Effect of acute and chronic autophagy deficiency on skeletal muscle apoptotic signaling, morphology, and function

Abstract

Autophagy is a catabolic process that targets and degrades cytoplasmic materials. In skeletal muscle, autophagy is required for the control of mass under catabolic conditions, but is also basally active in the maintenance of myofiber homeostasis. In this study, we found that some specific autophagic markers (LC3-I, LC3-II, SQSTM1) were basally lower in glycolytic muscle compared to oxidative muscle of autophagy competent mice. In contrast, basal autophagic flux was higher in glycolytic muscle. In addition, we used several skeletal muscle-specific Atg7 transgenic mouse models to investigate the effect of acute (iAtg7) and chronic (cAtg7) autophagy deficiency on skeletal muscle morphology, contractility, and apoptotic signaling. While acute autophagy ablation (iAtg7) resulted in increased centralized nuclei in glycolytic muscle, it did not alter contractile properties or measures of apoptosis and proteolysis. In contrast, with chronic autophagy deficiency (cAtg7) there was an increased proportion of centralized nuclei, as well as reduced force and altered twitch kinetics in glycolytic muscle. Glycolytic muscle of cAtg7 mice also displayed an increased level of the pro-apoptotic protein BAX, as well as calpain and proteasomal enzymatic activity. Collectively, our data demonstrate cumulative damage from chronic skeletal muscle-specific autophagy deficiency with associated apoptotic and proteasomal upregulation. These findings point towards the importance of investigating different muscle/fiber types when studying skeletal muscle autophagy, and the critical role of autophagy in the maintenance of myofiber function, integrity, and cellular health.

Effects of Endurance Training on Detrimental Structural, Cellular, and Functional Alterations in Skeletal Muscles of Heart Failure With Preserved Ejection Fraction

“…We speculate the significant increase of autophagy in the soleus but decrease in the EDL may have contributed, at least in part, to the muscle atrophy and dysfunction observed in HFpEF. Interestingly, previous data have shown that autophagic flux differs between oxidative and glycolytic muscles, which supports the suggestion that HFpEF could modulate this process in a fiber-dependent manner [20]. Moreover our findings also suggest that HFpEF could induce muscle alterations in both a fiber-and time-dependent manner determined by disease progression.…”

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

“…; Paré et al . ). Fibre type changes in response to our short protocol of CCA (3 h day −1 , 9 days) are unlikely to confound the results of this study, since a greater volume and time of stimulation is required to produce a shift in myosin heavy chain expression (Putman et al .…”

“…fast vs. slow) exhibit differences in autophagy/mitophagy turnover. Some studies have concluded that oxidative fibres have higher rates of flux (Lira et al 2013), while others have noted greater rates in predominantly glycolytic muscle (Mofarrahi et al 2013;Paré et al 2017). Fibre type changes in response to our short protocol of CCA (3 h day −1 , 9 days) are unlikely to confound the results of this study, since a greater volume J Physiol 596.16 and time of stimulation is required to produce a shift in myosin heavy chain expression (Putman et al 2001), and our previous work has documented enhanced fatigue resistance, but no change in half-relaxation time or time to peak tension in young or aged skeletal muscle following this CCA protocol ).…”

Autophagy Is a Promoter for Aerobic Exercise Performance during High Altitude Training

“…Protein degradation in skeletal muscle is mainly controlled by two proteolytic systems, namely ubiquitin proteasome system (UPS) and autophagy-lysosome system (ALS). Several studies have shown that autophagy is required for the control of skeletal muscle mass under catabolic conditions and plays an important role in maintaining the homeostasis and integrity of skeletal muscle [ 63 ], especially the autophagy at the appropriate level. Previous studies have proved the importance of autophagy in skeletal muscle of Atg7 gene knockout rats, and autophagy inhibition can lead to muscle atrophy and myopathy [ 64 ].…”

“…Under the basal autophagy, slow-twitch muscle fibers are obviously higher than hybrid fibers and fast-twitch muscle fibers [ 22 ]. Compared with oxidative muscle, specific autophagic markers (LC3-I, LC3-II, and SQSTM1) are basally lower, but basal autophagic flux is higher in glycolytic muscle [ 63 ].…”