INVESTIGADORES
PODEROSO Juan Jose
congresos y reuniones científicas
Título:
CONTROL OF MUSCLE MITOCHONDRIA BY INSULIN: AKT2-MTNOS PATHWAY
Autor/es:
PODEROSO JJ
Lugar:
Indianapolis, EEUU
Reunión:
Congreso; 15th Annual Meeting of the Society for Free Radical Biology and Medicine.; 2008
Institución organizadora:
Society for Free Radical Biology and Medicine.
Resumen:
A mitochondrial dysfunction characterized by reduced respiration and ATP synthesis has been reported in the metabolic syndrome associated to fat deposition and hyperinsulinemia. Nitric oxide (•NO) inhibits mitochondrial O2 utilization through reversible binding to cytochrome oxidase. We wondered whether an increase of mitochondrial •NO causes the lowering of muscle O2 utilization during insulin kinetics; a complementary hypothesis was that a synchronized increase of •NO yield facilitates muscle fat and glycogen accumulation by mitochondrial inhibition. Accordingly, we confi rmed here that the effects of long-lasting insulin selectively increases rat muscle phospho-Akt2 which translocates to mitochondria, phosphorylates mtNOS, and cooperatively increases its activity and matrix •NO concentration by 4-8 fold, with marked inhibition of muscle O2 uptake. We explored this insulin-NO pathway by direct in vivo electroporation of nNOS siRNA or empty vector in right and left gastrocnemius muscles from rats treated with insulin. In silenced muscles with disrupted mtNOS, O2 uptake and complete glucose oxidation remained high and glycogen-synthesis was reciprocally reduced respect to the contralateral muscles with normal mtNOS. To confi rm the link between •NO, mitochondrial dysfunction, insulin resistance, and obesity, we studied leptin-defi cient ob-/ob- mice which exhibited as well high mitochondrial •NO, nitration of complex I, and low O2 uptake that were reversed by administration of leptin or nNOS inhibitors. It is concluded that persistent hyperinsulinemia impairs muscle mitochondria and ATP synthesis via •NO and increases obesity and insulin resistance, thus favoring the progression of the metabolic syndrome.