Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts
TGF-β and myostatin are the two most important regulators of muscle growth. Both growth factors have been shown to signal through a Smad3-dependent pathway. However to date, the role of Smad3 in muscle growth and differentiation is not investigated. Here, we demonstrate that Smad3-null mice have dec...
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Published in | Cell research Vol. 21; no. 11; pp. 1591 - 1604 |
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Main Authors | , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
England
Nature Publishing Group
01.11.2011
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Subjects | |
Online Access | Get full text |
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Summary: | TGF-β and myostatin are the two most important regulators of muscle growth. Both growth factors have been shown to signal through a Smad3-dependent pathway. However to date, the role of Smad3 in muscle growth and differentiation is not investigated. Here, we demonstrate that Smad3-null mice have decreased muscle mass and pronounced skeletal muscle atrophy. Consistent with this, we also find increased protein ubiquitination and elevated levels of the ubiquitin E3 ligase MuRF1 in muscle tissue isolated from Smad3-null mice. Loss of Smad3 also led to defective satellite cell (SC) functionality. Smad3-null SCs showed reduced propensity for self-renewal, which may lead to a progressive loss of SC number. Indeed, decreased SC number was observed in skeletal muscle from Smad3- null mice showing signs of severe muscle wasting. Further in vitro analysis of primary myoblast cultures identified that Smad3-null myoblasts exhibit impaired proliferation, differentiation and fusion, resulting in the formation of atrophied myotubes. A search for the molecular mechanism revealed that loss of Smad3 results in increased myostatin expression in Smad3-null muscle and myoblasts. Given that myostatin is a negative regulator, we hypothesize that increased myostatin levels are responsible for the atrophic phenotype in Smad3-null mice. Consistent with this theory, inactivation of myostatin in Smad3-null mice rescues the muscle atrophy phenotype. |
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Bibliography: | Xiaojia Gel, Craig McFarlane2, Anuradha Vajjala, Sudarsanareddy Lokireddy, Zhi Hui Ng, Chek Kun Tanj, Nguan Soon Tan, Walter Wahli3, Mridula Sharma4, Ravi Kambadur1' 2 1School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore," :Singapore Institute for Clini- cal Sciences, Agency for Science, Technology and Research (A *STAR), Brenner Centre for Molecular Medicine, 30 Medical Drive, Singapore 117609; 3Center for Integrative Genomics, NCCR Frontiers in Genetics, University of Lausanne, Lausanne, Switzer- land," 4Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 31-1568/Q TGF-β and myostatin are the two most important regulators of muscle growth. Both growth factors have been shown to signal through a Smad3-dependent pathway. However to date, the role of Smad3 in muscle growth and differentiation is not investigated. Here, we demonstrate that Smad3-null mice have decreased muscle mass and pronounced skeletal muscle atrophy. Consistent with this, we also find increased protein ubiquitination and elevated levels of the ubiquitin E3 ligase MuRF1 in muscle tissue isolated from Smad3-null mice. Loss of Smad3 also led to defective satellite cell (SC) functionality. Smad3-null SCs showed reduced propensity for self-renewal, which may lead to a progressive loss of SC number. Indeed, decreased SC number was observed in skeletal muscle from Smad3- null mice showing signs of severe muscle wasting. Further in vitro analysis of primary myoblast cultures identified that Smad3-null myoblasts exhibit impaired proliferation, differentiation and fusion, resulting in the formation of atrophied myotubes. A search for the molecular mechanism revealed that loss of Smad3 results in increased myostatin expression in Smad3-null muscle and myoblasts. Given that myostatin is a negative regulator, we hypothesize that increased myostatin levels are responsible for the atrophic phenotype in Smad3-null mice. Consistent with this theory, inactivation of myostatin in Smad3-null mice rescues the muscle atrophy phenotype. Smad3; myostatin; muscle atrophy; satellite cells ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 1001-0602 1748-7838 |
DOI: | 10.1038/cr.2011.72 |