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Article Title

Skeletal Muscle Injury and Repair: Cellular Mechanisms Driving Potential Interventions

Abstract

Traumatic skeletal muscle injury affects contractile, molecular and histopathological properties of the muscle fiber. Muscle regeneration following injury is dependent on the ability of muscle satellite cells to activate, proliferate and fuse with damaged fibers. This process is controlled by the myogenic regulatory factors. Additionally, other genes and proteins, of which only a handful have been classified, have been discovered in relation to their role in skeletal muscle regeneration in both efficient and inefficient recovery. We have previously demonstrated that in response to traumatic injury in skeletal muscle there is a dysregulation of the Matrix Metalloproteases (MMPs) and their inhibitors (TIMPs), a response hypothesized to interfere with proper skeletal muscle regeneration. Currently, there are no drugs in development designed specifically to hasten the restoration of skeletal muscle function after injury, regardless of the mechanism of injury (e.g. eccentric-induced, traumatic, ischemia-reperfusion, and overuse). However, several drugs are being developed for cardiovascular injury (i.e. ischemia-reperfusion) that might also be effective in promoting skeletal muscle regeneration. An example of one of these drugs is the Adenosine A3 Receptor Agonist C1-IBMECA, which has been shown to attenuate ischemia-reperfusion injury in cardiac muscle, as well as ischemia-reperfusion and eccentric injury in skeletal muscle. These data concerning A3 protection in skeletal muscle provide evidence for a generalized cytoprotective property of the adenosine A3 receptor, a concept that we have aggressively pursued using a military-relevant injury model that mimics blast injury. Recent data from our laboratory has shown that in skeletal muscle, treatment with the C1-IBMECA two hours prior to onset of skeletal muscle injury modulates the critical events associated with traumatic muscle injury and muscle fiber breakdown in the first few hours post-injury. Specifically, 24 hours post-injury 56.8% of the fibers were damaged in vehicle-treated mice versus 35.4% in C1-IBMECA-treated mice (p=0.02). Along with this reduction in injured muscle fibers, we also observed a favorable modulation of the MMP signaling system. This signaling pathway is critical in skeletal muscle tissue remodeling through its effects on inflammatory processes, proteolysis of the extracellular matrix (ECM), and satellite cell activation. These data suggest that treatment with C1-IBMECA is protective during the early phase of skeletal muscle repair following traumatic injury and that the beneficial effects of C1-IBMECA on the MMP/TIMP system are related to the initial inflammatory response. However, we did not observe any function benefit of C1-IBMECA treatment when skeletal muscle function was tested 48h post-injury. Therefore, while a adenosine A3 receptor activation points to a new therapeutic strategy for this form of muscle injury future work must focus on how activation of the adenosine A3 receptor can be combined with other treatment modalities that address other factors associated with the complex and phasic nature of skeletal muscle injury progression and regeneration.

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