Abstract
Mistugumin 53 (MG53) is an essential molecule in facilitating cellular membrane repair. A member of the TRIM protein family, MG53 possesses a RING domain functioning as an E3 ligase to mediate the down-regulation of insulin receptor substrate-1 (IRS-1) in insulin signaling. Conflicting results have been presented that elevated MG53 expression may serve as a causative factor for the development of metabolic syndrome. This study was designed to test whether high-fat diet (HFD) treatment alters the expression and function of MG53 within mice models of metabolic syndrome. Western blotting showed that MG53 expression does not change within the skeletal and cardiac muscles of mice subjected to HFD treatment. This data contradicts earlier findings presented by Song et al. (Nature, 494: 375-379, 2013), who claimed that MG53 expression is markedly elevated in animal models of insulin resistance and metabolic syndrome. Rather, we found that stress provoked by metabolic syndrome in the mice models actually reduced MG53 levels in the serum. Immunohistochemical analyses revealed that skeletal muscle fibers of HFD-induced mice experience localization of intracellular MG53 around mitochondria. The reduced MG53 serum levels observed may explain the compromised tissue regenerative capacity of diabetic patients. Clustering of MG53 around mitochondria may represent an adaptive response to metabolic stress. Overall, our study supports the guardian function of MG53 in cell membrane repair and metabolic syndrome. Therapeutic approaches for an elevation of MG53 expression in tissues that bypasses its interaction with IRS-1 may be a novel approach to treating human diseases with degenerative tissue repair functions.
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