Abstract
An often-overlooked component of traumatic skeletal muscle injuries is the impact on the nervous system and resultant innervation of the affected muscles. Recent work in a rodent model of volumetric muscle loss (VML) injury demonstrated a progressive, secondary loss of neuromuscular junction (NMJ) innervation, supporting a role of NMJ dysregulation in chronic functional deficits. Terminal Schwann cells (tSCs) are known to be vital for the maintenance of NMJ structure and function, in addition to guiding repair and regeneration after injury. However, the tSC response to a traumatic muscle injury such as VML is not known. Thus, a study was conducted to investigate the effect of VML on tSC morphological characteristics and neurotrophic signaling proteins in adult male Lewis rats that underwent VML injury to the tibialis anterior muscle using a temporal design with outcome assessments at 3, 7, 14, 21, and 48 days post-injury. The following salient observations were made; first, although there is a loss of innervation over time, the number of tSCs per NMJ increases, significantly so at 48 days post-injury compared to control. The degree of NMJ fragmentation was positively correlated with tSC number after injury. Moreover, neurotrophic factors such as NRG1 and BDNF are elevated after injury through at least 48 days. These results were unanticipated and in contrast to neurodegenerative disease models, in which there is a reduction in tSC number that precedes denervation. However, we found that while there are more tSCs per NMJ after injury, they cover a significantly smaller percent of the post-synaptic endplate area compared to control. These findings support a sustained increase in neurotrophic activity and tSC number after VML, which is a maladaptive response occurring in parallel to other aspects of the VML injury, such as over-accumulation of collagen and aberrant inflammatory signaling.