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.
Highlights
Metabolic syndrome encompasses a series of risk factors that imperil the individual in developing cardiovascular diseases and an assortment of other health problems, including type II diabetes and stroke[1,2,3,4]
The mice treated with a high-fat diet (HFD) exhibited higher levels of total cholesterol and low-density lipoprotein (LDL) than the mice subjected to a normal diet (ND) (Fig 1D)
Song et al criticize this property of mitsugumin 53 (MG53) that prompts the ubiquitin-dependent degradation of insulin receptor substrate-1 (IRS-1)
Summary
Metabolic syndrome encompasses a series of risk factors that imperil the individual in developing cardiovascular diseases and an assortment of other health problems, including type II diabetes and stroke[1,2,3,4]. A less explored complication of metabolic syndrome is its impact on tissue repair; it has been widely recognized that injuries of diabetic patients are slow to recover[5,6]. One of the most notable instances of defective tissue healing in patients exhibiting metabolic disorders includes diabetic foot ulcers[5,6]. Expressed in hyperactive cells exposed to constant physical activity and stress, namely striated muscles, MG53 is a tripartite motif (TRIM) protein that presides over the mechanisms of plasma membrane repair. It facilitates the nucleation of intracellular transport vesicles to sites of membrane injury to form a mending patch. Research efforts have been devoted to translate this rudimentary discovery to clinical applications towards treatment of muscular dystrophy[9,10,11], acute lung injury[12], and other human diseases, including myocardial infarction [8,10,13,14] and neurodegeneration
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