Mechanism by which exercise regulates autophagy in different physiological systems

Zhang Shuli; Hou Chaowen; Yuan Shanshan; Ma Yuhua

doi:10.12307/2026.751

Abstract：BACKGROUND:Studies have shown that exercise can regulate autophagy through multiple signaling pathways,playing a crucial role in maintaining cellular homeostasis,improving metabolism,delaying aging,and preventing diseases. OBJECTIVE:To systematically review the molecular mechanism by which exercise regulates autophagy and to analyze its pathophysiological roles in different physiological systems. METHODS:An online search of the Web of Science,PubMed,CNKI,Wanfang,and VIP databases was conducted to retrieve relevant literature.The Chinese search terms included"exercise,mitophagy,AMPK/mTOR pathway,oxidative stress,Nrf2/Beclin1 pathway,LC3,ULK1,Beclin1,p62,"while the English search terms included"exercise,autophagy,mitophagy,lipophagy,AMPK/mTOR pathway,oxidative stress,Nrf2/Beclin1 pathway,LC3,ULK1,Beclin1,p62."Based on the inclusion and exclusion criteria,92 high-quality documents focusing on molecular mechanisms and multi-system effects were included in this systematic review. RESULTS AND CONCLUSION:Exercise phosphorylates Unc-51-like kinase 1 through AMP-activated protein kinase,inhibits the activation of mammalian target of rapamycin complex 1 involved in autophagy initiation.This process relies on Beclin1-Ⅲ phosphatidylinositol 3-kinase complex to promote the nucleation of autophagosomes,regulate the lipidation of microtubule-associated protein light chain 3,and Atg5-Atg12 complex mediated extension of autophagosomes.Oxidative stress forms an"antioxidant-autophagy"regulatory network through the Nrf2 Beclin1 pathway,promoting mitophagy to eliminate damaged organelles.Exercise degrades excess lipids in the liver via autophagy,while mitophagy enhances insulin sensitivity,thereby alleviating the progression of non-alcoholic fatty liver disease and diabetes.Mitophagy removes dysfunctional mitochondria from ischemic myocardial injury,inhibiting cardiomyocyte apoptosis and improving pathological conditions such as heart failure and atherosclerosis.Autophagy also clears amyloid-β protein plaques associated with Alzheimer's disease and α-synuclein associated with Parkinson's disease,delaying the progression of neurodegenerative diseases by enhancing neuronal activity and synaptic plasticity.Resistance exercise balances protein degradation through the insulin-like growth factor 1/mammalian target of rapamycin pathway,promoting muscle repair.Furthermore,autophagy can enhance the differentiation capacity of osteoblasts by activating the Wnt/β-catenin signaling pathway,thereby maintaining skeletal homeostasis.Exercise regulates autophagy through a multi-layered molecular network and exerts adaptive remodeling effects in various physiological systems.Although numerous studies have revealed the relationship between exercise and autophagy,the spatiotemporal specificity and precise regulatory mechanisms of different exercise modalities still require further investigation.