Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α PMID: 40993371

ADC Targets in Oncology

2026-04-10

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

Nat Cardiovasc Res. 2025 Oct;4(10):1277-1294. doi: 10.1038/s44161-025-00712-3.

Sumeet A Khetarpal ¹ ² ³ ⁴ , Haobo Li ⁵ , Tevis Vitale ² ³ , James Rhee ¹ ⁵ , Saketh Challa ¹ ⁶ ⁷ , Claire Castro ¹ , Steffen Pabel ⁸ , Yizhi Sun ² ³ , Jing Liu ⁹ , Dina Bogoslavski ² ³ , Ariana Vargas-Castillo ² ³ , Amanda L Smythers ² ³ , Katherine A Blackmore ² ³ , Louisa Grauvogel ² ³ , Melanie J Mittenbühler ² ³ , Melin J Khandekar ² ³ , Casie Curtin ⁹ , Jose Max Narvaez-Paliza ⁹ , Chunyan Wang ⁵ , Nicholas E Houstis ¹ , Hans-Georg Sprenger ² ³ , Sean J Jurgens ¹ ⁶ ⁷ ¹⁰ , Kiran J Biddinger ¹ ⁶ ⁷ , Alexandra Kuznetsov ¹ , Rebecca Freeman ¹ , Patrick T Ellinor ¹ ¹¹ , Matthias Nahrendorf ⁸ ¹² ¹³ ¹⁴ ¹⁵ , Joao A Paulo ³ , Steven P Gygi ³ , Phillip A Dumesic ² ³ , Aarti Asnani ⁹ , Krishna G Aragam ¹ ⁶ ⁷ , Pere Puigserver ² ³ , Jason D Roh ¹ , Bruce M Spiegelman ¹⁶ ¹⁷ , Anthony Rosenzweig ¹⁸

Affiliations

1. Corrigan Minehan Heart Center and Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA, USA.
2. Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA.
3. Department of Cell Biology, Harvard Medical School, Boston, MA, USA.
4. Robert M. Berne Cardiovascular Research Center and Division of Cardiology, Department of Medicine, University of Virginia School of Medicine, Charlottesville, VA, USA.
5. Department of Anesthesia, Critical Care, and Pain Medicine, Harvard Medical School, Massachusetts General Hospital, and the Massachusetts General Research Institute, Boston, MA, USA.
6. Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
7. Center for Genomic Medicine, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
8. Center for Systems Biology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
9. CardioVascular Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA.
10. Department of Experimental Cardiology and Amsterdam Cardiovascular Sciences, Heart Failure & Arrhythmias, Amsterdam UMC location, University of Amsterdam, Amsterdam, the Netherlands.
11. Cardiovascular Disease Initiative, the Broad Institute of Harvard and MIT, Cambridge, MA, USA.
12. Gordon Center for Medical Imaging, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
13. Department of Radiology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
14. Cardiovascular Research Center, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
15. Department of Internal Medicine I, University Hospital Würzburg, Würzburg, Germany.
16. Department of Cancer Biology, Dana Farber Cancer Institute, Boston, MA, USA. [email protected].
17. Department of Cell Biology, Harvard Medical School, Boston, MA, USA. [email protected].
18. Stanley and Judith Frankel Institute for Heart and Brain Health, University of Michigan, Ann Arbor, MI, USA. [email protected].

Abstract

Endurance exercise promotes adaptive growth and improved function of myocytes, which is supported by increased mitochondrial activity. In skeletal muscle, these benefits are in part transcriptionally coordinated by 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 training and instead leads to heart failure after just 6 weeks of training. Consistent with this, in humans, rare genetic variants in PPARGC1A, which encodes PGC-1α, are associated with increased risk of heart failure. In this model, we identify Growth Differentiation Factor 15 (GDF15) as a key heart-secreted mediator 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 PPARGC1A expression is associated with higher GDF15 expression and reduced cardiomyocyte density. These findings uncover a crucial role for cardiomyocyte PGC-1α in enabling healthy cardiac adaptation to exercise in part through suppression of GDF15.