Lifelong Aerobic Exercise Alleviates Sarcopenia by Activating Autophagy and Inhibiting Protein Degradation via the AMPK/PGC-1α Signaling Pathway

Abstract

Sarcopenia is an aging-induced syndrome characterized by a progressive reduction of skeletal muscle mass and strength. Increasing evidence has attested that appropriate and scientific exercise could induce autophagy or optimize the functional status of autophagy, which plays a critical role in senescent muscular dystrophy. As a publicly recognized strategy for extending lifespan and improving the health of the elderly, the underlying mechanisms of lifelong regular aerobic exercise for the prevention of sarcopenia have not been fully elucidated. To explore the role of lifelong aerobic exercise in the beneficial regulation of autophagic signaling pathways in senescent skeletal muscle, the natural aging mice were used as the sarcopenia model and subjected to lifelong treadmill running to evaluate corresponding parameters related to skeletal muscle atrophy and autophagic signaling pathways. Compared with the young control mice, the aged mice showed a significant reduction in skeletal muscle mass, gastrocnemius muscle weight/body weight (GMW/BW) ratio, and cross-sectional areas (CSA) of skeletal muscle fibers (p < 0.01). In contrast, lifelong aerobic exercise effectively rescued these reduced biomarkers associated with muscle atrophy. Moreover, as shown in the activated AMPK/PGC-1α signaling pathway, lifelong aerobic exercise successfully prevented the aging-induced impairment of the ubiquitin-proteasome system (UPS), excessive apoptosis, defective autophagy, and mitochondrial dysfunction. The exercise-induced autophagy suppressed the key regulatory components of the UPS, inhibited excessive apoptosis, and optimized mitochondrial quality control, thereby preventing and delaying aging-induced skeletal muscle atrophy.

Redox Signaling and Sarcopenia: Searching for the Primary Suspect

“…As stated in the Mitochondrial Biogenesis section, this is likely mediated by AMPK phosphorylation of PGC-1α. We and others have demonstrated exercise to be one of the most successful means to increase AMPK activity and mitigate sarcopenia [65,112,118]. The divergent responses of AMPK to these conditions highlight the multi-functional nature of this kinase.…”

“…However, AMPK activity has been shown to decrease with age in rat and human skeletal muscle, despite maintenance of its protein content [110,111]. Interestingly enough, combined treadmill running and resistance training or aerobic training alone in rodents were able to attenuate sarcopenia in part by upregulating AMPK and PGC-1α [112,113].…”

Exercise Therapy for People With Sarcopenic Obesity: Myokines and Adipokines as Effective Actors

“…Increased apoptosis can activate Atrogin-1 and MuRF1 ligases, increasing protein degradation and exacerbating age-related skeletal muscle loss. Therefore, one of the characteristics of older mice is an increase in Atrogin-1, MuRF1, and myostatin ( 112 ). Scientific studies have shown that mitochondrial damage and dysfunction due to inactivity can increase proteolysis via the AMPK-FOXO3 axis ( 111 ).…”

Paeoniflorin Ameliorates Skeletal Muscle Atrophy in Chronic Kidney Disease via AMPK/SIRT1/PGC-1α-Mediated Oxidative Stress and Mitochondrial Dysfunction

“…Swollen and enlarged mitochondria are considered a symbol of dysfunction and inability to perform normal fusion activities ( Navratil et al, 2008 ). The accumulation of enlarged and highly disordered arrangement mitochondria in skeletal muscle has been demonstrated in aged ( Liang et al, 2021 ), CKD ( Wang et al, 2019 ), cancer ( Mao et al, 2021 ) and obesity ( Guo et al, 2021 )-induced muscle atrophy. Nevertheless, conflicting experimental results have been observed on lots of occasions.…”