The Impact of Exogenous Mitochondrial Transfer on Skeletal Muscle Injury in Mice

Abstract

Musculoskeletal disorders are a global health burden that end up in amputation and lifelong dependency. Skeletal muscle injuries may be either pathological such as traumatic, myotoxic or physiological such as skeletal muscle atrophy. Muscle injuries are known to impair mitochondrial health, creating energy deficit, reduced muscle regeneration and activation of cell death pathways. Mitochondrial transplantation therapy has emerged as a novel promising therapeutic strategy to alleviate impacts of mitochondrial dysfunction in skeletal muscle injuries. This study was designed to assess the therapeutic impact of crude mitochondrial preparations from healthy mouse livers on the skeletal muscle atrophy and injuries in rodent models. To this end BALB/c albino mice were used to develop two different models of skeletal muscle injuries including muscle atrophy using dexamethasone (dexa) and myotoxic injury with barium chloride (BaCl2). Muscle injury models were evaluated by measuring changes in body and muscle weight, serum lactate dehydrogenase (LDH), limb muscle fiber cross-sectional area (CSA) and cell death through infarct size measurement using TTC staining. Mitochondria isolated from healthy mice liver through differential centrifugation method were functionally assessed using oxygen consumption rate and MTT assay prior to their use as therapeutic tool against muscle injuries. Dexa-treated mice showed a significant reduction in body weight, and muscle fiber cross sectional area. Likewise, a decreasing trend in muscle mass and size was observed as compared to vehicle control (VC). Similarly, dexa treatment resulted in increased serum LDH release compared to VC. BaCl2-treated mice also showed a non-significant decrease in muscle weight with an increase in necrotic area and serum LDH levels. Mitochondrial transplantation insignificantly increased muscle mass while lowered serum LDH level in dexa-treated mice undergoing muscle atrophy. Likewise mitochondrial transfer also insignificantly increased the weight of muscles in the BaCl2 group compared to control. Thus, our results confirm that mitochondrial transplantation can be used as a promising therapeutic strategy against muscle atrophy and myotoxic muscle injuries. vi Key word: Skeletal muscle injury, mitochondrial transplantation, muscle atrophy, dexamethasone, Barium Chloride (BaCl2), Lactate dehydrogenase (LDH)