Cardiomyocyte PGC-1α enables physiological adaptations to endurance exercise through suppression of GDF15 and cardiac atrophy

Author:

Khetarpal Sumeet A.ORCID,Li Haobo,Vitale Tevis,Rhee James,Grauvogel Louisa,Castro Claire,Mittenbühler Melanie J.,Houstis Nicholas E.,Vargas-Castillo Ariana,Smythers Amanda L.,Liu Jing,Curtin Casie,Sprenger Hans-Georg,Blackmore Katherine A.,Kuznetsov Alexandra,Freeman Rebecca,Bogoslavski Dina,Ellinor Patrick T.,Asnani Aarti,Dumesic Phillip A.,Puigserver Pere,Roh Jason D.,Spiegelman Bruce M.,Rosenzweig Anthony

Abstract

SummaryExercise training induces physiological cardiac hypertrophy, enhanced mitochondrial biogenesis and myocardial contractility. In skeletal muscle, the transcriptional coactivator PGC-1α is a key orchestrator of these responses. The heart expresses abundant and exercise-responsive PGC-1α, but it is unclear whether cardiomyocyte PGC-1α is necessary for cardiac adaptation to endurance training. Here we demonstrate that cardiomyocyte PGC-1α is required for physiological cardiac hypertrophy during exercise training in mice. In the absence of cardiomyocyte PGC-1α, voluntary wheel running does not improve exercise capacity and instead confers immune-fibrotic-atrophic heart failure after just 6 weeks of training. We identify cardiomyocyte PGC-1α as a negative regulator of stress-responsive senescence gene expression. The most enriched of these is the myomitokine GDF15. GDF15 is secreted locally but not systemically in PGC-1α-deficient mouse hearts and reduces cardiomyocyte size. Cardiomyocyte-specific reduction of GDF15 expression preserves exercise tolerance and cardiac contractility in PGC-1α-deficient mice during endurance training. Finally, we show that cardiomyocytePPARGC1Aexpression correlates with cardiomyocyte number and negatively with GDF15 expression in human cardiomyopathies through single nucleus RNA sequencing. Our data implicate cardiomyocyte PGC-1α as a vital safeguard against stress-induced atrophy and local GDF15-induced dysfunction during exercise.

Publisher

Cold Spring Harbor Laboratory

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