Regeneration of Neuromuscular Synapses by Inhibition of the Prostaglandin Degrading Enzyme 15-PGDH

Abstract

Background: Skeletal muscles require voluntary activation to move, which is supplied via motor neurons. The terminal axons of motor neurons innervate muscle fibers at the neuromuscular junction (NMJ). NMJ degeneration increases with age and injury, decreasing muscle contractility and strength and severely reducing individuals’ quality of life. Treatments able to restore NMJ integrity and muscle innervation after injury and in aging are currently lacking. Aim: Our lab has recently shown that boosting prostaglandin E2 (PGE2) levels in aged mice by inhibiting its degrading enzyme 15-prostaglandin dehydrogenase (15-PGDH) stimulates muscle growth and restores muscle strength and endurance. The present study aimed at investigating whether 15-PGDH inhibition promotes muscle reinnervation and NMJ restoration, thus improving muscle function. Methods and results: We treated young (3-month) and old (27-month) mice with a small molecule compound with high specificity for 15-PGDH inhibition for 30 days. Old treated mice displayed increased muscle mass and strength (p<0.05) compared to aged control mice. While aged control displayed, as expected, a high percentage of denervated NMJ (21.6%), denervation was partially rescued by 15-PGDH inhibition (12.1%, p<0.05). Similarly, NMJ fragmentation was lower in treated versus control mice (18.1% vs 29.3%, p<0.05). To translate our findings to a more acute scenario, we induced nerve-crush injury in young mice (3-month) and treated animals with 15-PGDH inhibition during injury recovery. Treated mice were able to exert a 37.2% higher tetanic force 14 days after injury compared to control mice. This was accompanied by increased muscle mass and specific force (+32.2%, p<0.05) and an increased percentage of innervated NMJs (97.4% versus 84.5%) in treated versus control mice, suggesting that 15-PGDH inhibition was promoting NMJ restoration and muscle reinnervation after injury. Conclusion: In this study we identify 15-PGDH inhibition as a new potential therapeutic strategy to promote reinnervation of NMJs and strength recovery after acute or chronic denervation due to injury or aging. Funding: E.M. is supported by a “Wu Tsai Human Performance Alliance” fellowship. This study was supported by the Donald E. and Delia B. Baxter Foundation, the Li Ka Shing Foundation, Milky Way Research Foundation MWRF-216064, California Institute for Regenerative Medicine grant DISC2-10604, and U.S. National Institutes of Health (NIH) grants R01-AG020961, R01-AG069858, and R01-RHG009674 to H.M.B. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.