Abstract 4365681: Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α

Background/Significance: Exercise training induces physiological cardiac hypertrophy, mitochondrial biogenesis and myocardial function. In skeletal muscle, the transcriptional coactivator PGC-1α is a key orchestrator of these. The heart expresses abundant and exercise-responsive PGC-1α, but it is unclear whether this is necessary for cardiac adaptation to endurance training. Approaches: We utilize a genetic mouse model of cardiomyocyte PGC-1α deficiency along with somatic overexpression and knockdown of a PGC-1α related protein GDF15 using adeno-associated virus. We further utilize neonatal rat ventricular myocytes, human single nucleus RNA sequencing of patients with cardiomyopathies, and whole exome sequencing of human participants from the UK BioBank to address the relationship of PGC-1α with GDF15 and with cardiac dysfunction. Results: Wild-type and cardiomyocyte PGC-1α KO mice were subjected to voluntary wheel running for 5 weeks. Mice ran comparably over that time. Despite this, cardiomyocyte PGC-1α KO mice demonstrated no improvement in peak exercise capacity compared to WT mice (exercise work 33 J in WT vs 19 J in KO, p<0.001). Instead, PGC-1α KO mice demonstrated resting dilated cardiomyopathy after just 5 weeks of training (cardiac fractional shortening after training 60% in WT vs. 31% in KO, p<0.0001). Supporting this, extremely rare protein human genetic coding variants in PPARGC1A are associated with all-cause heart failure in the UK BioBank (RR 3.23, 95% CI 1.41-6.45, p=0.002). Cardiomyocyte PGC-1α-deficient trained hearts demonstrated absence of physiological hypertrophy (area 1170 vs. 555 μm 2 , p<0.0001) and markedly increased expression of the myomitokine GDF15 . GDF15 was secreted exclusively from cardiomyocytes but is not systemically elevated in PGC-1α-deficient mouse hearts. In cardiomyocytes, this occurs through the integrated stress response pathway, which is suppressed by PGC-1α overexpression. Cardiomyocyte-specific reduction of GDF15 preserves exercise tolerance, cardiac function, and exercise-induced cardiomyocyte hypertrophy in PGC-1α-deficient mice. We also find that cardiomyocyte PPARGC1A expression correlates with cardiomyocyte number and negatively with cardiomyocyte GDF15 expression in human cardiomyopathies through single nucleus RNA sequencing. Conclusions: Our data implicate cardiomyocyte PGC-1α as a vital enabler of physiological adaptation to endurance exercise through suppression of GDF15-mediated cardiac dysfunction.