Regulation of lysosomes in skeletal muscle during exercise, disuse and aging

Abstract

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.