Interventions for Ischemia-Reperfusion Injury in Skeletal Muscle

Tissues in our body rely on continuous supply of blood to receive O2, nutrients and remove waste products. When blood flow is arrested it causes ischemia and homeostatic imbalance that jeopardizes tissue function and leads to tissue death if prolonged. Reperfusion, the restoration of blood flow, is required to resuscitate the ischemic tissue, however, it ignites a cascade of deleterious events that augment the initial ischemic insult exacerbating tissue dysfunction and/or death. Peripheral tissues, such as motor nerve fibers and skeletal muscle fibers (myofibers), are vulnerable to IR injury as a corollary of tourniquet application, a commonly used approach to prevent hemorrhage and provide bloodless field in trauma and surgical situations. A consequence of IR injury to motor nerve fiber and myofibers is reduced neuromuscular function, which compromises voluntary movement and reduces quality of life. Despite the prevalence of tourniquet use, there are currently no efficacious interventions that attenuate IR injury.
A vast body of interdisciplinary studies has revealed that mitochondria play a causal role in initiation and progression of IR pathology. The studies presented herein investigate the contribution that mitochondrial perturbations have on motor nerve fibers and myofibers in the context of tourniquet-induced IR injury to the hindlimb. We found that IR causes reduction in neuromuscular function, myofiber denervation, as well as mitochondrial oxidative stress. These studies uncovered that directly targeting mitochondria and enhancing covalent linkage of nitric oxide to protein thiols (protein S-nitrosation) in mitochondria as well as endurance exercise training preserved neuromuscular function following IR injury by two distinct mechanisms. These findings unveil practical and effective interventions that attenuate IR injury, which will likely improve outcome of tourniquet use.