11: MOLECULAR MECHANISM OF ADIPOGENIC CONVERSION OF SKELETAL MUSCLE STEM CELLS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Both myogenic and adipogenic cells are generally considered to be derived from the common progenitors. Satellite cells from muscle are differentiated into adipocytes in culture. In addition to satellite cells, PDGF¿-positive interstitial cells in adult skeletal muscle also showed a strong adipogenic potential. To clinically control intramuscular fat mass increase in obese condition and skeletal muscle diseases, it is important to identify the signaling molecules and their molecular mechanisms by which ectopic adipogenic cells are derived from multipotent stem and progenitor cells. We discovered that Wnt signaling activators, R-spondins, are expressed during myogenic differentiation and regeneration. Rspo induced expression of myogenic determination factor Myf5 and downregulated adipogenic factor C/EBP¿ expression in myogenic progenitor cells, suggesting its inhibitory function in adipogenesis. Furthermore, Follistatin, an antagonist of proadipogenic Myostatin, was also increased in the same cells. We hypothesize that R-spondin is a key regulator for positively regulating myogenic commitment of myogenic stem/progenitor cells, but preventing aberrant adipogenesis by inhibiting Myostatin signaling. Two specific aims are proposed to test this hypothesis: 1) to determine how R-spondin regulates Myostatin signaling and adipogenic differentiation; 2) to determine how Rspo2 overexpression in skeletal muscle regulates IMAT mass in obese mice and muscular dystrophic mice. This proposed study is anticipated to uncover the molecular mechanisms by which decision between adipogenic and myogenic fates is regulated and may identify the therapeutic targets that can control adipogenesis and obesity.