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15-PGDH Inhibition Overcomes Muscle Regenerative Deficit Seen With GLP1-Receptor Agonist-Induced Weight Loss.
Minas Nalbandian1,2,3, Jameel Lone4, Emmeran Le Moal1,2
1Baxter Laboratory for Stem Cell Biology, Department of Microbiology and Immunology, Stanford School of Medicine, Stanford, CA, USA.
Biorxiv : the Preprint Server for Biology
|May 13, 2026
Summary
Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) like semaglutide cause muscle loss. Combining semaglutide with a 15-hydroxyprostaglandin dehydrogenase inhibitor (PGDHi) preserves muscle mass and enhances regeneration.
Area of Science:
- Biochemistry
- Physiology
- Pharmacology
Background:
- Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) are effective anti-obesity treatments.
- Weight loss induced by GLP-1 RAs may negatively impact skeletal muscle mass and function.
- Skeletal muscle is crucial for mobility, metabolic health, and overall well-being.
Purpose of the Study:
- To investigate the effects of semaglutide on skeletal muscle mass, strength, and regeneration.
- To determine if inhibiting 15-hydroxyprostaglandin dehydrogenase (PGDHi) can counteract semaglutide-induced muscle loss.
- To elucidate the mechanisms underlying semaglutide's impact on muscle stem cell function.
Main Methods:
- Utilized a high-fat diet-induced mouse model of obesity.
- Administered semaglutide alone and in combination with a PGDHi.
- Assessed skeletal muscle mass, contractile function, and regenerative capacity post-injury.
- Evaluated muscle stem cell function.
Main Results:
- Semaglutide treatment led to significant loss of skeletal muscle mass but preserved contractile function.
- Muscle regeneration and strength recovery after injury were impaired by semaglutide.
- PGDHi co-treatment prevented muscle mass loss and restored muscle regeneration and strength.
- The combination therapy improved impaired muscle stem cell function.
Conclusions:
- GLP-1 RAs like semaglutide can interfere with skeletal muscle maintenance and regeneration.
- Inhibiting 15-hydroxyprostaglandin dehydrogenase (PGDHi) counteracts these negative effects.
- Combined PGDHi and semaglutide therapy promotes muscle health during weight loss.
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