| Title: | Cardiac adaptation to endurance exercise training requires suppression of GDF15 via PGC-1α |
| Journal: | Nature Cardiovascular Research |
| Published: | 24 Sep 2025 |
| Pubmed: | https://pubmed.ncbi.nlm.nih.gov/40993371/ |
| DOI: | https://doi.org/10.1038/s44161-025-00712-3 |
Publication 19424
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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.</p>
17 Keywords
- Adaptation, Physiological
- Animals
- Disease Models, Animal
- Endurance Training
- Exercise Tolerance
- Growth Differentiation Factor 15
- Heart Failure
- Humans
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Myocytes, Cardiac
- Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha
- Physical Conditioning, Animal
- Physical Endurance
- Signal Transduction
36 Authors
- Sumeet A. Khetarpal
- Haobo Li
- Tevis Vitale
- James Rhee
- Saketh Challa
- Claire Castro
- Steffen Pabel
- Yizhi Sun
- Jing Liu
- Dina Bogoslavski
- Ariana Vargas-Castillo
- Amanda L. Smythers
- Katherine A. Blackmore
- Louisa Grauvogel
- Melanie J. Mittenbühler
- Melin J. Khandekar
- Casie Curtin
- Jose Max Narvaez-Paliza
- Chunyan Wang
- Nicholas E. Houstis
- Hans-Georg Sprenger
- Sean J. Jurgens
- Kiran J. Biddinger
- Alexandra Kuznetsov
- Rebecca Freeman
- Patrick T. Ellinor
- Matthias Nahrendorf
- Joao A. Paulo
- Steven P. Gygi
- Phillip A. Dumesic
- Aarti Asnani
- Krishna G. Aragam
- Pere Puigserver
- Jason D. Roh
- Bruce M. Spiegelman
- Anthony Rosenzweig
1 Application
| Application ID | Title |
|---|---|
| 7089 | Exome Sequencing of All Premature Coronary Artery Disease Participants in UK Biobank |
Enabling scientific discoveries that improve human health