidence, strongly suggest that functional overloading may facilitate the regeneration of injured skeletal muscles.
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Affiliation(s)
- Shigeta Morioka
- Department of Physiology, St. Marianna University School of Medicine, Kawasaki, 216-8511 Japan
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Dennis RG, Smith B, Philp A, Donnelly K, Baar K. Bioreactors for guiding muscle tissue growth and development. ADVANCES IN BIOCHEMICAL ENGINEERING/BIOTECHNOLOGY 2009; 112:39-79. [PMID: 19290497 DOI: 10.1007/978-3-540-69357-4_3] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Muscle tissue bioreactors are devices which are employed to guide and monitor the development of engineered muscle tissue. These devices have a modern history that can be traced back more than a century, because the key elements of muscle tissue bioreactors have been studied for a very long time. These include barrier isolation and culture of cells, tissues and organs after isolation from a host organism; the provision of various stimuli intended to promote growth and maintain the muscle, such as electrical and mechanical stimulation; and the provision of a perfusate such as culture media or blood derived substances. An accurate appraisal of our current progress in the development of muscle bioreactors can only be made in the context of the history of this endeavor. Modern efforts tend to focus more upon the use of computer control and the application of mechanical strain as a stimulus, as well as substrate surface modifications to induce cellular organization at the early stages of culture of isolated muscle cells.
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Affiliation(s)
- R G Dennis
- Department of Biomedical Engineering, University of North Carolina at Chapel Hill, Chapel Hill, USA
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Iwata Y, Katanosaka Y, Arai Y, Shigekawa M, Wakabayashi S. Dominant-negative inhibition of Ca2+ influx via TRPV2 ameliorates muscular dystrophy in animal models. Hum Mol Genet 2008; 18:824-34. [PMID: 19050039 DOI: 10.1093/hmg/ddn408] [Citation(s) in RCA: 110] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022] Open
Abstract
Muscular dystrophy is a severe degenerative disorder of skeletal muscle characterized by progressive muscle weakness. One subgroup of this disease is caused by a defect in the gene encoding one of the components of the dystrophin-glycoprotein complex, resulting in a significant disruption of membrane integrity and/or stability and, consequently, a sustained increase in the cytosolic Ca(2+) concentration ([Ca(2+)](i)). In the present study, we demonstrate that muscular dystrophy is ameliorated in two animal models, dystrophin-deficient mdx mice and delta-sarcoglycan-deficient BIO14.6 hamsters by dominant-negative inhibition of the transient receptor potential cation channel, TRPV2, a principal candidate for Ca(2+)-entry pathways. When transgenic (Tg) mice expressing a TRPV2 mutant in muscle were crossed with mdx mice, the [Ca(2+)](i) increase in muscle fibers was reduced by dominant-negative inhibition of endogenous TRPV2. Furthermore, histological, biochemical and physiological indices characterizing dystrophic pathology, such as an increased number of central nuclei and fiber size variability/fibrosis/apoptosis, elevated serum creatine kinase levels, and reduced muscle performance, were all ameliorated in the mdx/Tg mice. Similar beneficial effects were also observed in the muscles of BIO14.6 hamsters infected with adenovirus carrying mutant TRPV2. We propose that TRPV2 is a principal Ca(2+)-entry route leading to a sustained [Ca(2+)](i) increase and muscle degeneration, and that it is a promising therapeutic target for the treatment of muscular dystrophy.
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Affiliation(s)
- Yuko Iwata
- Department of Molecular Physiology, National Cardiovascular Center Research Institute Suita, Osaka 565-8565, Japan.
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TATSUMI R, ALLEN RE. Mechano-biology of resident myogenic stem cells: Molecular mechanism of stretch-induced activation of satellite cells. Anim Sci J 2008. [DOI: 10.1111/j.1740-0929.2008.00528.x] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
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Favier FB, Benoit H, Freyssenet D. Cellular and molecular events controlling skeletal muscle mass in response to altered use. Pflugers Arch 2008; 456:587-600. [DOI: 10.1007/s00424-007-0423-z] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2007] [Accepted: 12/06/2007] [Indexed: 12/21/2022]
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