Stabilizing neuromuscular contacts increases motoneuron survival after neonatal nerve injury in rats

Following sciatic nerve crush at birth the rat soleus muscle is rendered permanently weak. This reduction in muscle force is caused by the loss of a proportion of its motoneurons. Furthermore, motoneurons that survive and reach the muscle fail to reoccupy a sufficient number of denervated muscle fibres to compensate for the loss of neurons. Both the loss of motoneurons and poor reinnervation may be due to the inability of the regenerating axons to establish and maintain neuromuscular contacts. Application of leupeptin, an inhibitor of a calcium-activated neutral protease and some serine proteases, is known to help in the maintenance of neuromuscular contacts during development and axonal sprouting. Here we examined whether protecting new neuromuscular contacts formed between regenerating axons and denervated muscle fibres after nerve injury, would influence the survival of motoneurons and improve muscle recovery. This study shows that in muscles treated with leupeptin the reduction in weight and force output after nerve crush at birth was significantly less than in those that were untreated. Moreover, the number of motor units in the leupeptin-treated muscles was significantly higher than in untreated muscles. Thus, treating regenerating nerve terminals with leupeptin during early stages of reinnervation rescues motoneurons and improves muscle recovery.