Myogenic Stem Cell Function in Aging Skeletal Muscle

描述（由申请人提供）：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如何受到影响。与年龄相关的骨骼肌退化（肌肉减少症）的特征是质量、力量、耐力和修复能力的下降，以及肌纤维之间和内部的脂肪积累。肌纤维修复是由卫星细胞，肌源性干细胞位于肌纤维基底层。在日常肌肉活动中发生的细微肌肉损伤，在整个生命过程中都需要功能性肌纤维的持续修复。然而，卫星细胞的性能随着年龄的增长而下降，这种下降可能是肌肉减少症的一个因素。虽然卫星细胞通常被认为是组织特异性肌源性祖细胞，但我们已经证明它们也可以进入间充质替代途径，最终导致最终的成脂分化。这样一种可选择的谱系承诺可能导致老年时肌肉性受损和肌肉脂肪增加。深入了解卫星细胞自我更新和肌质性受损的机制，以及促进其间质可塑性的机制，将有助于设计治疗方法，以改善衰老肌肉中肌源性祖细胞的数量和功能。因此，本研究的目的是：1)研究卫星细胞在整个生命过程中产生肌源性后代和自我更新的潜力。2)确定肌源性转录因子Myf5和MyoD以及肌肉整合素alpha7在卫星细胞肌源性与间充质替代命运平衡中的作用。3)研究金属蛋白酶和崩解素活性对卫星细胞间质命运和自我更新的影响。野生型和转基因小鼠，年龄范围从幼年到老年，将被调查。卫星细胞的性能将在分离的肌纤维和克隆中进行检查，使用蛋白质和RNA表达方法。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。这些研究将有助于对卫星细胞在成年和衰老肌肉中的状态有新的认识，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.