Regulation of the autophagy system during chronic contractile activity-induced muscle adaptations

Abstract

Skeletal muscle is adaptable to exercise stimuli via the upregulation of mitochondrial biogenesis, and recent studies have suggested that autophagy also plays a role in exercise‐induced muscle adaptations. However, it is still obscure how muscle regulates autophagy over the time course of training adaptations. This study examined the expression of autophagic proteins in skeletal muscle of rats exposed to chronic contractile activity (CCA; 6 h/day, 9V, 10 Hz continuous, 0.1 msec pulse duration) for 1, 3, and 7 days (n = 8/group). CCA‐induced mitochondrial adaptations were observed by day 7, as shown by the increase in mitochondrial proteins (PGC‐1α, COX I, and COX IV), as well as COX activity. Notably, the ratio of LC3 II/LC3 I, an indicator of autophagy, decreased by day 7 largely due to a significant increase in LC3 I. The autophagic induction marker p62 was elevated on day 3 and returned to basal levels by day 7, suggesting a time‐dependent increase in autophagic flux. The lysosomal system was upregulated early, prior to changes in mitochondrial proteins, as represented by increases in lysosomal system markers LAMP1, LAMP2A, and MCOLN1 as early as by day 1, as well as TFEB, a primary regulator of lysosomal biogenesis and autophagy flux. Our findings suggest that, in response to chronic exercise, autophagy is upregulated concomitant with mitochondrial adaptations. Notably, our data reveal the surprising adaptive plasticity of the lysosome in response to chronic contractile activity which enhances muscle health by providing cells with a greater capacity for macromolecular and organelle turnover.

Autophagy and mitophagy flux in young and aged skeletal muscle following chronic contractile activity

“…We examined markers of the lysosome in young and aged conditions, and also with CCA. In muscle of young animals, we have previously observed that CCA leads to an early adaptive increase in lysosomal markers, indicative of organelle biogenesis prior to mitochondrial adaptations (Kim & Hood, 2017). In the current study, we observed a CCA-induced increase in LAMP-1, supporting this increase in the capacity of muscle with respect to the terminal step of autophagy.…”

“…; Mejías‐Peña et al . ; Kim & Hood, ). He and colleagues () observed a decreased association of Beclin 1 with Bcl‐2 within 30 min of acute exercise, despite a rise in total protein levels of Beclin 1.…”

“…We also observed an increase in Beclin 1 protein expression in young muscle exposed to CCA. Previous reports have identified an increase in Beclin 1 following both acute and chronic exercise (He et al 2012;Ju et al 2016), but some opposing results have also been documented (McMillan et al 2015;Mejías-Peña et al 2016;Kim & Hood, 2017). He and colleagues (2012) observed a decreased association of Beclin 1 with Bcl-2 within 30 min of acute exercise, despite a rise in total protein levels of Beclin 1.…”

Mitophagy Regulation in Skeletal Muscle: Effect of Endurance Exercise and Age

“…They contain pHdependent enzymes for the breakdown of macromolecules and organelles. They also possess a number of lysosomeassociated membrane proteins (LAMPs) that are involved in autophagosome-lysosome fusion [14,26,28,49,56]. Lysosomal permeases and transporters then export amino acids and other by-products of degradation back out to the cytoplasm, where they can be re-used for building macromolecules or for metabolism ( Fig.…”

“…It is well known that exercise has multiple beneficial health effects. Engaging in regular exercise facilitates an improvement in glucose homeostasis, cardiovascular health, the maintenance of muscle mass, and can help reduce complications that occur with aging [2,6,19,26,28,43,57]. On a molecular level, regular exercise exerts favorable effects on bioenergetics and nutrient delivery and uptake, which largely occur due to the accumulated adaptation of muscle in response to individual acute exercise bouts [18,19,48].…”