Effect of Metabolic Syndrome on Mitsugumin 53 Expression and Function

Abstract

Metabolic syndrome is a cluster of risk factors, such as obesity, insulin resistance, and hyperlipidemia that increases the individual’s likelihood of developing cardiovascular diseases. Patients inflicted with metabolic disorders also suffer from tissue repair defect. Mitsugumin 53 (MG53) is a protein essential to cellular membrane repair. It facilitates the nucleation of intracellular vesicles to sites of membrane disruption to create repair patches, contributing to the regenerative capacity of skeletal and cardiac muscle tissues upon injury. Since individuals suffering from metabolic syndrome possess tissue regeneration deficiency and MG53 plays a crucial role in restoring membrane integrity, we studied MG53 activity in mice models exhibiting metabolic disorders induced by a 6 month high-fat diet (HFD) feeding. Western blotting showed that MG53 expression is not altered within the skeletal and cardiac muscles of mice with metabolic syndrome. Rather, we found that MG53 levels in blood circulation were actually reduced. This data directly contradicts findings presented by Song et. al that indict MG53 as a causative factor for metabolic syndrome (Nature 494, 375-379). The diminished MG53 serum level observed may contribute to the inadequate tissue repair aptitude exhibited by diabetic patients. Furthermore, immunohistochemical analyses reveal that skeletal muscle fibers of mice with metabolic disorders experience localization of subcellular MG53 around mitochondria. This clustering may represent an adaptive response to oxidative stress resulting from HFD feeding and may implicate MG53 as a guardian to protect damaged mitochondria. Therapeutic approaches that elevate MG53 expression in serum circulation may be a novel method to treat the degenerative tissue repair function of diabetic patients.

Swimming Exercise Alleviated Insulin Resistance by Regulating Tripartite Motif Family Protein 72 Expression and AKT Signal Pathway in Sprague-Dawley Rats Fed with High-Fat Diet

“…Several studies have shown that systemic IR can be effectively improved by exercise through reduction of oxidative stress [46, 47]. In the present study, we tested SOD, MDA, GSH-Px, 8-OHdG, and TRIM72 levels in the skeletal muscles of rats in all the groups; the oxidative stress was found increased after long-term feeding with high-fat diet, and, in HFD group, the TRIM72 showed a significant-level promotion on both mRNA and protein expression; this is in accordance with Song et al [8] (published in “ Nature ” 2013), although some publications from different groups showed that HFD treatment does not alter expression of TRIM72 [48–53]. We analyzed and inferred the possible reasons: firstly, the differences of the high-fat diet composition: the multiple researchers use the high-fat diet with 45% or more calories from fat or extra cholesterol added.…”

N‐acetylcysteine prevents oxidized low‐density lipoprotein‐induced reduction of MG53 and enhances MG53 protective effect on bone marrow stem cells

“…It has been shown that mice with metabolic syndrome induced by 6-month highfat diet (HFD) feeding exhibited a significant increase in serum lipid levels and a significant reduction in circulating MG53 level without change in MG53 expression within skeletal and cardiac muscles. 19 In the present study, we also observed that serum MG53 level was significantly decreased in hyperlipidemic LDLR −/− mice ( Figure 2C).…”

“…Little is known on the metabolism of MG53 in vivo. However, it has been shown that serum MG53 levels in mice with metabolic syndrome induced by a 6‐month high‐fat diet were significantly reduced . S‐nitrosylation of MG53 at C144 (cysteine 144) prevented oxidation‐induced degradation of MG53 following oxidative insult, therefore enhancing cardiomyocyte survival .…”

“…However, it has been shown that serum MG53 levels in mice with metabolic syndrome induced by a 6-month high-fat diet were significantly reduced. 19 S-nitrosylation of MG53 at C144 (cysteine 144) prevented oxidation-induced degradation of MG53 following oxidative insult, therefore enhancing cardiomyocyte survival. 20 In the present study, we tested the hypothesis that the limited protective effect of MG53 on BMSCs against ox-LDL was due to ox-LDL-induced reduction of MG53.…”

Tripartite Motif Protein 72 Regulates the Proliferation and Migration of Rat Cardiac Fibroblasts via the Transforming Growth Factor-β Signaling Pathway

“…To investigate the cell-molecular mechanisms of Trim proteins, studies have focused on the role of various protein motifs in mediating intracellular signaling events. Similar to other Trim family members, the molecular mechanism of Trim72 has not yet been extensively studied in cardiac fibroblasts [30,31] .…”