Expression of Mfn2, the Charcot-Marie-Tooth Neuropathy Type 2A Gene, in Human Skeletal Muscle
Author:
Bach Daniel1, Naon Deborah1, Pich Sara1, Soriano Francesc X.1, Vega Nathalie2, Rieusset Jennifer2, Laville Martine2, Guillet Christelle3, Boirie Yves3, Wallberg-Henriksson Harriet4, Manco Melania5, Calvani Menotti5, Castagneto Marco5, Palacín Manuel1, Mingrone Geltrude5, Zierath Juleen R.4, Vidal Hubert2, Zorzano Antonio1
Affiliation:
1. Departament de Bioquímica i Biologia Molecular, Facultat de Biologia, Universitat de Barcelona, and IRB-PCB, Parc Científic de Barcelona, Barcelona, Spain 2. Institut National de la Santé et de la Recherche Médicale Unité-449 and Centre de Recherche en Nutrition Humaine de Lyon, Faculté de Médecine R.T.H., Laennec Lyon, France 3. Unite du Metabolisme Proteino-Energetique, UMR Universite d’Auvergne/INRA, CRNH, Centre Hospitalier Universitaire, Clermont-Ferrand, France 4. Department of Surgical Sciences, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden 5. Istituto di Medicina Interna, Facoltà di Medicina e Chirurgia, Università Cattolica, Roma, Italy
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)α 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 TNFα 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, TNFα 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.
Publisher
American Diabetes Association
Subject
Endocrinology, Diabetes and Metabolism,Internal Medicine
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