Adipogenic vs Myogenic Signaling in Muscle Regeneration

描述（由申请人提供）：位于骨骼肌纤维附近的一群正常静止的卫星细胞负责损伤后的肌肉再生。这些卫星细胞的激活和受损肌肉的再生可能依赖于巨噬细胞的浸润。对炎症改变小鼠的初步研究表明，损伤后肌肉再生延迟，肌肉脂肪增加。由于肌肉再生受损，骨骼肌纤维内部和之间的脂肪沉积也会随着年龄的增长而增加。在损伤和炎症改变期间，存在于愈合微环境中的因子可能通过改变特定转录因子的表达，引导卫星细胞向脂肪细胞而不是肌肉细胞的分化命运。拟议的研究将确定愈合微环境和转录信号事件的贡献，这些事件直接导致卫星细胞的成脂分化而不是成肌分化。具体目标是：1)确定成肌和成脂转录因子的表达水平，以揭示损伤后CCR2 -/-小鼠中观察到的导致肌肉再生改变的转录事件的变化；2)利用体外卫星细胞培养验证愈合微环境有助于改变肌肉再生；3)证明有利于脂肪生成和成肌转录因子上调的条件促进了脂肪生成或成肌表型。分别用于再生肌肉。

DESCRIPTION (provided by applicant): A population of normally quiescent satellite cells that reside adjacent to skeletal muscle fibers is responsible for muscle regeneration following injury. Activation of these satellite cells and the regeneration of damaged muscle may be dependent on macrophage infiltration. Preliminary studies of mice with altered inflammation demonstrated delays in muscle regeneration and increased adiposity within muscle following injury. Increased fat deposition within and between skeletal muscle fibers also occurs in aging due to impairments in muscle regeneration. Factors present in the healing microenvironment during injury and altered inflammation may direct the differentiation fate of satellite cells to adipocyte rather than muscle by shifting the expression of specific transcription factors. The proposed studies will determine the contribution of the healing microenvironment and transcriptional signaling events that direct adipogenic rather than myogenic differentiation of satellite cells. The specific aims are to: 1) determine the expression levels of myogenic and adipogenic transcription factors to uncover changes in transcriptional events leading to the altered muscle regeneration observed in CCR2 -/- mice following injury, 2) verify that the healing microenvironment contributes to altered muscle regeneration using in vitro satellite cell culture and 3) demonstrate that conditions which favor the upregulation of adipogenic vs myogenic transcription factors promote an adipogenic or myogenic phenotype, respectively, in regenerating muscle.