Neuromuscular junction disassembly and muscle fatigue in mice lacking neurotrophin-4

Neurotrophin-4 (NT-4) is produced by slow muscle fibers in an activity-depe ndent manner and promotes growth and remodeling of adult motorneuron innerv ation. However, both muscle fibers and motor neurons express NT-4 receptors , suggesting bidirectional NT-4 signaling at the neuromuscular junction. Mi ce lacking NT-4 displayed enlarged and fragmented neuromuscular junctions w ith disassembled postsynaptic acetylcholine receptor (AChR) clusters, reduc ed AChR binding, and acetylcholinesterase activity. Electromyographic respo nses, posttetanic potentiation, and action potential amplitude were also si gnificantly reduced in muscle fibers from NT-4 knock-out mice. Slow-twitch soleus muscles from these mice fatigued twice as rapidly as those from wild -type mice during repeated tetanic stimulation. Thus, muscle-derived NT-4 i s required for maintenance of postsynaptic AChR regions, normal muscular el ectrophysiological responses, and resistance to muscle fatigue. This neurot rophin may therefore be a key component of an activity-dependent feedback m echanism regulating maintenance of neuromuscular connections and muscular p erformance.