Identification of signaling cascades involved in myostatin-mediated repression of skeletal muscle growth

Steelman, Carissa
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Myostatin, a member of the TGF-[Beta] superfamily, negatively regulates skeletal muscle growth. Lack of functional myostatin is responsible for the double-muscled phenotype in cattle, which is characterized by an approximate 20% increase in muscle mass. Myostatin-knockout mice have individual muscles that weigh 2-3 times those of wild-type mice. In addition, an instance of human muscle hypertrophy resulting from a mutation in the myostatin gene has been reported. Despite recent advances in the identification of myostatin pathway components, including a putative receptor, the precise mechanism by which myostatin signals remains unknown. The objective of this study was to identify differences in gene expression between myo statin-null and wild-type mice at 3 developmental time points: 13.5 d.p.c, 17.5 d.p.c, and 35 days of age. With a false discovery rate (FDR) of 0.05, there were 472 genes differentially expressed at 13.5 d.p.c, 73 at 17.5 d.p.c, and 2109 at 35 days of age. At all three time points, changes were observed in genes involved in metabolism, enzyme activity, cell communication, and stimulus response. Further analysis focused on the results obtained at 35 days of age. At this time point, numerous changes were observed in genes implicated in translation and protein modification, differentiation, homeostasis, and energy production. In addition, the results indicated a switch in myogenic fiber type, with several genes encoding slow contractile protein isoforms down-regulated in myostatin-null tissue. It was also observed that a number of genes for Wnt pathway components, including Wnt4, were differentially expressed. Wnt4 has been shown to stimulate proliferation of a variety of cell types. Since it can also induce expression of myogenic regulatory genes, and was upregulated in the absence of myostatin, it was hypothesized that Wnt4 may be able to promote proliferation of muscle satellite cells. In this study, exposure to Wnt4 stimulated proliferation of satellite cells obtained from wild-type mice. In contrast, the Wnt inhibitors sFRPl and -2 decreased proliferation of myostatin-null satellite cells. Taken together, this research provides evidence of a role for Wnt4 in postnatal skeletal muscle growth and hypertrophy and offers insight into possible downstream effectors of myostatin signaling.