Expression of Mfn2, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle

Abstract

The primary gene mutated in Charcot-Marie-Tooth type 2A is mitofusin-2 (Mfn2). Mfn2 encodes a mitochondrial protein that participates in the maintenance of the mitochondrial network and that regulates mitochondrial metabolism and intracellular signaling. The potential for regulation of human Mfn2 gene expression in vivo is largely unknown. Based on the presence of mitochondrial dysfunction in insulin-resistant conditions, we have examined whether Mfn2 expression is dysregulated in skeletal muscle from obese or nonobese type 2 diabetic subjects, whether muscle Mfn2 expression is regulated by body weight loss, and the potential regulatory role of tumor necrosis factor (TNF)␣ or interleukin-6. We show that mRNA concentration of Mfn2 is decreased in skeletal muscle from both male and female obese subjects. Muscle Mfn2 expression was also reduced in lean or in obese type 2 diabetic patients. There was a strong negative correlation between the Mfn2 expression and the BMI in nondiabetic and type 2 diabetic subjects. A positive correlation between the Mfn2 expression and the insulin sensitivity was also detected in nondiabetic and type 2 diabetic subjects. To determine the effect of weight loss on Mfn2 mRNA expression, six morbidly obese subjects were subjected to weight loss by bilio-pancreatic diversion. Mean expression of muscle Mfn2 mRNA increased threefold after reduction in body weight, and a positive correlation between muscle Mfn2 expression and insulin sensitivity was again detected. In vitro experiments revealed an inhibitory effect of TNF␣ or interleukin-6 on Mfn2 expression in cultured cells. We conclude that body weight loss upregulates the expression of Mfn2 mRNA in skeletal muscle of obese humans, type 2 diabetes downregulates the expression of Mfn2 mRNA in skeletal muscle, Mfn2 expression in skeletal muscle is directly proportional to insulin sensitivity and is inversely proportional to the BMI, TNF␣ and interleukin-6 downregulate Mfn2 expression and may participate in the dysregulation of Mfn2 expression in obesity or type 2 diabetes, and the in vivo modulation of Mfn2 mRNA levels is an additional level of regulation for the control of muscle metabolism and could provide a molecular mechanism for alterations in mitochondrial function in obesity or type 2 diabetes. Diabetes 54: [2685][2686][2687][2688][2689][2690][2691][2692][2693] 2005

Mitofusin 2 (Mfn2) links mitochondrial and endoplasmic reticulum function with insulin signaling and is essential for normal glucose homeostasis

“…Here, we demonstrate that Mfn2 deficiency in mice induces susceptibility to develop insulin resistance in response to both age and HFD treatment. These data fit with the observations that muscle Mfn2 is repressed in human obesity or in type 2 diabetes (13,14) and allow us to propose that Mfn2 is a regulator of in vivo insulin sensitivity and a potential target in diabetes drug development.…”

“…Mfn2 is relevant in human disease, and mutations in Mfn2 have been reported in patients affected by Charcot-Marie-Tooth neuropathy type 2A (10)(11)(12). In addition, we have reported that Mfn2 expression is reduced in skeletal muscle of obese subjects and in type 2 diabetic patients (13,14).…”

Genes involved in mitochondrial biogenesis/function are induced in response to bilio-pancreatic diversion in morbidly obese individuals with normal glucose tolerance but not in type 2 diabetic patients

“…Muscle mitochondria from patients with type 2 diabetes show reduced size, reduced activity of the electron transport chain and reduced ADP-stimulated and maximal mitochondrial respiratory capacity [1,36,37]. In parallel, type 2 diabetes is associated with reduced expression of genes of oxidative metabolism as well as with repression of MFN2 [38][39][40]. In skeletal muscle of non-diabetic individuals with a family history of type 2 diabetes, decreased expression of nuclear genes encoding proteins of oxidative phosphorylation has been reported [39,40], along with reduced in vivo oxidative phosphorylation [35,41].…”

Mitochondrial respiratory chain dysfunction: Implications in neurodegeneration

“…In liver and cardiovascular cells, this high glucose-induced fission and rise in ROS production was mediated by increased intracellular calcium levels and ERK1/2-dependent Drp1 phosphorylation (Yu et al, 2011), whereas in muscle cells under chronic hyperglycemia the mitochondrial fragmented state was associated to a decrease in Mfn2 (Bach et al, 2003;Bach et al, 2005). Decreased mitochondrial fission due to FIS1 down-regulation also induced sublethal stress associated to mitochondrial elongation, loss of mitochondrial potential and increased ROS levels (Lee et al, 2004).…”