title: Exercise training decreases activation of the mitochondrial fission protein dynamin-related protein-1 in insulin-resistant human skeletal muscle.
abstract: Defects in mitochondrial dynamics, the processes of fission, fusion, and mitochondrial autophagy, may contribute to metabolic disease including type 2 diabetes. Dynamin-related protein-1 (Drp1) is a GTPase protein that plays a central role in mitochondrial fission. We hypothesized that aerobic exercise training would decrease Drp1 Ser(616) phosphorylation and increase fat oxidation and insulin sensitivity in obese (body mass index: 34.6 ± 0.8 kg/m(2)) insulin-resistant adults. Seventeen subjects performed supervised exercise for 60 min/day, 5 days/wk at 80-85% of maximal heart rate for 12 wk. Insulin sensitivity was measured by hyperinsulinemic-euglycemic clamp, and fat oxidation was determined by indirect calorimetry. Skeletal muscle biopsies were obtained from the vastus lateralis muscle before and after the 12-wk program. The exercise intervention increased insulin sensitivity 2.1 ± 0.2-fold (P < 0.01) and fat oxidation 1.3 ± 0.3-fold (P < 0.01). Phosphorylation of Drp1 at Ser(616) was decreased (pre vs. post: 0.81 ± 0.15 vs. 0.58 ± 0.14 arbitrary units; P < 0.05) following the intervention. Furthermore, reductions in Drp1 Ser(616) phosphorylation were negatively correlated with increases in fat oxidation (r = -0.58; P < 0.05) and insulin sensitivity (rho = -0.52; P < 0.05). We also examined expression of genes related to mitochondrial dynamics. Dynamin1-like protein (DNM1L; P < 0.01), the gene that codes for Drp1, and Optic atrophy 1 (OPA1; P = 0.05) were significantly upregulated following the intervention, while there was a trend towards an increase in expression of both mitofusin protein MFN1 (P = 0.08) and MFN2 (P = 0.07). These are the first data to suggest that lifestyle-mediated improvements in substrate metabolism and insulin sensitivity in obese insulin-resistant adults may be regulated through decreased activation of the mitochondrial fission protein Drp1.
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Department of Biomedical Sciences, Kent State University, Kent, Ohio;
authors.forename: Ciaran E
authors.initials: CE
authors.lastname: Fealy
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Metabolic Translational Research Center, Cleveland Clinic, Cleveland, Ohio; and.
authors.forename: Anny
authors.initials: A
authors.lastname: Mulya
authors.affiliation: Department of Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio.
authors.forename: Nicola
authors.initials: N
authors.lastname: Lai
authors.affiliation: Department of Pathobiology, Lerner Research Institute, Cleveland Clinic, Cleveland, Ohio; Metabolic Translational Research Center, Cleveland Clinic, Cleveland, Ohio; and kirwanj@ccf.org.
authors.forename: John P
authors.initials: JP
authors.lastname: Kirwan
mesh_terms: D000368:Aged; D015992:Body Mass Index; D002153:Calorimetry, Indirect / Q000379:methods; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism / Q000503:physiopathology; D034281:Dynamins; D015444:Exercise / Q000502:physiology*; D005223:Fats / Q000378:metabolism; D005260:Female; D020558:GTP Phosphohydrolases / Q000378:metabolism*; D015309:Glucose Clamp Technique / Q000379:methods; D006339:Heart Rate / Q000502:physiology; D006801:Humans; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D008869:Microtubule-Associated Proteins / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism* / Q000502:physiology; D063154:Mitochondrial Dynamics / Q000502:physiology*; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000502:physiology; D009765:Obesity / Q000378:metabolism / Q000503:physiopathology; D010084:Oxidation-Reduction; D010766:Phosphorylation / Q000502:physiology
chemical_list: D005223:Fats; D007328:Insulin; D008869:Microtubule-Associated Proteins; D033681:Mitochondrial Membrane Transport Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C470018:MFN2 protein, human; C470017:Mfn1 protein, human; C110768:DNM1L protein, human; D034281:Dynamins
keywords: aerobic exercise; fat oxidation; insulin sensitivity; mitochondrial dynamics; mitochondrial fission