Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation

Abstract

In humans, nutrient deprivation and extreme endurance exercise both activate autophagy. We hypothesized that cumulating fasting and cycling exercise would potentiate activation of autophagy in skeletal muscle. Well-trained athletes were divided into control (n = 8), low-intensity (LI, n = 8), and high-intensity (HI, n = 7) exercise groups and submitted to fed and fasting sessions. Muscle biopsy samples were obtained from the vastus lateralis before, at the end, and 1 h after a 2 h LI or HI bout of exercise. Phosphorylation of ULK1 Ser317 was higher after exercise (P < 0.001). In both the fed and the fasted states, LC3bII protein level and LC3bII/I were decreased after LI and HI (P < 0.05), while p62/ SQSTM1 was decreased only 1 h after HI (P < 0.05), indicating an increased autophagic flux after HI. The autophagic transcriptional program was also activated, as evidenced by the increased level of LC3b, p62/ SQSTM1, GabarapL1, and Cathepsin L mRNAs observed after HI but not after LI. The increased autophagic flux after HI exercise could be due to increased AMPactivated protein kinase a (AMPKa) activity, as both AMPKa Thr172 and ACC Ser79 had a higher phosphorylation state after HI (P < 0.001). In summary, the most effective strategy to activate autophagy in human skeletal muscle seems to rely on exercise intensity more than diet.-Schwalm, C., Jamart, C., Benoit, N., Naslain, D., Prémont, C., Prévet, J., Van Thienen, R., Deldicque, L., Francaux, M. Activation of autophagy in human skeletal muscle is dependent on exercise intensity and AMPK activation. FASEB J. 29, 3515-3526 (2015). www.fasebj.org

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.…”

“…Among interventions aimed to prevent or reverse these undesirable effects, the role of exercise is growing (Vainshtein et al 2014). 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).…”

“…Thus, phosphorylation of ULK-1 at Ser 555 is an important stimulus of autophagy, whereas phosphorylation at Ser 757 promotes an inhibitory effect (Kim et al 2011). Regulation of ULK-1 phosphorylation by feeding has been associated with an activation by AMP-activated protein kinase α in humans (Schwalm et al 2015), and short-term aerobic exercise seems to increase the expression of ULK-1 phosphorylated at Ser 555 (Moller et al 2015). In mice, LC3I is lipidated in response to running exercise, and this is accompanied by decreased ULK-1 Ser 757 phosphorylation (Pagano et al 2014).…”

“…In skeletal muscle, the activation of autophagy during muscle contraction is important for maintaining cellular energy homeostasis as well as for efficient organelle and protein turnover following exercise (Vainshtein et al 2014). Thus, autophagy biomarkers measured in skeletal muscle biopsies are upregulated after ultraendurance running (Jamart et al 2012) or high-intensity cycling (Schwalm et al 2015). Moreover, both interval and continuous aerobic exercise training promote autophagy in CD4 lymphocytes (Weng et al 2013).…”

Effects of skeletal muscle energy availability on protein turnover responses to exercise

“…However, in well-trained human skeletal muscle there is no synergistic effect of prior fasting on autophagy signalling compared with commencing the exercise bout in the fed state, with exercise intensity mitigating the largest autophagic response to contraction (Schwalm et al, 2015). Regardless, specific autophagosomal targeting of mitochondria for degradation, termed mitophagy, constitutes a form of mitochondrial remodelling provoked by endurance exercise.…”