title: Overexpression of manganese superoxide dismutase ameliorates high-fat diet-induced insulin resistance in rat skeletal muscle.
abstract: Elevated mitochondrial reactive oxygen species have been suggested to play a causative role in some forms of muscle insulin resistance. However, the extent of their involvement in the development of diet-induced insulin resistance remains unclear. To investigate, manganese superoxide dismutase (MnSOD), a key mitochondrial-specific enzyme with antioxidant modality, was overexpressed, and the effect on in vivo muscle insulin resistance induced by a high-fat (HF) diet in rats was evaluated. Male Wistar rats were maintained on chow or HF diet. After 3 wk, in vivo electroporation (IVE) of MnSOD expression and empty vectors was undertaken in right and left tibialis cranialis (TC) muscles, respectively. After one more week, insulin action was evaluated using hyperinsulinemic euglycemic clamp, and tissues were subsequently analyzed for antioxidant enzyme capacity and markers of oxidative stress. MnSOD mRNA was overexpressed 4.5-fold, and protein levels were increased by 70%, with protein detected primarily in the mitochondrial fraction of muscle fibers. This was associated with elevated MnSOD and glutathione peroxidase activity, indicating that the overexpressed MnSOD was functionally active. The HF diet significantly reduced whole body and TC muscle insulin action, whereas overexpression of MnSOD in HF diet animals ameliorated this reduction in TC muscle glucose uptake by 50% (P < 0.05). Decreased protein carbonylation was seen in MnSOD overexpressing TC muscle in HF-treated animals (20% vs. contralateral control leg, P < 0.05), suggesting that this effect was mediated through an altered redox state. Thus interventions causing elevation of mitochondrial antioxidant activity may offer protection against diet-induced insulin resistance in skeletal muscle.
authors: Diabetes and Obesity Program, Garvan Institute for Medical Research, Darlinghurst, NSW, Australia 2010.
authors: Michael J
authors: MJ
authors: Boden
authors: Amanda E
authors: AE
authors: Brandon
authors: Jennifer D
authors: JD
authors: Tid-Ang
authors: Elaine
authors: E
authors: Preston
authors: Donna
authors: D
authors: Wilks
authors: Ella
authors: E
authors: Stuart
authors: Mark E
authors: ME
authors: Cleasby
authors: Nigel
authors: N
authors: Turner
authors: Gregory J
authors: GJ
authors: Cooney
authors: Edward W
authors: EW
authors: Kraegen
mesh_terms: D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects*; D018274:Electroporation; D018014:Gene Transfer Techniques; D005979:Glutathione Peroxidase / Q000378:metabolism; D006801:Humans; D007333:Insulin Resistance; D035002:Lower Extremity; D008297:Male; D008931:Mitochondria, Muscle / Q000201:enzymology / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000378:metabolism; D018482:Muscle, Skeletal / Q000201:enzymology* / Q000378:metabolism; D018384:Oxidative Stress; D050050:Protein Carbonylation; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D013482:Superoxide Dismutase / Q000235:genetics / Q000378:metabolism*; D015854:Up-Regulation; D000099156:Superoxide Dismutase 2
chemical_list: D005979:Glutathione Peroxidase; D012333:RNA, Messenger; D011993:Recombinant Fusion Proteins; D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2