Exercise‐mediated modulation of autophagy in skeletal muscle

Abstract

Although exercise exerts multiple beneficial health effects, it may also damage cellular structures. Damaged elements are continuously degraded and its constituents recycled to produce renovated structures through a process called autophagy, which is essential for the adaptation to training. Autophagy is particularly active in skeletal muscle, where it can be evaluated using specific molecular markers of activation (unc-51-like kinase 1 [ULK1] phosphorylation) and specific proteins indicating increased autophagosome content (increased total LC3, LC3-II, LC3-II/LC3-I ratio). Studies in humans are technically limited but have provided evidence suggesting the activation of autophagy in skeletal muscle through AMP-activated protein kinase (AMPK) and its downstream target ULK1. Autophagy activation is more likely when the intensity is elevated and the exercise performed in the fasted state. The autophagy-gene program and autophagosome content are upregulated after ultraendurance running competitions. However, autophagosome content is reduced after endurance exercise at moderate intensities (50% and 70% of VO max) for 60-120 minutes. Autophagosome content is decreased within the first few hours after resistance training. The effects of regular endurance and strength training on basal autophagy remain to be established in humans. One study has reported that acute severe hypoxia increases autophagosome content in human skeletal muscle, which is reverted by 20 minutes of low-intensity exercise. Experiments with transgenic mice have shown that autophagy is necessary for skeletal muscle adaptation to training. Little is known on how genetic factors, environment, nutrition, drugs and diseases may interact with exercise to modulate autophagy at rest and during exercise in humans.

Early endplate remodeling and skeletal muscle signaling events following rat hindlimb suspension

“…Mammalian Atg13 forms a complex with the ULK1/2, which localizes to autophagic isolation membranes and regulates autophagosome biogenesis. ULK1‐dependent phosphorylation of Atg13 at Ser 355 , leads to the recruitment of Atg13 to damaged mitochondria, enabling efficient mitophagy (Martin‐Rincon, Morales‐Alamo, & Calbet, ). AMPK, activated during low nutrient conditions, directly phosphorylates ULK1 at multiple sites (Ha, Guan, & Kim, ).…”

“…AMPK, activated during low nutrient conditions, directly phosphorylates ULK1 at multiple sites (Ha, Guan, & Kim, ). Conversely, mTOR, which is an inhibitor of autophagy, phosphorylates ULK1 at Ser 757 and disrupts the interaction between ULK1 and AMPK (Martin‐Rincon et al, ). However, despite the increased mTOR phosphorylation at Ser 2448 (Figures b and e) we do not see an increase in ULK1 phosphorylation at Ser 757 (Figures c and e).…”

Autophagy is induced by resistance exercise in young men, but unfolded protein response is induced regardless of age

“…The effects of a long‐term RT period on autophagy have never been investigated in human skeletal muscle . In young men, RT increased LC3II, which indicates an increased number of autophagosomes and possibly increased autophagic flux, because the result was accompanied by unchanged LC3I and P62.…”

Exercise Preserves Lean Mass and Performance during Severe Energy Deficit: The Role of Exercise Volume and Dietary Protein Content

“…The legs performed an amount of exercise proportionally similar to that carried out by ultra-endurance athletes, which could have damaged mitochondria (Fernstrom et al, 2007; Sahlin et al, 2010) and promoted autophagy and mitophagy (Jamart et al, 2012a,b; Martin-Rincon et al, 2017). The combination of a small reduction in muscle mass with a potentially lower mitochondrial density could have lowered the extraction and utilization of O 2 , thereby limiting VO 2 peak (Holmberg, 2015).…”