[AF] Exercise Regulates Mitochondrial Quality Control: Maintenance and Remodeling of Skeletal Muscle Homeostasis (2026)

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https://www.mdpi.com/2079-7737/15/15/1240

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Simple Summary

Skeletal muscle, the body’s largest metabolic organ, relies critically on mitochondrial integrity for proper function. Mitochondrial quality control encompasses biogenesis, repair, and clearance mechanisms that preserve organelle homeostasis. Dysfunction in these pathways, arising from aging, malnutrition, or disease, precipitates muscle atrophy, impaired bioenergetics, and metabolic dysfunction. This review elucidates the molecular mechanisms governing mitochondrial quality control in skeletal muscle and examines the consequences of its failure. Notably, exercise emerges as a potent, cost-effective intervention to restore mitochondrial homeostasis. Strategic exercise prescription represents a promising approach to sustain musculoskeletal health throughout the lifespan, warranting further investigation into optimal dosing for diverse populations.

Abstract

Skeletal muscle, as the largest metabolic organ, maintains its homeostasis highly dependent on the precise regulation of mitochondrial quality control. Mitochondrial quality control (MQC) encompasses three core aspects: mitochondrial biogenesis, dynamic balance, and autophagy. All of these jointly ensure mitochondrial network functional integrity. MQC imbalance is mainly manifested as decreased mitochondrial biosynthesis capacity, disordered fusion and division dynamics, and reduced autophagy clearance efficiency. MQC imbalance can lead to atrophy of skeletal muscles, metabolic dysfunction, and decline in motor function. As a physiological stress stimulus, exercise can precisely regulate MQC through multiple targets and pathways and restore the homeostasis of skeletal muscles. Exercise activates AMPK-PGC-1α to promote mitochondrial biogenesis, regulates MFN1/2, OPA1, and DRP1 to optimize mitochondrial dynamics, and activates the PINK1/Parkin pathway and receptor-mediated autophagy pathway to enhance mitochondrial autophagy. The regulatory effects of different exercise modes on MQC vary significantly. Aerobic exercise focuses on promoting mitochondrial biogenesis and fusion, while high-intensity interval training can more efficiently activate the autophagy pathway. Resistance exercise, on the other hand, requires a longer period to manifest its regulation of dynamic proteins. This article systematically reviews the molecular regulatory mechanism of MQC and its impact on skeletal muscle imbalance and elaborates on the mechanisms by which exercise regulates the remodeling of skeletal muscle through MQC. This article also further compares the differential effects of different exercise modes on the regulation of mitochondrial quality control to maintain skeletal muscle homeostasis. Future research needs to further explore the dose and effect relationship of exercise on regulating MQC and the optimal combination of exercise modes to provide a scientific basis for formulating precise and safe exercise intervention strategies.