I thought this deserved its own post:
Regeneration of neuromuscular synapses after acute and chronic denervation by inhibiting the gerozyme 15-prostaglandin dehydrogenase
Skeletal muscle denervation, which can occur because of disease, trauma or disuse, results in muscle weakness and atrophy, with no available treatments to promote axon regeneration or to restore neuromuscular junctions (NMJs). Here, Bakooshli, Wang, and colleagues found that 15-prostaglandin dehydrogenase (15-PGDH), which accumulates with age and promotes muscle atrophy, markedly increased in denervated mouse myofibers and aggregated in ‘target fibers, hallmarks of chronic nerve damage in human myogenic neuropathies. In a mouse model of sciatic nerve crush injury, small molecule inhibition of 15-PGDH promoted motor axon regeneration and NMJ restoration, leading to improvement in muscle force 14 days after injury. In aged mice, treatment improved NMJ number and morphology and elicited a pro-regenerative response in motor neurons, suggesting that 15-PGDH may be a therapeutic target for neuromuscular recovery after denervation. —Melissa L. Norton
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.