Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis

Abstract

Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes1. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control2. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism3. Moreover, in animal models, autophagy protects against diseases such as cancer, neuro-degenerative disorders, infections, inflammatory diseases, ageing and insulin resistance4-6. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)- induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.

Effects of aerobic training on markers of autophagy in the elderly

“…Our data show that aerobic exercise induces a reduction in p62/SQSTM1, suggesting an increase in the expression of autophagy regulatory proteins after the training program. These results are in line with previous studies which showed an increase in LC3II and a decrease in p62/SQSTM1 expression after exercise in different rodent (He et al 2012;Lira et al 2013;Bayod et al 2014) and human models (Schwalm et al 2015), hence supporting the notion that high-intensity exercise induces an increased autophagy.…”

“…Indeed, both acute and chronic endurance exercise seem to induce adaptations in the autophagy pathway Jamart et al 2012;Schwalm et al 2015;Weng et al 2013). However, it should be noted that most of the available data related to the effects of exercise on autophagy proteins in different tissues have been obtained from rodent studies, where long training periods induce a significant increase in the protein expression of beclin-1 and LC3I/II associated to a lowered expression of p62/SQSTM1 in muscles (He et al 2012;Kim et al 2013;Lira et al 2013; (Bayod et al 2014). Nevertheless and as far as we know, few investigations have studied the effects of exercise on the age-related impairment of autophagy using a murine model.…”

Autophagy at the crossroads of catabolism and anabolism

“…Detailed metabolic analysis revealed that Atg7 ablation causes a failure to mobilize serum-free fatty acids and initiates the rapid depletion of liver glycogen stores, resulting in low serum glucose levels and impaired metabolic fitness in starved animals 95 . Moreover, during exercise, autophagy is induced in cardiac and skeletal muscles, adipose tissue and pancreatic β-cells, which provides protection against glucose intolerance 101 . Similarly, in pancreatic β-cells, autophagy is important for maintaining glucose tolerance because mice lacking ATG7 in β-cells have reduced serum insulin levels and hyperglycaemia 102,103 .…”

Proteostasis in cardiac health and disease

“…Indeed, exercise has been proven beneficial in the treatment of neuro degenerative diseases associated with misfolded pro teins 169 . Interestingly, exercise induces autophagy in cardiac muscle of mice 170 . In addition, voluntary exercise in a mouse model of desmin related cardiomyopathy reduced protein aggregation and disease progression 171 .…”