Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

Ge, Xiaojia; McFarlane, Craig; Vajjala, Anuradha; Lokireddy, Sudarsanareddy; Ng, Zhi Hui; Tan, Chee Leong; Tan, Nguan Soon; Wahli, Walter; Sharma, Mridula; Kambadur, Ravi

doi:10.1038/cr.2011.72

Cited by 89 publications

(93 citation statements)

References 43 publications

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“…Vincent Mouly and Gillian Butler-Browne, were maintained as described previously (36,37). Primary myoblasts were isolated from PPAR␤/␦-null mice as described previously (38). To induce differentiation, C2C12, human, and PPAR␤/␦-null primary myoblasts were plated at a density of 25,000 cells/cm 2 and grown in differentiation medium consisting of DMEM containing 2% horse serum and 1% penicillin/ streptomycin (Invitrogen).…”

Section: Methodsmentioning

confidence: 99%

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Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

Bonala

Lokireddy

Harikumar

et al. 2012

Journal of Biological Chemistry

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Background: PPAR␤/␦ has been implicated in muscle regeneration; however the signaling mechanism(s) is unclear. Results: Activation of PPAR␤/␦-promoted Gasp-1 expression blocked myostatin activity and enhanced myogenesis. Conclusion: Activation of PPAR␤/␦ led to inhibition of myostatin activity and thus increased myogenesis. Significance: PPAR␤/␦ agonists are novel myostatin antagonists that have potential benefits toward improving postnatal muscle growth and repair.Classically, peroxisome proliferator-activated receptor ␤/␦ (PPAR␤/␦) function was thought to be restricted to enhancing adipocyte differentiation and development of adipose-like cells from other lineages. However, recent studies have revealed a critical role for PPAR␤/␦ during skeletal muscle growth and regeneration. Although PPAR␤/␦ has been implicated in regulating myogenesis, little is presently known about the role and, for that matter, the mechanism(s) of action of PPAR␤/␦ in regulating postnatal myogenesis. Here we report for the first time, using a PPAR␤/␦-specific ligand (L165041) and the PPAR␤/␦-null mouse model, that PPAR␤/␦ enhances postnatal myogenesis through increasing both myoblast proliferation and differentiation. In addition, we have identified Gasp-1 (growth and differentiation factor-associated serum protein-1) as a novel downstream target of PPAR␤/␦ in skeletal muscle. In agreement, reduced Gasp-1 expression was detected in PPAR␤/␦-null mice muscle tissue. We further report that a functional PPAR-responsive element within the 1.5-kb proximal Gasp-1 promoter region is critical for PPAR␤/␦ regulation of Gasp-1. Gasp-1 has been reported to bind to and inhibit the activity of myostatin; consistent with this, we found that enhanced secretion of Gasp-1, increased Gasp-1 myostatin interaction and significantly reduced myostatin activity upon L165041-mediated activation of PPAR␤/␦. Moreover, we analyzed the ability of hGASP-1 to regulate myogenesis independently of PPAR␤/␦ activation. The results revealed that hGASP-1 protein treatment enhances myoblast proliferation and differentiation, whereas silencing of hGASP-1 results in defective myogenesis. Taken together these data revealed that PPAR␤/␦ is a positive regulator of skeletal muscle myogenesis, which functions through negatively modulating myostatin activity via a mechanism involving Gasp-1.In the late 1960s, work performed by De Duve et al.(1) led to the identification of a series of compounds that promote peroxisome proliferation. These compounds were subsequently grouped into a family known as peroxisome proliferators. Peroxisome proliferators were shown to elicit biological function through binding to ligand-inducible nuclear hormone receptors, of which the first receptor, cloned from mouse liver, was termed peroxisome proliferator-activated receptor (PPAR) 2 (2). Upon ligand binding, PPARs become activated and bind to their target genes by forming heterodimeric complexes with retinoid-X receptors (RXR) (3, 4). The activated PPAR-RXR complex then binds to consensus peroxisome pr...

