Potential mechanisms of uremic muscle wasting and the protective role of the mitochondria-targeted antioxidant Mito-TEMPO.

BACKGROUND Muscle wasting is common in patients with chronic kidney disease (CKD). Many studies report that mitochondrial dysfunction and endoplasmic reticulum (ER) stress are involved in the development of muscle wasting. However, treatment approaches to protect against muscle wasting are limited. In this study, we investigated the benefits and potential mechanism of Mito-TEMPO, a mitochondria-targeted antioxidant on uremic-induced muscle wasting. METHODS Mice were randomly divided into four groups as follows: control group, CKD group, CKD + Mito-TEMPO group, and Mito-TEMPO group. Renal injury was assessed by measurement of serum creatinine and BUN along with PAS and Masson's staining. Bodyweight, gastrocnemius muscle mass, grip strength, and myofiber cross-sectional areas were investigated to evaluate muscle atrophy. Muscle protein synthesis and proteolysis were evaluated by Western blot and real-time PCR. Inflammatory cytokines including TNF-α, IL-6, IL-1β, and MCP-1 were measured by ELISA kits. Oxidative stress markers such as SOD2 activity and MDA level in gastrocnemius muscle tissue were measured by colorimetric assay. Mitochondrial dysfunction was evaluated by transmission electron microscopy and real-time PCR. ER stress was evaluated by Western blot. RESULTS Impaired renal function was significantly restored by Mito-TEMPO treatment. Severe muscle atrophy was observed in muscle tissues of CKD mice along with increased inflammatory factors, oxidative stress markers, mitochondrial dysfunction, and ER stress. However, these effects were significantly attenuated with Mito-TEMPO treatment. CONCLUSIONS Mito-TEMPO improved muscle wasting in CKD mice possibly through alleviating mitochondrial dysfunction and endoplasmic reticulum stress, providing a potential new therapeutic approach for preventing muscle wasting in chronic kidney disease.