Regeneration of neuromuscular synapses after acute and chronic denervation by inhibiting the gerozyme 15-prostaglandin dehydrogenase

Abstract

To date, there are no approved treatments for the diminished strength and paralysis that result from the loss of peripheral nerve function due to trauma, heritable neuromuscular diseases, or aging. Here, we showed that denervation resulting from transection of the sciatic nerve triggered a marked increase in the prostaglandin-degrading enzyme 15-hydroxyprostaglandin dehydrogenase (15-PGDH) in skeletal muscle in mice, providing evidence that injury drives early expression of this aging-associated enzyme or gerozyme. Treating mice with a small-molecule inhibitor of 15-PGDH promoted regeneration of motor axons and formation of neuromuscular synapses leading to an acceleration in recovery of force after an acute nerve crush injury. In aged mice with chronic denervation of muscles, treatment with the 15-PGDH inhibitor increased motor neuron viability and restored neuromuscular junctions and function. These presynaptic changes synergized with previously reported muscle tissue remodeling to result in a marked increase in the strength of aged muscles. We further found that 15-PGDH aggregates defined the target fibers that are histopathologic hallmarks of human neurogenic myopathies, suggesting that the gerozyme may be involved in their etiology. Our data suggest that inhibition of 15-PGDH may constitute a therapeutic strategy to physiologically boost prostaglandin E2, restore neuromuscular connectivity, and promote recovery of strength after acute or chronic denervation due to injury, disease, or aging.

Muscle-resident mesenchymal progenitors sense and repair peripheral nerve injury via the GDNF-BDNF axis

“…It is generally understood that after a successful tissue regeneration process, resolution of immune response allow for the tissue to return to homeostasis (Ortega-Gomez, et al, 2013; Aurora and Olson, 2014; Julier, et al, 2017); our results suggest the role of FAPs in regulating immune resolution near the end of nerve regeneration. Furthermore, the role of prostaglandin in peripheral nerve regeneration has recently been described (Forese, et al, 2020; Bakooshli, et al, 2023); our ORA results suggested that FAPs may also be involved in regulation of prostaglandin levels during peripheral nerve regeneration.…”

Agonists of melatonin receptors strongly promote the functional recovery from the neuroparalysis induced by neurotoxic snakes

“…VAMP-1 signal and distribution, clearly shows that both MT1 agonists speed up the recovery of presynapse with respect to mock controls. The extent of recovery was estimated by calculating the percentage of denervated, partially innervated, and innervated NMJs, as well as the NMJ occupancy, which characterizes the overlap between the presynaptic and postsynaptic morphology [62]. Results are reported in panels B, C, of Fig 3 and parallel the electrophysiological findings.…”