Cell Death Signaling in Skeletal Muscle

细胞凋亡和自噬是参与细胞死亡的两个生物学过程，但在正常组织发育、重塑和功能中也起着重要作用。因此，这些过程必须得到很好的控制，以维持适当的细胞和组织稳态。例如，一些凋亡信号是骨骼肌正常发育所必需的，但如果不适当调节，这些信号也会导致细胞死亡。虽然自噬可以参与细胞死亡，但在大多数情况下，自噬可能起着存活作用。这种生存功能是通过自噬降解部分细胞的能力来实现的，从而减少细胞压力。线粒体自噬是一种特殊形式的自噬，专门去除/降解线粒体。鉴于线粒体是细胞凋亡的关键调节因子，线粒体自噬能够减少线粒体凋亡信号传导。目前，骨骼肌中自噬和有丝自噬的作用以及自噬/有丝自噬与细胞凋亡的相互作用尚未得到充分的研究。近年来，人们发现自噬是骨骼肌干细胞维持和分化所必需的。此外，新的研究发现，有丝分裂是骨骼肌细胞分化所必需的。我们实验室的新发现表明，在分化过程中，自噬通过控制凋亡信号是骨骼肌分化所必需的。线粒体自噬是否通过调控凋亡信号传导影响骨骼肌干细胞的功能和分化尚不清楚。此外，影响这些过程的分子信号机制尚未完全确定。因此，这个NSERC项目将利用细胞培养和小鼠模型，以及先进的生化、细胞和分子生物学以及生理学方法，来研究骨骼肌形成、表型、适应和功能中的细胞死亡信号。具体而言，本研究将探讨：1)骨骼肌分化过程中自噬和有丝自噬对凋亡信号的作用；2)骨骼肌分化、表型和功能中Notch信号、自噬和有丝自噬之间的关系；3)自噬和有丝自噬预处理对骨骼肌凋亡易感性、损伤和再生的影响；4)几个关键机制对这些反应的影响。此外，这个NSERC项目将为一些HQP提供最新研究方法和工具的培训。总的来说，这个项目代表了细胞死亡信号和骨骼肌生物学领域的一个新的研究方向。值得注意的是，这笔NSERC拨款将继续支持加拿大唯一一个完全致力于研究骨骼肌细胞死亡过程的实验室。

Apoptosis and autophagy are two biological processes that can participate in cell death, but that also have important roles in normal tissue development, remodeling, and function. Thus, these processes must be finely controlled in order to maintain proper cell and tissue homeostasis. For example, some apoptotic signals are required for proper skeletal muscle development, but these same signals can lead to cell death if not appropriately regulated. Although autophagy can participate in cell death, in most cases autophagy is likely playing a survival role. This survival function is achieved through autophagy's ability to degrade parts of the cell and thereby reduce cellular stress. Mitophagy is a specialized form of autophagy that specifically removes/degrades mitochondria. Given that mitochondria are key regulators of apoptosis, mitophagy is able to reduce mitochondrial apoptotic signaling. Currently, the roles of autophagy and mitophagy, and interplay between autophagy/mitophagy and apoptosis, in skeletal muscle have not been fully investigated. Recently, it was found that autophagy was required for skeletal muscle stem cell maintenance and differentiation. In addition, new research has found that mitophagy is required for skeletal muscle cell differentiation. New findings from our lab show that autophagy is required for skeletal muscle differentiation by controlling apoptotic signals during the differentiation program. What is still unknown is whether mitophagy influences skeletal muscle stem cell function and differentiation through regulation of apoptotic signaling. Further, the molecular signaling mechanisms influencing these processes have not been fully defined. As such, this NSERC program will utilize cell culture and mouse models, along with advanced biochemical, cellular and molecular biology, and physiological approaches, to investigate cell death signaling in skeletal muscle formation, phenotype, adaptation, and function. More specifically, this research will investigate: 1) the function of autophagy and mitophagy on apoptotic signaling during skeletal muscle differentiation, 2) the relationship between Notch signaling, autophagy, and mitophagy in skeletal muscle differentiation, phenotype, and function, 3) the effect of autophagic and mitophagic preconditioning on skeletal muscle apoptotic susceptibility, damage, and regeneration, and 4) the influence of several key mechanisms on these responses. Moreover, this NSERC program will provide training for a number of HQP in the latest research approaches and tools. Overall, this program represents a novel research direction in the area of cell death signaling and skeletal muscle biology. Notably, this NSERC grant will continue to support the only laboratory in Canada fully devoted to studying cell death processes in skeletal muscle.