School of Kinesiology, University of Minnesota, Minneapolis, MN 55455, United States of America.
Department of Physiology and Pharmacology, University of Georgia, Athens, GA 30602, United States of America.
Exp Neurol. 2023 Jul;365:114431. doi: 10.1016/j.expneurol.2023.114431. Epub 2023 May 2.
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.
创伤性骨骼肌损伤的一个经常被忽视的组成部分是对神经系统的影响以及受影响肌肉的神经支配。最近在容积性肌肉损失（VML）损伤的啮齿动物模型中的工作表明，神经肌肉接点（NMJ）支配的进行性继发性丧失，支持 NMJ 调节异常在慢性功能缺陷中的作用。已知终端雪旺细胞（tSC）对于 NMJ 结构和功能的维持以及损伤后的修复和再生的指导至关重要。然而，tSC 对 VML 等创伤性肌肉损伤的反应尚不清楚。因此，进行了一项研究，以调查 VML 对成年雄性 Lewis 大鼠前胫骨前肌 VML 损伤后 tSC 形态特征和神经营养信号蛋白的影响，使用时间设计进行，结果评估在损伤后 3、7、14、21 和 48 天进行。有以下显著观察结果；首先，尽管随着时间的推移神经支配丧失，但每个 NMJ 的 tSC 数量增加，与对照组相比，在损伤后 48 天显著增加。NMJ 碎片化的程度与损伤后 tSC 数量呈正相关。此外，神经生长因子如 NRG1 和 BDNF 在损伤后至少升高 48 天。这些结果出乎意料，与神经退行性疾病模型相反，在这些模型中，tSC 数量的减少先于去神经支配。然而，我们发现，尽管损伤后每个 NMJ 的 tSC 数量增加，但与对照组相比，它们覆盖的突触后终板区域的比例显著减小。这些发现支持 VML 后神经生长因子活性和 tSC 数量的持续增加，这是与 VML 损伤的其他方面平行发生的适应性反应，例如胶原过度积累和异常炎症信号。
