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


Topic:

Translational Research

Poster Number: M279

Author(s):

Elena Monti, PhD, Stanford University, Mohsen Afshar, PhD, Stanford University, Yu Xin Wang, PhD, Sanford Burnham Prebys Medical Discovery Institute, ShiQi Su, Sanford Burnham Prebys Medical Discovery Institute, Peggy Kraft, Stanford University, Ludmila Alexandrova, Stanford University, Joshua R. Wheeler, Stanford University, Hannes Vogel, Stanford University, Helen M. Blau, PhD, Stanford University

Background: Neuromuscular disease and aging are accompanied by denervation of skeletal muscle, which impacts patients’ quality of life. Denervation is caused by degeneration of the synapses connecting motor neurons and skeletal muscles, termed neuromuscular junctions (NMJ). There is a major unmet need for therapeutic agents that restore NMJ integrity and muscle innervation.

Aim: Our lab recently showed that boosting prostaglandin E2 levels in aged mice by inhibiting its degradation by 15-prostaglandin dehydrogenase (15-PGDH) stimulates muscle growth and restores strength. We termed 15-PGDH a gerozyme, a pivotal molecular determinant of aging that is also triggered by injury. The present study investigates whether muscle reinnervation and NMJ restoration following 15-PGDH inhibition underlies improved muscle function.

Methods/results: We treated young (3-month) and aged (27-month) mice with a small molecule that inhibits 15-PGDH for 30 days. Aged treated mice displayed increased muscle mass and strength (p<0.05) compared to aged controls. While aged control mice exhibited, 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 reduced in treated versus control mice (18.1% vs 29.3%, p<0.05). Next, we tested the rate of recovery from a nerve-crush injury in young mice, and whether it was accelerated upon 15-PGDH inhibition. Treated mice exhibited 68.7% higher tetanic force 14 days after injury compared to controls. This was accompanied by a significant increase in muscle mass and specific force (+51.7%), an increased percentage of innervated NMJs (97.4% versus 84.5%) and, strikingly, a higher number (+92%) of motor neuron axons (all p<0.05), suggesting that 15-PGDH inhibition not only restores NMJ and muscle innervation but also promotes axonal regrowth. Conclusion: We identify 15-PGDH inhibition as a new potential therapeutic strategy to promote reinnervation of NMJs and recovery of muscle strength after acute or chronic denervation. 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.