The aim of the present study was to examine the role of PGC-1α in intensity dependent exercise and exercise training-induced metabolic adaptations in mouse skeletal muscle. Whole body PGC-1α knockout (KO) and littermate wildtype (WT) mice performed a single treadmill running bout at either low intensity (LI) for 40 min or moderate intensity (MI) for 20 min. Blood and quadriceps muscles were removed either immediately after exercise or at 3h or 6h into recovery from exercise and from resting controls. In addition PGC-1α KO and littermate WT mice were exercise trained at either low intensity (LIT) for 40 min or at moderate intensity (MIT) for 20 min 2 times pr. day for 5 weeks. In the first and the last week of the intervention period, mice performed a graded running endurance test. Quadriceps muscles were removed before and after the training period for analyses. The acute exercise bout elicited intensity dependent increases in LC3I and LC3II protein and intensity independent decrease in p62 protein in skeletal muscle late in recovery and increased LC3II with exercise training independent of exercise intensity and volume in WT mice. Furthermore, acute exercise and exercise training did not increase LC3I and LC3II protein in PGC-1α KO. In addition, exercise-induced mRNA responses of PGC-1α isoforms were intensity dependent. In conclusion, these findings indicate that exercise intensity affected autophagy markers differently in skeletal muscle and suggest that PGC-1α regulates both acute and exercise training-induced autophagy in skeletal muscle potentially in a PGC-1α isoform specific manner.

No abstract

Hepatic autophagy has been shown to be regulated by acute exercise and exercise training. Moreover, high‐fat diet‐induced steatosis has been reported to be associated with impaired hepatic autophagy. In addition, autophagy has been shown to be regulated by acute exercise and exercise training in a PGC‐1α dependent manner in skeletal muscle. The aim of this study was to test the hypotheses that high‐fat high‐fructose (HFF) diet changes hepatic autophagy and mitophagy, that exercise training can restore this through a PGC‐1α‐mediated mechanism, and that acute exercise regulates autophagy and mitophagy in the liver. Liver samples were obtained from liver‐specific PGC‐1α KO mice and their littermate Lox/Lox mice fed a HFF diet or a control diet for 13 weeks. The HFF mice were either exercise trained (ExT) on a treadmill the final 5 weeks or remained sedentary (UT). In addition, half of each group performed at the end of the intervention an acute 1 h exercise bout. HFF resulted in increased hepatic BNIP3 dimer and Parkin protein, while exercise training increased BNIP3 total protein without affecting the elevated BNIP3 dimer protein. In addition, exercise training reversed a HFF‐induced increase in hepatic LC3II/LC3I protein ratio, as well as a decreased PGC‐1α mRNA level. Acute exercise increased hepatic PGC‐1α mRNA in HFF UT mice only. In conclusion, this indicates that exercise training in part reverses a HFF‐induced increase in hepatic autophagy and capacity for mitophagy in a PGC‐1α‐independent manner. Moreover, HFF may blunt acute exercise‐induced regulation of hepatic autophagy.

The present study aimed at investigating fasting-induced responses in regulators and markers of autophagy in vastus lateralis muscle from untrained and trained human subjects. Untrained and trained subjects (based on level of maximum oxygen uptake, muscle CS activity and OXPHOS protein level) fasted for 36h with vastus lateralis muscle biopsies obtained at 2, 12, 24 and 36h after a standardized meal. Fasting reduced (p<0.05) skeletal muscle microtubule-associated protein-1A/1B light chain 3 (LC3)I, (LC3)II and adaptor protein sequestosome 1/p62 (p62) protein content in untrained subjects only. Moreover, skeletal muscle RAC-alpha serine/threonine-protein kinase (AKT), AMP-activated protein kinase (AMPK), Unc-51 like autophagy activating kinase 1 (ULK1) phosphorylation state, as well as Bcl-2-interacting coiled-coil protein 1 (Beclin1) and ULK1 phosphorylation was lower (p<0.05) in trained than untrained subjects during fasting. In addition, the concentrations of several amino acids were lower (p<0.05) in trained than untrained, and the plasma concentration profile of several amino acids was different in untrained and trained subjects during fasting. Taken together, these findings suggest that 36h of fasting has effects on some mediators of autophagy in untrained human skeletal muscle and that training state influences the effect of fasting on autophagy signaling and on mediators of autophagy in skeletal muscle.

Diet‐induced obesity is associated with hepatic steatosis, which has been linked with activation of the unfolded protein response (UPR). PGC‐1α is a transcriptional coactivator involved in exercise training‐induced adaptations in muscle and liver. Therefore, the aim of this study was to test the hypothesis that PGC‐1α is required for exercise training‐mediated prevention of diet‐induced steatosis and UPR activation in liver. Male liver‐specific PGC‐1α knockout (LKO) and littermate floxed (lox/lox) mice were divided into two groups receiving either control diet (CON) or high‐fat high‐fructose diet (HFF). After 9 weeks, half of the HFF mice were treadmill exercise trained for 4 weeks (HFF+ExT), while the rest were kept sedentary. HFF resulted in increased body and liver weight, adiposity, hepatic steatosis and whole body glucose intolerance as well as decreased hepatic IRE1α phosphorylation. Exercise training prevented the HFF‐induced weight gain and partially prevented increased liver weight, adiposity and glucose intolerance, but with no effect on liver triglycerides. In addition, BiP protein and CHOP mRNA content increased with exercise training compared with CON and HFF, respectively. Lack of PGC‐1α in the liver only resulted in minor changes in the PERK pathway. In conclusion, this study provides evidence for dissociation between diet‐induced hepatic triglyceride accumulation and hepatic UPR activation. In addition, PGC‐1α was not required for maintenance of basal UPR in the liver and due to only minor exercise training effects on UPR further studies are needed to conclude on the potential role of PGC‐1α in exercise training‐induced adaptations in hepatic UPR.