Abstract P3180: Cardiomyocyte Pgc-1α Mediates The Adaptive Response To Endurance Exercise Training In Mice

Exercise has myriad systemic benefits in reducing the incidence from and morbidity of cardio-metabolic diseases. In healthy individuals, aerobic exercise promotes physiologic hypertrophy of the heart, which requires increased mitochondrial numbers and function. In skeletal muscle and heart, a key orchestrator of the adaptation to increased energetic needs is the transcriptional regulator PGC-1α. PGC-1α may mediate cardiac adaptation to physiological stress through its function in mitochondrial biogenesis but also through other mechanisms. The role of cardiac PGC-1α to the systemic training response is poorly understood. We generated PGC-1α cardiomyocyte-specific knockout (cKO) mice to study its role in endurance exercise training. Sedentary cKO mice demonstrated normal cardiac function and no significant differences in acute treadmill exercise tolerance. However, cKO mice demonstrated a lack of ability to augment exercise capacity after 6 weeks of wheel running compared to WT (work achieved 32.9 J in WT [39% increase] vs 23.1 J in cKOs [no change vs baseline], p<0.001, unpaired t-test). This was despite comparable voluntary wheel distance run during training (2.93-3.67 km/day for both over 5 weeks, p=0.58). Unexpectedly, after 6 weeks of training, cKO mice developed a dilated cardiomyopathy at rest and exercise-related dysfunction (contractile reserve [ΔFS stress-rest ] +6.0 in WT vs -6.4% in KO, p<0.05, unpaired t-test). They also demonstrated features of cardiac cachexia as measured by 30% and 21% reductions in inguinal adipose and gastrocnemius mass, respectively (P<0.05, unpaired t-test). Gene expression profiling demonstrated activation of pathological ( Nppa , Nppb , Myh7/Myh6 ) and atrophic pathways ( Gdf11 , Gdf15 , Fstl3 ) in the trained cKOs. In vitro, gain of function studies using adenoviral expression in neonatal rat ventricular myocytes demonstrated that PGC-1α overexpression could abrogate pathologic hypertrophy and atrophy gene expression pathways stimulated by phenylephrine. Our preliminary studies support cardiomyocyte PGC-1α as a key mediator of the adaptive response to exercise training and unveil a key role of this transcriptional activator in protecting from exercise-related cardiac dysfunction in mice.