Myogenic Stem Cell Function in Aging Skeletal Muscle

描述(申请人提供)：本申请旨在破译支持卫星细胞功能的分子途径，并了解这些途径在衰老过程中是如何受到影响的。与年龄相关的骨骼肌退化(骨质疏松症)的特征是质量、力量、耐力和修复能力的下降，以及肌纤维之间和肌纤维内脂肪的积累。肌纤维修复是由卫星细胞实现的，卫星细胞是位于肌纤维基板下的肌源性干细胞。在日常肌肉活动中发生的细微肌肉损伤增加了一生中对功能性肌纤维修复的持续需求。然而，卫星细胞的性能在老年时会下降，这种下降可能是导致石棺减少的一个因素。虽然卫星细胞传统上被认为是组织特异性的生肌前体细胞，但我们已经证明，它们也可以进入间质替代途径，最终导致成脂分化。这种替代的世系承诺可能会导致老年时肌质受损和肌肉脂肪增加。深入了解影响卫星细胞自我更新和肌质化的机制，促进其间充质可塑性，将有助于设计治疗方案，以改善衰老肌肉中成肌祖细胞的数量和功能。因此，这一提议的目的是：1)研究卫星细胞贡献肌源性后代并在一生中经历自我更新的潜力。2)确定肌源性转录因子Myf5和MyoD以及肌肉整合素α7在卫星细胞肌源性和间质交替命运平衡中的作用。3)研究基质金属蛋白酶和去整合素活性对星形细胞间充质细胞命运和自我更新的影响。野生型和转基因小鼠的年龄段从青少年到老年，将被调查。卫星细胞的性能将在分离的肌纤维和克隆中使用蛋白质和RNA表达方法进行检测。此外，相关基因的功能作用将通过用基于病毒的表达载体转导卫星细胞来确定。建议的研究将有助于对成年和衰老肌肉中卫星细胞的状态进行新的洞察，因此将为疾病和衰老期间的肌肉康复策略提供重要信息。 骨骼肌修复是由称为卫星细胞的肌源性前体细胞实现的。随着年龄的增长，这些细胞的功能下降可能是老年骨骼肌退化(骨质疏松症)的一个促成因素。拟议的研究将有助于对生命周期中卫星细胞功能的调节提供新的见解，因此将为疾病和衰老期间的肌肉康复策略提供重要信息。

DESCRIPTION (provided by applicant): This application aims at deciphering the molecular pathways supporting satellite cell function and at understanding how these are influenced during aging. Age-related skeletal muscle deterioration (sarcopenia) is characterized by a decline in mass, strength, endurance and repair capacity, and by fat accumulation between and within myofibers. Myofiber repair is enabled by satellite cells, myogenic stem cells situated underneath the myofiber basal lamina. Subtle muscle injuries that occur during routine muscle activity raise a continuous demand for functional myofiber repair throughout life. However, satellite cell performance declines in old age and this decline can be a contributory factor to sarcopenia. While satellite cells have classically been thought to function as tissue-specific myogenic progenitors, we have shown that they can also enter a mesenchymal alternative path, which culminates in terminal adipogenic differentiation. Such an alternative lineage commitment may contribute to impaired myogeneity and increased muscle adipostiy in old age. Gaining insight into mechanisms involved in impairing satellite cell self-renewal and myogeneity, and in promoting their mesenchymal plasticity, will contribute to the design of therapies to improve the number and function of myogenic progenitors in aging muscle. Accordingly, the aims of this proposal are: 1) Investigate the potential of satellite cells to contribute myogenic progeny and undergo self-renewal throughout life. 2) Determine the role of the myogenic transcription factors Myf5 and MyoD, and the muscle integrin alpha7, in the balance between myogenic versus mesenchymal alternative fate of satellite cells. 3) Investigate the effect of metalloproteinase and disintegrin activities on mesenchymal fate and self-renewal of satellite cells. Wildtype and genetically modified mice, of age groups ranging from juvenile to senile, will be investigated. Satellite cell performance will be examined in isolated myofibers and clones, using protein and RNA expression methodologies. Additionally, the functional role of relevant genes will be determined by transducing satellite cells with viral-based expression vectors. The proposed studies will contribute new insight into the status of satellite cells in adult and aging muscles, and will, therefore, provide important information for muscle rehabilitation strategies during disease and aging. Skeletal muscle repair is enabled by myogenic progenitors named satellite cells. Age-associated decline in the performance of these cells can be a contributory factor to the deterioration of skeletal muscle in old age (sarcopenia). The proposed studies will contribute new insight into the regulation of satellite cell function throughout the lifespan and will, therefore, provide important information for muscle rehabilitation strategies during disease and aging.