Does Exercise Regulate Autophagy in Humans? A Systematic Review and Meta-Analysis.

Background: Macroautophagy/autophagy is an essential recycling process that is involved in a wide range of biological functions as well as in diseases. The regulation of autophagy by exercise and the associated health benefits have been revealed by rodent studies over the past decade, but the evidence from human studies remains inconclusive.

Methods: The MEDLINE, Embase, Cochrane, Scopus, and Web of Science databases were systematically searched from inception until September 2022. Human studies that explored potential effects of physical exercise on autophagy at the protein level were selected according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A random-effects model was used for the meta-analysis.

Results: Twenty-six studies were included in the meta-analysis. Subgroup analyses revealed that an acute bout of resistance exercise attenuated autophagy, as characterized by lower levels of microtubule-associated proteins 1A/1B light chain 3B (LC3-II) and higher levels of sequestosome 1 (SQSTM1). In contrast, the long-term resistance exercise elevated autophagy, as shown by higher levels of LC3-II and lower levels of SQSTM1. No significant changes in LC3-II levels were observed with moderate- or vigorous-intensity endurance exercise either as an acute bout or long-term. In terms of tissue types, exercise exerted opposite effects between skeletal muscles and peripheral blood mononuclear cells (PBMCs), whereby autophagy was suppressed in skeletal muscles when activated in the PBMCs. Other meta-analyses have also shown significant alterations in the level of many canonical autophagic and mitophagic proteins, including unc-51 like autophagy activating kinase (ULK1)^S317, ULK1^S757, Beclin-1, ATG12, BCL2/adenovirus E1B 19 kDa protein-interacting protein 3, and PARKIN following exercise, suggesting the activation of canonical autophagy and mitophagy, although the scope of those analyses was more limited.

Conclusion: Our findings demonstrate that physical exercise probably regulates autophagy in an exercise modality- and tissue-dependent manner in humans, although further investigation is needed. Customized exercise prescriptions should be aimed for when implementing exercise to regulate autophagy in humans.Abbreviations: ATG: autophagy-related gene; BCL2L13: BCL2-like 13; BECN1: beclin1; BNIP3: BCL2/adenovirus E1B 19 kDa protein-interacting protein 3; GABARAP: gamma-aminobutyric acid receptor-associated protein; GAPDH: glyceraldehyde 3-phosphate dehydrogenase; LAMP2: lysosome-associated membrane protein 2; LC3B: microtubule-associated proteins 1A/1B light chain 3B; MD: mean difference; mTOR: mammalian target of rapamycin; PBMC: peripheral blood mononuclear cells; PINK1: PTEN-induced kinase 1; PRISMA: preferred reporting items for systematic review and meta-analysis; SD: standard deviation; SQSTM1: sequestosome 1; ULK1: unc-51 like autophagy activating kinase 1; VDAC1: voltage-dependent anion-selective channel 1.