Title: Amelioration of Ischemia-Reperfusion Induced Muscle Injury by the Recombinant Human MG53 Protein
Abstract: Acute compartment syndrome (CS) in skeletal muscle is caused by lack of blood supply due to the rise of compartment pressure after various injuries. CS requires timely surgical treatment, known as fasciotomy, to reduce the compartmental pressure and re-establish blood circulation. In previous studies, we found that MG53 plays an important role in membrane repair in multiple tissues. Here we test whether recombinant human MG53(rhMG53) protein can protect muscle injury associated with CS. With our suture-induced hindlimb CS mouse model, we found that the mg53-/- muscle released more creatine kinase (CK) into blood circulation as compared to wild type control following ischemia-reperfusion, indicating mg53-/- mice are more susceptible to CS injury. rhMG53 protein (6 mg/kg) applied intravenously to the wild type mice prior to the onset of CS could protect skeletal muscle injury, as demonstrated by the reduction of CK in serum and Evans Blue positive (injured) muscle fibers. Histochemical studies revealed that rhMG53 treatment could ameliorate pathological changes in mouse skeletal muscle associated with CS. When rhMG53 was examined in a rat model of CS-induced muscle injury, we saw a lesser degree of muscle injury and minimum effect for the exogenous rhMG53 in protection against the development of CS. The lack of effect of rhMG53 in the rat model was likely due to the fact that serum level of endogenous MG53 protein in the rat is more than 20-fold higher than that in the mouse and other animal models. Taken together, our data suggest that rhMG53 can protect ischemia-reperfusion induced muscle injury as a potential therapy for protection against compartment syndrome.