Muscle PGC-1α in exercise and fasting-induced regulation of hepatic UPR in mice

Aim To provide a detailed time course of hepatic autophagy and all UPR branches in response to an acute bout of exercise and 24 hours of fasting and test the hypothesis that muscle-specific PGC-1 alpha overexpression dampens the UPR and autophagy responses to these metabolic challenges. Methods Results Muscle-specific PGC-1 alpha overexpression (TG) and wild-type (WT) mice (a) performed a single bout of exercise, where the liver was obtained immediately after exercise, 2, 6 or 10 hours into recovery as well as from resting mice or (b) fasted for 24 hours or remained fed and the liver was obtained. In both genotypes, hepatic PERK and eIF2 alpha phosphorylation increased immediately after exercise, with no change in IRE1 alpha phosphorylation and cleaved ATF6 protein. Fasting decreased PERK, eIF2 alpha and IRE1 alpha phosphorylation as well as increased cleaved ATF6 protein in both genotypes. Hepatic p62 was unchanged, while LC3II/LC3I ratio increased immediately after exercise and LC3II protein increased in response to fasting in both genotypes. TG mice had lower eIF2 alpha phosphorylation after exercise, a blunted fasting-induced CHOP and HSP72 mRNA response and in fasted mice lower GADD34 and BiP mRNA as well as FAS protein in the liver than WT mice. Conclusion This study provides for the first time evidence for transient pathway-specific activation of hepatic UPR and increase in markers of autophagy in the liver with acute exercise. On the other hand, fasting both increased and decreased UPR branches and seemed to increase autophagy. In addition, muscle PGC-1 alpha seemed to dampen some of these responses.