Traumatic muscle injury and the neuromuscular junction

Abstract

The ability of skeletal muscle to adapt to various stressors throughout the lifespan is paramount to one’s quality of life. Comprising roughly 30-40% of total body weight, skeletal muscle is not only vital for movement, but also for maintaining posture, breathing, and regulating metabolism. The plasticity of muscle is evident by its ever-changing size; the more a person exercises, the more it will grow, or hypertrophy, while the lack of stress placed upon a muscle will result in rapid loss of fiber size, or atrophy. Minor injuries to muscle, such as a strain or contusion, undergo a regenerative process led by muscle stem cells to repair damaged tissue. Remarkably, most strain injuries result in full recovery of function, and thus allow affected individuals to resume their normal activities. However, in more severe cases there is an inability for endogenous repair mechanisms to fully recover function, leading to lifelong disability. These injuries involve the removal of significant portions of muscle tissue due to a traumatic event, such as a car crash or blast wound. While there have been many studies over the past decade testing various treatment strategies for volumetric muscle loss (VML), there is still much unknown about the pathophysiology behind the injury. One area that has been underdeveloped is the impact of injury on the neuromuscular system. It has been shown that while there is no motor neuron death from VML-injury, there is evidence of disruptions to the neuromuscular junctions (NMJ). Thus, the goal of this work was to better explore how the NMJ and associated cells respond to a traumatic muscle injury. To achieve this, NMJ morphology and terminal Schwann cells were assessed temporally in a rat model of VML-injury using fluorescent confocal microscopy. Secondary outcomes included neurotrophic signaling in the muscle tissue. Next, in order to evaluate how these changes compare to successful NMJ regeneration, mouse models of nerve crush injury and VML-injury were compared. Nerve crush injury is known to induce complete denervation of NMJs and muscle function followed by full recovery of both. Divergent trends identified here-in can help guide therapeutic development for traumatic muscle injury.