Impaired mitochondrial function has been implicated in the pathogenesis of age-associated metabolic diseases through regulation of cellular redox balance. Exercise training is known to promote mitochondrial biogenesis in part through induction of the transcriptional coactivator peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α). Recently, mitochondrial ADP sensitivity has been linked to reactive oxygen species (ROS) emission with potential impact on age-associated physiological outcomes, but the underlying molecular mechanisms remain unclear. Therefore, the present study investigated the effects of aging and exercise training on mitochondrial properties beyond biogenesis, including respiratory capacity, ADP sensitivity, ROS emission, and mitochondrial network structure, in myofibers from inducible muscle-specific PGC-1α-knockout mice and control mice. Aged mice displayed lower running endurance and mitochondrial respiratory capacity than young mice. This was associated with intermyofibrillar mitochondrial network fragmentation, diminished submaximal ADP-stimulated respiration, increased mitochondrial ROS emission, and oxidative stress. Exercise training reversed the decline in maximal respiratory capacity independent of PGC-1α, whereas exercise training rescued the age-related mitochondrial network fragmentation and the impaired submaximal ADP-stimulated respiration in a PGC-1α-dependent manner. Furthermore, lack of PGC-1α was associated with altered phosphorylation and carbonylation of the inner mitochondrial membrane ADP/ATP exchanger adenine nucleotide translocase 1. In conclusion, the present study provides evidence that PGC-1α regulates submaximal ADP-stimulated respiration, ROS emission, and mitochondrial network structure in mouse skeletal muscle during aging and exercise training.

PGC-1α has been suggested to regulate exercise training-induced metabolic adaptations and autophagy in skeletal muscle. The factors regulating PGC-1α, however, have not been fully resolved. The aim was to investigate the impact of β-adrenergic signaling in PGC-1α-mediated metabolic adaptations in skeletal muscle with exercise training. Muscle was obtained from muscle-specific PGC-1α knockout (MKO) and lox/lox mice 1) 3 h after a single exercise bout with or without prior injection of propranolol or 3 h after a single injection of clenbuterol and 2) after 5 wk of wheel running exercise training with or without propranolol treatment or after 5 wk of clenbuterol treatment. A single clenbuterol injection and an acute exercise bout similarly increased the mRNA content of both N-terminal and full-length PGC-1α isoforms, and prior propranolol treatment reduced the exercise-induced increase in mRNA of all isoforms. Furthermore, a single clenbuterol injection elicited a PGC-1α-dependent increase in cytochrome c and vascular endothelial growth factor mRNA, whereas prolonged clenbuterol treatment increased fiber size but reduced capillary density. Exercise training increased the protein content of OXPHOS, LC3I, and Parkin in a PGC-1α-dependent manner without effect of propranolol, while an exercise training-induced increase in Akt2 and p62 protein required PGC-1α and was blunted by prolonged propranolol treatment. This suggests that β-adrenergic signaling is not required for PGC-1α-mediated exercise training-induced adaptations in mitochondrial proteins, but contributes to exercise training-mediated adaptations in insulin signaling and autophagy regulation through PGC-1α. Furthermore, changes observed with acute stimulation of compounds like clenbuterol and propranolol may not lead to corresponding adaptations with prolonged treatment.

The aim of the study was to investigate the impact of autophagy inhibition on skeletal muscle mitochondrial function and glucose homeostasis in young and aged mice. The transcriptional co‐activator PGC‐1α regulates muscle oxidative phenotype which has been shown to be linked with basal autophagic capacity. Therefore, young and aged inducible muscle‐specific PGC‐1α knockout (iMKO) mice and littermate lox/lox controls were used in three separate experiments performed after either saline or colchicine injections on two consecutive days: (1) Euthanization in the basal state obtaining skeletal muscle for mitochondrial respirometry, (2) whole body glucose tolerance test, and (3) in vivo insulin‐stimulated 2‐deoxyglucose (2‐DG) uptake into skeletal muscle. Muscle PGC‐1α was not required for maintaining basal autophagy flux, regardless of age. Colchicine‐induced inhibition of autophagy was associated with impairments of skeletal muscle mitochondrial function, including reduced ADP sensitivity and altered mitochondrial redox balance in both young and aged mice. Colchicine treatment reduced the glucose tolerance in aged, but not young mice, and similarly in iMKO and lox/lox mice. Colchicine reduced insulin‐stimulated 2‐DG uptake in soleus muscle in aged mice, independently of PGC‐1α, and without affecting insulin‐regulated phosphorylation of proximal or distal mediators of insulin signaling. In conclusion, the results indicate that autophagy regulates the mitochondrial ADP sensitivity and redox balance as well as whole body glucose tolerance and skeletal muscle insulin sensitivity in aged mice, with no additional effects of inducible PGC‐1α deletion.

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