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

Endurance exercise promotes adaptive growth and improved function of cardiomyocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are coordinated by the transcriptional protein peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α). The importance of PGC-1α to exercise-induced adaptations in the heart has been unclear. Here, we show that deleting PGC-1α specifically in cardiomyocytes prevents the expected benefits from exercise and instead confers heart failure after just six weeks of training. Supporting this, rare genetic variants in the human PPARGC1A gene, which encodes PGC-1α, are associated with risk of heart failure in the UK Biobank. We identify the stress-induced cytokine growth-differentiation factor 15 (GDF15) as a key factor increased in PGC-1α–deficient hearts that contributes to this dysfunction. Blocking cardiac Gdf15 expression improves cardiac performance and exercise capacity in these mice. Finally, in human heart tissue, lower cardiomyocyte PGC-1α expression is associated with higher GDF15 and with fewer cardiomyocytes. These findings implicate a crucial role for cardiomyocyte PGC-1α in enabling healthy heart adaptation to exercise in part through suppression of GDF15.