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Peer-reviewedCC BY-NC-NDProceedings of the National Academy of Sciences

15-PGDH inhibition promotes muscle repair and strength recovery during GLP-1 receptor agonist–induced weight loss

  • Minas Nalbandian1,2,3
  • Jameel Barkat Lone4
  • Emméran Le Moal1,2
  • Ireh Kim1
  • Kaitlin Jeuris1
  • Yutong Kelly Li1,5
  • Peggy E. Kraft1,2
  • Meng Zhao5,4
  • Kassie Koleckar1,2
  • Zeyuan Zhang4
  • Katrin J. Svensson6,4,7
  • Helen M. Blau1,2,3
7 affiliations
  1. 1Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford School of Medicine
  2. 2Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine
  3. 3Stanford Cardiovascular Institute, Stanford University School of Medicine
  4. 4Department of Pathology, Stanford University School of Medicine
  5. 5Department of Animal Science, University of California
  6. 6Arc Institute
  7. 7Stanford Diabetes Research Center, Stanford University School of Medicine
Open at sourcePDFDOICite

Abstract

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including long-acting semaglutide, are revolutionary anti-obesity therapies. However, emerging evidence indicates that weight loss may come at the expense of skeletal muscle mass, a tissue essential for mobility, metabolic regulation, and overall health. Here, we show that an inhibitor of the gerozyme 15-hydroxyprostaglandin dehydrogenase (PGDHi), which boosts PGE2 levels, increases skeletal muscle mass, strength, and regeneration in the presence of semaglutide. We find that in a high fat diet-induced mouse model of obesity, semaglutide alone induces significant loss of muscle mass, while retaining contractile function. However, muscle regeneration and recovery of strength post-injury are hindered by semaglutide. This regenerative deficit is due to impeded stem cell function, which is overcome if mice are treated with a combination of PGDHi and semaglutide. Our data show that GLP-1-mediated weight loss interferes with this key muscle-building function, which PGDHi co-treatment counteracts to promote proper muscle regeneration and restored strength.

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Cite

BibTeXRIS
BibTeX
@article{nalbandian202615pgdh,
  title = {{15-PGDH inhibition promotes muscle repair and strength recovery during GLP-1 receptor agonist–induced weight loss}},
  author = {Minas Nalbandian and Jameel Barkat Lone and Emméran Le Moal and Ireh Kim and Kaitlin Jeuris and Yutong Kelly Li and Peggy E. Kraft and Meng Zhao and Kassie Koleckar and Zeyuan Zhang and Katrin J. Svensson and Helen M. Blau},
  journal = {Proceedings of the National Academy of Sciences},
  year = {2026},
  month = jun,
  doi = {10.1073/pnas.2606533123},
  url = {https://doi.org/10.1073/pnas.2606533123},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - 15-PGDH inhibition promotes muscle repair and strength recovery during GLP-1 receptor agonist–induced weight loss
AU  - Minas Nalbandian
AU  - Jameel Barkat Lone
AU  - Emméran Le Moal
AU  - Ireh Kim
AU  - Kaitlin Jeuris
AU  - Yutong Kelly Li
AU  - Peggy E. Kraft
AU  - Meng Zhao
AU  - Kassie Koleckar
AU  - Zeyuan Zhang
AU  - Katrin J. Svensson
AU  - Helen M. Blau
PY  - 2026
DA  - 2026/06/02
JO  - Proceedings of the National Academy of Sciences
DO  - 10.1073/pnas.2606533123
UR  - https://doi.org/10.1073/pnas.2606533123
AB  - Glucagon-like peptide-1 receptor agonists (GLP-1 RAs), including long-acting semaglutide, are revolutionary anti-obesity therapies. However, emerging evidence indicates that weight loss may come at the expense of skeletal muscle mass, a tissue essential for mobility, metabolic regulation, and overall health. Here, we show that an inhibitor of the gerozyme 15-hydroxyprostaglandin dehydrogenase (PGDHi), which boosts PGE2 levels, increases skeletal muscle mass, strength, and regeneration in the presence of semaglutide. We find that in a high fat diet-induced mouse model of obesity, semaglutide alone induces significant loss of muscle mass, while retaining contractile function. However, muscle regeneration and recovery of strength post-injury are hindered by semaglutide. This regenerative deficit is due to impeded stem cell function, which is overcome if mice are treated with a combination of PGDHi and semaglutide. Our data show that GLP-1-mediated weight loss interferes with this key muscle-building function, which PGDHi co-treatment counteracts to promote proper muscle regeneration and restored strength.
SN  - 0027-8424
SN  - 1091-6490
ER  -