Abstract
Methylglyoxal (MG) is a reactive dicarbonyl intermediate and a precursor of advanced glycation end products (AGEs). The authors investigated the role played by AGEs in muscle myopathy and the amelioration of its effects by curcumin and gingerol. In addition to producing phenotypical changes, MG increased oxidative stress and reduced myotube formation in C2C12 cells. RAGE (receptor for AGEs) expression was up-regulated and MYOD and myogenin (MYOG) expressions were concomitantly down-regulated in MG-treated cells. Interestingly, AGE levels were higher in plasma (~32 fold) and muscle (~26 fold) of diabetic mice than in control mice. RAGE knock-down (RAGEkd) reduced the expressions of MYOD and MYOG and myotube formation in C2C12 cells. In silico studies of interactions between curcumin or gingerol and myostatin (MSTN; an inhibitor of myogenesis) and their observed affinities for activin receptor type IIB (ACVRIIB) suggested curcumin and gingerol reduce the interaction between MSTN and ACVRIIB. The findings of this study suggest enhanced AGE production and subsequent RAGE-AGE interaction obstruct the muscle development program, and that curcumin and gingerol attenuate the effect of AGEs on myoblasts.
Highlights
Skeletal muscle is a contractile tissue that consists of cylindrical multinucleated myofibers and resident stem cells, that is, muscle satellite cells (MSCs)[1,2,3]
C2C12 cells treated with 200 μM MG for 0, 2, 4 or 6 days showed gradual increases in advanced glycation end products (AGEs) levels by ELISA, whereas AGE levels remained unchanged in controls (Fig. 1C)
AGEs produced by the glycation of proteins act as link between hyperglycemia and the development of diabetes
Summary
Skeletal muscle is a contractile tissue that consists of cylindrical multinucleated myofibers and resident stem cells, that is, muscle satellite cells (MSCs)[1,2,3] Though quiescent, these cells have a remarkable capacity to regenerate muscle and replenish the reserve cell pool. AGE-modified proteins may exert their effects by binding to RAGE (AGE-specific cell surface receptors), and elevated RAGE expression has been reported on the endothelial cells, vascular smooth muscle cells, and cardiac myocytes of diabetic patients[17]. Interactions between AGEs and RAGE have been reported to activate intracellular signaling, induce gene expression, produce pro-inflammatory cytokines and free radicals, and this interaction has been suggested to play an important role in the development and progression of diabetes[18]. We sought to elucidate the mechanism responsible for AGE mediated decrease in muscle mass, to determine the effects of curcumin and gingerol supplementation on AGE production, and relationships between increased AGE production, functional impairments of myoblasts, and their possible reversal by curcumin or gingerol in diet
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