15-PGDH Inhibition Overcomes Muscle Regenerative Deficit Seen With GLP1-Receptor Agonist–Induced Weight Loss

May 13, 2026bioRxiv : the preprint server for biology

Blocking 15-PGDH May Improve Muscle Repair Reduced by Weight Loss from GLP1-Receptor Agonists

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Abstract

GLP-1 receptor agonists like semaglutide may cause significant loss of muscle mass in obesity models.

Semaglutide treatment is associated with decreased skeletal muscle mass in mice on a high-fat diet.
Despite the loss of muscle mass, contractile function remains intact with semaglutide use.
Muscle regeneration and strength recovery following injury are impaired by semaglutide treatment.
This impairment in muscle recovery is linked to reduced function of muscle stem cells.
Co-treatment with an inhibitor of a specific enzyme boosts muscle mass and improves regeneration when combined with semaglutide.

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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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15-PGDH Inhibition Overcomes Muscle Regenerative Deficit Seen With GLP1-Receptor Agonist–Induced Weight Loss

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