Exercise as a Metabolic Regulator: Targeting AMPK/mTOR-Autophagy Crosstalk to Counteract Sarcopenic Obesity

Sarcopenic obesity (SO), a geriatric syndrome characterized by the coexistence of progressive skeletal muscle atrophy and excessive adipose tissue accumulation, represents a growing public health challenge associated with aging populations. While multifactorial pathogenesis involves chronic inflammation, hormonal changes, and mitochondrial dysfunction, sedentary lifestyles and aging remain primary modifiable and non-modifiable risk factors, respectively. Mechanistically, exercise exerts dual therapeutic effects: (1) hypertrophy of type II muscle fibers through IGF-1/Akt/mTORC1 signaling activation, and (2) enhanced lipid β-oxidation via AMPK/PGC1α axis stimulation, thereby mitigating both sarcopenia and adiposity. The autophagy-lysosome system, a conserved cellular quality-control mechanism, orchestrates organelle turnover and nutrient recycling through three distinct pathways: macroautophagic, chaperone-mediated autophagy, and mitophagy. In SO, impaired proteolytic and lipolytic processes converge to induce autophagic flux blockade, manifested by accumulated p62/SQSTM1 and reduced LC3-II/LC3-I ratio. Targeting the AMPK/mTOR signaling nexus, which senses cellular energy status, emerges as a strategic intervention. Exercise-mediated ATP depletion activates AMPK while suppressing mTORC1, thereby synchronously inducing autophagy initiation (ULK1 phosphorylation) and lysosomal biogenesis (TFEB nuclear translocation). This metabolic reprogramming ultimately restores proteostasis and lipid homeostasis in myocytes and adipocytes.