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Section: Methodsmentioning

confidence: 99%

“…Synthesis of cDNA, qPCR, and subsequent data analysis were performed as described previously (38). The gene-specific primers used in this manuscript are listed in supplemental Table S1.…”

Section: Methodsmentioning

confidence: 99%

Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

Bonala

Lokireddy

Harikumar

et al. 2012

Journal of Biological Chemistry

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“…It is possible that Mstn governs satellite cell proliferation through still undefined mechanisms not relying on changes in the Smad3/Notch balance. The recent observation that the atrophy seen in Smad3 −/− muscles could be due to altered Mstn levels supports this idea (65). Mstn may signal independently of Smad3 via either Smad2 or other pathways such as the phosphatidylinositol 3-kinase Wnt and c-Jun N-terminal kinase pathways (66)(67)(68).…”

Section: Discussionmentioning

confidence: 51%

Numb-deficient satellite cells have regeneration and proliferation defects

George

Biressi

Beres

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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Significance This study discloses a role for Numb in the activation and proliferation of adult muscle satellite cells and a unique function in the regulation of the muscle mass determinant Myostatin. Using two different genetic approaches to ablate Numb , one that ablated Numb in the myogenic lineage developmentally leading to reduced muscle mass. We determined that, in Numb-deficient muscle, regeneration was impaired, there was reduced stem cell proliferation, and there was an up-regulation of Myostatin. Overexpression of Numb suppressed Myostatin expression, and Myostatin-specific siRNA rescued the proliferation defect. These studies increase our knowledge of the signaling pathways involved in stem cell function and raise the possibility of regulating the Numb/Myostatin balance as a therapeutic approach to enhance muscle regeneration.

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“…This may be partly due to the repression effects of SMAD3 on myogenesis. SMAD3 was essential for regulating muscle growth by interacting with other muscle specific regulatory factors (Liu et al 2001;Ge et al 2011;Sriram et al 2014). It was known that muscle development and growth could partly determine body weight in animals (Huang et al 2015).…”

Section: Discussionmentioning

confidence: 99%

Genetic variation, association analysis, and expression pattern of SMAD3 gene in Chinese cattle

Shi¹,

Xu²,

Yang³

et al. 2016

CZECH J ANIM SCI

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SMAD3, a member of SMAD transcription factors, plays a key role in transforming growth factorbeta (TGF-β) signalling pathway and regulation of muscle growth. However, there was no strong evidence of association between SMAD3 polymorphisms and body traits in animals. In this study, single nucleotide polymorphisms (SNPs) in SMAD3 gene were detected in four Chinese cattle breeds (Qinchuan, Jiaxian, Nanyang, and Caoyuan) by using DNA pool sequencing and PCR-RFLP, and their effects on gene expression and growth traits were evaluated in Qinchuan cattle. The results showed that four novel SNPs (NC_007308.5 c.-2017A>G, g.101664C>G, g.105829A>G, and g.114523A>G) in promoter, intron 3, and intron 5 were found in four cattle breeds. NC_007308.5 c.-2017A>G and g.114523A>G were significantly (P < 0.05) associated with SMAD3 gene expression. Furthermore, the four SNPs were strikingly (P < 0.05) associated with rump length, chest girth, and body weight in two-year-old Qinchuan cattle. Our results provided the evidence that SNPs in SMAD3 were associated with cattle traits, which showed the possibility that the four SNPs could be novel molecular markers for beef cattle breeding and genetics.

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Smad3 signaling is required for satellite cell function and myogenic differentiation of myoblasts

Cited by 89 publications

References 43 publications

Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

Peroxisome Proliferator-activated Receptor β/δ Induces Myogenesis by Modulating Myostatin Activity

Numb-deficient satellite cells have regeneration and proliferation defects

Genetic variation, association analysis, and expression pattern of SMAD3 gene in Chinese cattle

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