15-PGDH Inhibition Restores Muscle Repair and Strength During Semaglutide-Induced Weight Loss

Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) like semaglutide are highly effective anti-obesity therapies. However, a significant concern is the concomitant loss of skeletal muscle mass, a critical tissue for mobility, metabolic health, and overall function. This muscle loss can undermine the long-term benefits of weight reduction. The enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH), a prostaglandin-degrading gerozyme, increases with injury and aging, potentially contributing to impaired muscle regeneration.

Researchers investigated the effects of semaglutide alone and in combination with a 15-PGDH inhibitor (PGDHi) in a high-fat diet-induced mouse model of obesity. The study assessed muscle repair and strength recovery following injury. Key endpoints included changes in muscle mass, contractile function, the presence of pathological calcifications, regenerated myofiber sizes, muscle stem cell function, and overall muscle strength. The control arm likely involved obese mice receiving placebo or vehicle, though not explicitly detailed in the abstract.

In obese mice, semaglutide alone caused a significant loss of muscle mass while preserving contractile function. Following muscle injury, obese mice exhibited pathological calcifications, similar to those seen in Duchenne Muscular Dystrophy. Semaglutide demonstrated a dual effect: it reduced calcific remodeling but also caused reduced regenerated myofiber sizes. This impairment in regenerative myofiber growth was a critical finding. > Co-treatment with a 15-PGDH inhibitor (PGDHi) effectively surmounted this impaired regenerative myofiber growth in semaglutide-treated mice. PGDHi stimulated muscle stem cell function and myofiber growth, leading to enhanced strength. Importantly, PGDHi synergized with semaglutide to boost post-injury muscle quality and muscle force without compromising the beneficial weight loss effects of semaglutide.