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

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 成肌细胞和成脂细胞通常被认为是从共同的祖细胞起源的。来自肌肉的卫星细胞在培养中分化为脂肪细胞。除卫星细胞外，成人骨骼肌中PDGF阳性的间质细胞也显示出很强的成脂潜能。为了在临床上控制肥胖和骨骼肌疾病中肌内脂肪的增加，鉴定异位成脂细胞来源于多能干细胞和祖细胞的信号分子及其分子机制至关重要。我们发现Wnt信号激活物R-Spinins在肌细胞分化和再生过程中有表达。RSPO诱导成肌祖细胞表达成肌决定因子Myf5，下调成脂因子C/EBP的表达，提示其在成脂过程中具有抑制作用。此外，成脂Myostatin的拮抗剂Follistatin在同一细胞中也增加。我们假设，R-Respondin是积极调节肌源性干细胞/祖细胞的成肌承诺的关键调节因子，但通过抑制Myostatin信号来防止异常的脂肪生成。为了验证这一假说，我们提出了两个具体的目标：1)确定R-Respondin如何调节Myostatin信号和成脂分化；2)确定Rspo2在骨骼肌过表达如何调节肥胖小鼠和肌肉营养不良小鼠的IMAT质量。这项拟议的研究有望揭示决定成脂和成肌命运的分子机制，并可能确定可以控制成脂和肥胖的治疗靶点。

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.