Hydrogen peroxide production regulates the mitochondrial function in insulin resistant muscle cells: Effect of catalase overexpression

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• 作者：Marina R. Barbosa ; Igor H. Sampaio ; Bruno G. Teodoro ; Thais A. Sousa ; Claudio C. Zoppi ; Andr¨¦ L. Queiroz ; Madla A. Passos ; Luciane C. Alberici ; Felipe R. Teixeira ; Adriana O. Manfiolli ; Thiago M. Batista ; Ana Paula Gameiro Cappelli ; Rosana I. Reis ; Dan¨²bia Frasson ; Isis C. Kettelhut ; Lucas T. Parreiras-e-Silva ; Claudio M. Costa-Neto ; Everardo M. Carneiro ; Rui Curi ; Leonardo R. Silveira ; et al.
• 关键词：ROS ; reactive oxygen species ; DMEM ; Dulbecco's Modified Eagle's Medium ; PGM ; prime growth medium (PGM) ; siRNA ; Small interfering RNA ; PGC1¦Á ; peroxisome proliferative activated receptor-¦Ã (PPAR¦Ã) co-activator 1¦Á ; CREB ; cAMP response element-binding ; Ak
• 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Basis of Disease
• 出版年：2013
• 出版时间：October, 2013
• 年：2013
• 卷：1832
• 期：10
• 页码：1591-1604
• 全文大小：2310 K

文摘

The mitochondrial redox state plays a central role in the link between mitochondrial overloading and insulin resistance. However, the mechanism by which the ROS induce insulin resistance in skeletal muscle cells is not completely understood. We examined the association between mitochondrial function and H₂O₂ production in insulin resistant cells. Our hypothesis is that the low mitochondrial oxygen consumption leads to elevated ROS production by a mechanism associated with reduced PGC1¦Á transcription and low content of phosphorylated CREB. The cells were transfected with either the encoded sequence for catalase overexpression or the specific siRNA for catalase inhibition. After transfection, myotubes were incubated with palmitic acid (500 ¦ÌM) and the insulin response, as well as mitochondrial function and fatty acid metabolism, was determined. The low mitochondrial oxygen consumption led to elevated ROS production by a mechanism associated with ¦Â-oxidation of fatty acids. Rotenone was observed to reduce the ratio of ROS production. The elevated H₂O₂ production markedly decreased the PGC1¦Á transcription, an effect that was accompanied by a reduced phosphorylation of Akt and CREB. The catalase transfection prevented the reduction in the phosphorylated level of Akt and upregulated the levels of phosphorylated CREB. The mitochondrial function was elevated and H₂O₂ production reduced, thus increasing the insulin sensitivity. The catalase overexpression improved mitochondrial respiration protecting the cells from fatty acid-induced, insulin resistance. This effect indicates that control of hydrogen peroxide production regulates the mitochondrial respiration preventing the insulin resistance in skeletal muscle cells by a mechanism associated with CREB phosphorylation and ¦Â-oxidation of fatty acids.