PGC-1 alpha deficiency reveals sex-specific links between cardiac energy metabolism and EC-coupling during development of heart failure in mice

Aims Biological sex has fundamental effects on mammalian heart physiology and pathogenesis. While it has been established that female sex is a protective factor against most cardiovascular diseases (CVDs), this beneficial effect may involve pathways associated with cardiac energy metabolism. Our aim was to elucidate the role of transcriptional coactivator PGC-1 alpha in sex dimorphism of heart failure (HF) development. Methods and results Here, we show that mice deficient in cardiac expression of the peroxisome proliferator-activated receptor gamma (PPAR-gamma) coactivator-1 alpha (PGC-1 alpha) develop dilated HF associated with changes in aerobic and anaerobic metabolism, calcium handling, cell structure, electrophysiology, as well as gene expression. These cardiac changes occur in both sexes, but female mice develop an earlier and more severe structural and functional phenotype associated with dyssynchronous local calcium release resulting from disruption of t-tubular structures of the cardiomyocytes. Conclusions These data reveal that the integrity of the subcellular Ca2+ release and uptake machinery is dependent on energy metabolism and that female hearts are more prone to suffer from contractile dysfunction in conditions with compromised production of cellular energy. Furthermore, these findings suggest that PGC-1 alpha is a central mediator of sex-specific differences in heart function and CVD susceptibility.