Resistance exercise has been confirmed to be important for maintaining muscle mass and function. However, despite considerable experimental studies, the underlying mechanisms still requires further investigation to be elucidated. Sestrin1 is a stress-inducible protein strongly associated with the occurrence and development of skeletal muscle dysfunction. Besides, oxidative stress is believed to be a major pathogenic mechanism in the development of skeletal muscle atrophy, whereas regular exercise training induces the endogenous antioxidative system and protects the body against adverse effects of oxidative stress. Nevertheless, whether Sestrin1 is involved in the amelioration of resistance exercise on muscle atrophy and the role of its antioxidant function in this process remains unknown. Here we show that six-week resistance exercise training significantly improved muscle function, muscle mass, and oxidative damage and maintained the level of Sestrin1 in dexamethasone-treated C57BL/6J mice. Mechanistically, Sestrin1 overexpression rescued protein degradation and oxidative stress in atrophied myotubes. Furthermore, an emerging regulator of cellular defense against toxic and oxidative insults, nuclear factor erythroid2–related factor 2 (Nrf2) controls the basal and induced expression of an array of antioxidant response element–dependent genes to regulate the pathophysiological outcomes of oxidant exposure. In this study, we found that Nrf2 is a target of Sestrin1, and Nrf2 nuclear translocation is facilitated by Sestrin1. ML385 (an Nrf2 inhibitor) treatment mitigated the regulatory effects of overexpression-Sestrin1. Therefore, Sestrin1 was involved in the process of resistance exercise against skeletal muscle atrophy, which may be closely related to its antioxidant capacity, revealing a potential therapeutic strategy for reducing the loss of skeletal muscle.

Gut dysbiosis is associated with several pathological processes. Previous study showed that regular exercise can protect against dysmetabolism in high-fat diet (HFD) fed mice through butyrate-SESN2 pathway, and SESN2 ablation weakened the protective effects of exercise. Here, we investigated whether SESN2-deficiency suppresses the exercise response to microbiota composition and subsequently reduces the benefits of exercise on dysmetabolism induced by HFD. Wild type (WT) and SESN2^−/− mice were assigned to five-groups, fed with either normal chow or HFD and with or without exercise training for 15-week. Fecal microbiota composition and function were assessed by 16S rRNA sequencing. The sequencing results showed that SESN2^−/− mice displayed differed microbiome profile from WT mice. Exercise enriched the microflora diversity and increased the beneficial microbial species in WT mice, and SESN2 ablation weakened the beneficial effects of exercise on microbial resilience following HFD consumption. Moreover, network analysis revealed that exercise increased correlation density and clustering of operational taxonomic units in WT mice only. KEGG demonstrated that some dominant metabolism-related enzymes and modules increased in SESN2^−/− mice. Our results indicated that the effects of exercise on metabolism are associated with the perturbations of gut microbiota composition and function, suggesting that SESN2 contributes to maintain metabolic homeostasis.

The health benefits of exercise have attracted substantial attention, because regular exercise can strengthen muscles and improve endurance. Physical activity is an integral part of an overall healthy lifestyle, which helps protect against chronic diseases, such as obesity, insulin resistance and type 2 diabetes. In consideration of the differences in duration, intensity, and type of activity of exercise, it is likely to involve different signaling pathways and bring different benefits in different tissues. Here we review our growing knowledge of exercise training adaptations and regulation in cellular processes related to energy metabolism, aging and autophagy, and many important findings remain to be discovered.