Fiber apoptosis in developing rat muscles is regulated by activity, neuregulin

Motor neurons are thought to critically regulate the survival of a subset of developing muscle fibers. In muscles that develop in the absence of innervation, primary muscle fibers appear to form in normal numbers, but their long-term survival is thought to require innervation-induced suprathreshold activity. Here I examine interactions between motor neurons and muscle fibers in newborn rats. I report that a small fraction of muscle fibers in developing muscles undergo apoptosis. Many, if not all, of these fibers appear to have lost innervation owing to the retraction of nerve terminals. That the apoptosis is initiated by the loss of functional innervation is suggested by a severalfold increase in the magnitude of fiber apoptosis following denervation and muscle paralysis. Finally, both naturally occurring and denervation-induced muscle fiber apoptosis can be prevented by exogenous administration of neuregulin. These results argue that the survival of all or a subset of developing muscle fibers is ultimately regulated by neuregulin. Furthermore, these results suggest a model in which innervation-induced suprathreshold activity indirectly regulates muscle fiber survival by modulating the levels of neuregulin at developing neuromuscular junctions.