Methylglyoxal and Advanced Glycation End products: Insight of the regulatory machinery affecting the myogenic program and of its modulation by natural compounds

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.

Effects of combined treatment with blood flow restriction and low‐intensity electrical stimulation on diabetes mellitus‐associated muscle atrophy in rats

“…In the DM group, increased production of AGEs by glycation of proteins depends on the development of hyperglycemia and diabetes. In addition, the AGEs produced accumulate in a variety of cells, including muscle cells . Furthermore, it has been suggested that activation of the AGEs/RAGE pathway decreases protein synthesis by deactivating the mTOR pathway .…”

“…Hyperglycemia leads to the glycation of proteins and enzymes involved in various cellular processes . In addition, endogenous metabolites are generated by the auto‐oxidation of glucose . Endogenous metabolites act as reactive glycating agents and reduce sugars such as glucose to produce AGEs .…”

“…4,5 In addition, endogenous metabolites are generated by the auto-oxidation of glucose. [6][7][8][9] Endogenous metabolites act as reactive glycating agents and reduce sugars such as glucose to produce AGEs. [6][7][8][9] It has been suggested that diabetes-associated accumulation of AGEs can be induced by downregulation of protein synthesis in skeletal muscle.…”

“…[6][7][8][9] Endogenous metabolites act as reactive glycating agents and reduce sugars such as glucose to produce AGEs. [6][7][8][9] It has been suggested that diabetes-associated accumulation of AGEs can be induced by downregulation of protein synthesis in skeletal muscle. 3 Skeletal muscle atrophy is induced by the imbalance between protein synthesis and protein degradation, resulting in reduced cross-sectional area (CSA) of muscle fibers and loss of muscle mass.…”

Fibromodulin and regulation of the intricate balance between myoblast differentiation to myocytes or adipocyte‐like cells

“…Study of its role in the regulation of MSCs revealed that it interfered with the interaction between the negative muscle regulator myostatin and its receptor, activin receptor type IIB (13). In addition, binding of curcumin or gingerol with myostatin decreased the binding affinity of myostatin to activin receptor type IIB (19). The involvement of FMOD in different cellular processes (14) made us study its regulatory function on MSC fate in the myogenic program.…”