Cell Death Mechanisms in Skeletal Muscle

细胞凋亡和自噬是参与细胞死亡的两种生物学机制。虽然这些途径通常都是独立研究的，但最近的证据表明，它们是高度整合的。在各种情况下，骨骼肌都会发生自噬和细胞凋亡。有趣的是，凋亡和自噬信号对于肌肉的正常形成和功能是必不可少的，但也在骨骼肌的降解和功能障碍中发挥作用。也有证据表明，自噬影响细胞凋亡，这可能会影响肌肉在应激后的恢复和重塑。目前，这两条死亡相关通路在骨骼肌中的作用还不是很清楚。自噬和细胞凋亡似乎也可以通过运动来改变；然而，这种现象还没有被很好地理解。这项拟议的工作将使用细胞培养和动物模型来研究自噬机制对骨骼肌细胞分化、适应、恢复和对凋亡应激的敏感性的直接影响。使用具有改变的自噬信号的细胞进行的体外实验将检验自噬在肌肉细胞分化中的作用，以及在骨骼肌形成和细胞死亡过程中自噬和凋亡之间的相互作用。此外，还将利用一种特定的转基因动物模型，减少骨骼肌的自噬。这些体内实验将确定自噬和细胞凋亡在骨骼肌急性剧烈运动恢复中的作用。此外，这些实验将专门研究自噬在运动训练相关的骨骼肌适应变化和细胞凋亡易感性中的作用。这项拟议的工作将显著提高我们对骨骼肌细胞死亡过程的理解，并提供关于骨骼肌分化、发育、适应和功能的基础知识和理解。

Apoptosis and autophagy are two biological mechanisms that participate in cell death. Although these pathways have commonly been studied independently, recent evidence suggests that they are highly integrated. Autophagy and apoptosis occur in skeletal muscle during a variety of conditions. Interestingly, apoptotic and autophagic signaling are essential for proper muscle formation and function, but also have a role in skeletal muscle degradation and dysfunction. There is also evidence that autophagy influences apoptosis, which may affect muscle recovery and remodeling after stress. Currently, the roles of these two death-associated pathways on skeletal muscle are not well known. Autophagy and apoptosis also appear to be altered by exercise; however, this phenomenon is not well understood. The proposed work will use cell culture and animal models to investigate the direct influence of autophagic mechanisms on skeletal muscle cell differentiation, adaptation, recovery, and susceptibility to apoptotic stress. In vitro experiments using cells with altered autophagy signaling will examine the role of autophagy on muscle cell differentiation, as well as the interplay between autophagy and apoptosis during skeletal muscle formation and cell death. Furthermore, a specific transgenic animal model with reduced skeletal muscle autophagy will be utilized. These in vivo experiments will determine the role of autophagy and apoptosis on skeletal muscle recovery to acute strenuous exercise. In addition, these experiments will specifically investigate the role of autophagy on exercise training-associated changes in skeletal muscle adaptation and apoptotic susceptibility. The proposed work will significantly improve our comprehension of cell death processes in skeletal muscle, as well as provide fundamental knowledge and understanding of skeletal muscle differentiation, development, adaptation, and function.