PGC-1 alpha accelerates cytosolic Ca2+ clearance without disturbing Ca2+ homeostasis in cardiac myocytes

Energy metabolism and Ca(2+) handling serve critical roles in cardiac physiology and pathophysiology. Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1 alpha) is a multi-functional coactivator that is involved in the regulation of cardiac mitochondrial functional capacity and cellular energy metabolism. However, the regulation of PGC-1 alpha in cardiac Ca(2+) signaling has not been fully elucidated. To address this issue, we combined confocal line-scan imaging with off-line imaging processing to characterize calcium signaling in cultured adult rat ventricular myocytes expressing PGC-1 alpha via adenoviral transduction. Our data shows that overexpressing PGC-1 alpha improved myocyte contractility without increasing the amplitude of Ca(2+) transients, suggesting that myofilament sensitivity to Ca(2+) increased. Interestingly, the decay kinetics of global Ca(2+) transients and Ca(2+) waves accelerated in PGC-1 alpha-expressing cells, but the decay rate of caffeine-elicited Ca(2+) transients showed no significant change. This suggests that sarcoplasmic reticulum (SR) Ca(2+)-ATPase (SERCA2a), but not Na(+)/Ca(2+) exchange (NCX) contribute to PGC-1 alpha-induced cytosolic Ca(2+) clearance. Furthermore, PGC-1 alpha induced the expression of SERCA2a in cultured cardiac myocytes. Importantly, overexpressing PGC-1 alpha did not disturb cardiac Ca(2+) homeostasis, because SR Ca(2+) load and the propensity for Ca(2+) waves remained unchanged. These data suggest that PGC-1 alpha can ameliorate cardiac Ca(2+) cycling and improve cardiac work output in response to physiological stress. Unraveling the PGC-1 alpha-calcium handling pathway sheds new light on the role of PGC-1 alpha in the therapy of cardiac diseases.