Moradi N, Sanfrancesco V C, Champsi S, Hood D A
Muscle Health Research Centre, Kinesiology and Health Science, York University, Toronto, ON, Canada.
Muscle Health Research Centre, Kinesiology and Health Science, York University, Toronto, ON, Canada.
Free Radic Biol Med. 2024 Nov 20;225:323-332. doi: 10.1016/j.freeradbiomed.2024.09.028. Epub 2024 Sep 25.
Lysosomes play a critical role as a terminal organelle in autophagy flux and in regulating protein degradation, but their function and adaptability in skeletal muscle is understudied. Lysosome functions include both housekeeping and signaling functions essential for cellular homeostasis. This review focuses on the regulation of lysosomes in skeletal muscle during exercise, disuse, and aging, with a consideration of sex differences as well as the role of lysosomes in mediating the degradation of mitochondria, termed mitophagy. Exercise enhances mitophagy during elevated mitochondrial stress and energy demand. A critical response to this deviation from homeostasis is the activation of transcription factors TFEB and TFE3, which drive the expression of lysosomal and autophagic genes. Conversely, during muscle disuse, the suppression of lysosomal activity contributes to the accumulation of defective mitochondria and other cellular debris, impairing muscle function. Aging further exacerbates these effects by diminishing lysosomal efficacy, leading to the accumulation of damaged cellular components. mTORC1, a key nutrient sensor, modulates lysosomal activity by inhibiting TFEB/TFE3 translocation to the nucleus under nutrient-rich conditions, thereby suppressing autophagy. During nutrient deprivation or exercise, AMPK activation inhibits mTORC1, facilitating TFEB/TFE3 nuclear translocation and promoting lysosomal biogenesis and autophagy. TRPML1 activation by mitochondrial ROS enhances lysosomal calcium release, which is essential for autophagy and maintaining mitochondrial quality. Overall, the intricate regulation of lysosomal functions and signaling pathways in skeletal muscle is crucial for adaptation to physiological demands, and disruptions in these processes during disuse and aging underscore the ubiquitous power of exercise-induced adaptations, and also highlight the potential for targeted therapeutic interventions to preserve muscle health.
溶酶体作为自噬通量和调节蛋白质降解的终末细胞器发挥着关键作用，但其在骨骼肌中的功能和适应性尚未得到充分研究。溶酶体功能包括维持细胞内稳态所必需的看家功能和信号传导功能。本综述重点关注运动、废用和衰老过程中骨骼肌溶酶体的调节，同时考虑性别差异以及溶酶体在介导线粒体降解（即线粒体自噬）中的作用。运动可在线粒体应激和能量需求增加时增强线粒体自噬。对这种偏离稳态的关键反应是转录因子TFEB和TFE3的激活，它们驱动溶酶体和自噬基因的表达。相反，在肌肉废用期间，溶酶体活性的抑制会导致有缺陷的线粒体和其他细胞碎片积累，损害肌肉功能。衰老通过降低溶酶体功效进一步加剧这些影响，导致受损细胞成分的积累。mTORC1是一种关键的营养传感器，在营养丰富的条件下通过抑制TFEB/TFE3向细胞核的转位来调节溶酶体活性，从而抑制自噬。在营养剥夺或运动期间，AMPK的激活会抑制mTORC1，促进TFEB/TFE3的核转位，并促进溶酶体生物发生和自噬。线粒体ROS激活TRPML1可增强溶酶体钙释放，这对自噬和维持线粒体质量至关重要。总体而言，骨骼肌中溶酶体功能和信号通路的复杂调节对于适应生理需求至关重要；在废用和衰老过程中这些过程的破坏凸显了运动诱导适应的普遍作用，也突出了靶向治疗干预以维持肌肉健康的潜力。
