The aim of the present study was to test the hypothesis that PGC-1α is involved in the regulation of hepatic UPR and autophagy in response to both exercise and fasting in mice. Liver-specific PGC-1α knockout (LKO) mice and their floxed littermates (lox/lox) were used in two experimental parts. Liver and plasma were obtained from (1) fed and 18 h fasted mice and (2) immediately after, 2, 6, and 10 h after 1-h treadmill running as well as from resting mice, where one resting group was euthanized at time points corresponding to 0 and 2 h and another corresponding to 6 and 10 h of recovery. Hepatic eIF2α phosphorylation and sXBP1 mRNA content increased immediately after exercise and IRE1α phosphorylation as well as cleaved ATF6 protein content was higher 2 h into recovery than at rest in both genotypes. Fasting reduced hepatic IRE1α phosphorylation and protein content as well as PERK protein and sXBP1 mRNA content similarly in lox/lox and LKO mice. In addition, the hepatic LC3II/LC3I protein ratio increased immediately after exercise and with fasting in both genotypes, while fasting decreased p62 protein content in lox/lox mice. Liver-specific PGC-1α knockout did not affect these responses, but the LC3II/LC3I protein ratio was higher in LKO than lox/lox mice in both rest groups. In conclusion, the present study provides evidence for pathway-specific exercise-induced activation and fasting-induced downregulation of the UPR as well as exercise and fasting-induced regulation of autophagy in mouse liver. In addition, overall PGC-1α does not seem to be required for the fasting and exercise-induced regulation of UPR and autophagy, but may be involved in regulating basal hepatic autophagy.

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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