The effects of neuregulin-1β on intrafusal muscle fiber formation in neuromuscular coculture of dorsal root ganglion explants and skeletal muscle cells

The formation of intrafusal muscle (IM) fibers and their contact with afferent proprioceptive axons is critical for construction, function, and maintenance of the stretch reflex. Many factors affect the formation of IM fibers. Finding new factors and mechanisms of IM fiber formation is essential for the reconstruction of stretch reflex arc after injury. We established a coculture system of organotypic dorsal root ganglion (DRG) explants and dissociated skeletal muscle (SKM) cells. The formation of IM fibers was observed in this coculture system after neuregulin-1β (NRG-1β) incubation. We found that NRG-1β promoted outgrowth of neurites and migration of neurons from the organotypic DRG explants and that this correlated with an induction of growth-associated protein 43 (GAP-43) expression. NRG-1β also increased the amount of nuclear bag fibers and nuclear chain fibers by elevating the proportion of tyrosine kinase receptor C (TrkC) phenotypic DRG neurons. In addition, we found that the effects of NRG-1β could be blocked by inhibiting ERK1/2, PI3K/Akt, and JAK2/STAT3 signaling pathways. These data imply that NRG-1β promoted neurite outgrowth and neuronal migration from the organotypic DRG explants and that this correlated with an induction of GAP-43 expression. The modulating effects of NRG-1β on TrkC DRG neuronal phenotype may link to promote IM fiber formation. The effects produced by NRG-1β in this neuromuscular coculture system provide new data for the therapeutic potential on IM fiber formation after muscle injury.