Regulation of cardiac metabolism by autophagy

Autophagy is a catabolic pathway thatdegradesdamaged proteins and organelles in lysosome; however, the exact role ofautophagy in cardiac function in physiological and pathological statesis incompletely understood. To investigate the role of autophagy in the heart, we generated a cardiac-specific autophagy-deficient mousemodel with deletion of ATG3 gene (cATG3 KO)incardiomyocytes. ATG3-deficient heartsexhibited reduced ATG3 proteinand decreased autophagic flux. cATG3 KOmice developed cardiac contractile dysfunction at 4 weeks old in the absence of fibrosis. Mitochondrial function was impairedin cATG3 KO mouseheartsat 1 week old, which precedes cardiac contractile dysfunction. Interestingly, we found thatNAD+metabolic fluxwas alteredin cATG3 KO mousehearts, characterized by increased nicotinamide N-Methyltransferase(NNMT) expression and accelerated NAD+degradation.NNMT overexpression was sufficient to cause mitochondrial dysfunction and NNMT inhibition prevented mitochondrial dysfunctionin CQ-treated H9C2 cells. Moreover, nicotinamide mononucleotide(NMN), the precursor of NAD+, raised cardiac NAD+content and rescuedcardiac contractile dysfunction in cATG3 KO mice. Thesedatasuggest that autophagy playsan essential role in maintaining cardiac functionby regulating NNMT expression and NAD+homeostasis in the heart.Exercise training has been shownto be beneficial for cardiac function, although the exact molecularmechanism isunclear. To investigate the role of autophagy in maintaining cardiac homeostasisunder exercise conditions, mice with germline haplo-insufficiency of the autophagy regulator beclin 1(Atg6)weresubject to6 weeks treadmill ivtraining, and wild-type (WT) mice were used as control. Compared to WT mice,beclin 1 heterozygous mice exhibitedimpaired autophagyin response to exercise training.Interestingly, we found mitochondrial biogenesis andcardiac contractilefunction improvement wasattenuated after exercise trainingin beclin 1 heterozygous mouse heart. These results indicate autophagyalso plays anessentialrolefor mediating the increase in cardiac functionin response to exerciseby promoting mitochondrial biogenesis.