Abstract 16612: Cardiomyocyte PGC-1α Prevents Cardiac Atrophy and Failure in Response to Endurance Exercise Training
Sumeet Khetarpal, Haobo LI, Claire Castro, Nicholas A Houstis, James Rhee, Hans-Georg Sprenger, Melanie Mittenbuhler, Alexandra Kuznetsov, Rebecca Freeman, Aarti Asnani, Phillip Dumesic, Jason D Roh, Anthony Rosenzweig, Bruce Spiegelman- Physiology (medical)
- Cardiology and Cardiovascular Medicine
Introduction: Aerobic exercise promotes physiologic hypertrophy of the heart in healthy individuals. In skeletal muscle and heart, a key orchestrator of the adaptation to exercise is the transcriptional regulator PGC-1α. PGC-1α may mediate cardiac adaptation to physiological stress through myriad mechanisms. The role of cardiac PGC-1α to the systemic training response is poorly understood.
Methods: We generated PGC-1α cardiomyocyte-specific knockout (KO) mice to study its role in endurance exercise. We also silenced Ppargc1a expression in a cell model of physiologic cardiomyocyte hypertrophy.
Results: Sedentary KO mice demonstrated normal cardiac function and minimal differences in acute exercise tolerance. However, KO mice demonstrated a lack of ability to augment exercise capacity after 6 weeks of wheel running (work achieved 32.9 J in WT [39% increase] vs 23.1 J in KOs [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, KO mice developed a dilated cardiomyopathy 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 27% and 19% reductions in inguinal adipose and gastrocnemius mass, respectively (P<0.05, unpaired t-test). RNA sequencing of the hearts from these mice demonstrated activation of pathological ( Nppa , Nppb , Myh7/Myh6 ), fibrotic and atrophic secreted factors ( Gdf15 , Fstl3 ). Silencing Ppargc1a in rat cardiomyocytes after IGF1 treatment failed to induce physiologic hypertrophy and activated fibrotic programs and conferred atrophy.
Conclusions: Our studies posit cardiomyocyte PGC-1α as a key mediator of the adaptive response to exercise training and unveil its central role in protecting from exercise-related cardiac atrophy and fibrosis.