Insulin modulates muscle oxygen and glucose metabolism via mitochondrial nitric oxide.

FINOCCHIETTO, PV; HOLOD, SA; CARRERAS, MC; PODEROSO JJ.

Montevideo, Uruguay

Congreso; V Meeting of SFRBM- South American Group. V International Conference on Peroxynitrite and Reactive Nitrogen Species.; 2007

SFRBM- South American Group.

Mitochondria slow down at the transition between glucose oxidation and storage at high-energy intake. Nitric oxide is a typical modulator that reversibly inhibits cytochrome oxidase and controls the O2 utilization; this effect is specially driven by PDZ-interaction between neuronal nitric oxide synthase (nNOSá) translocated to mitochondria (mtNOS) and cytochrome oxidase. Insulin stimulates both glucose oxidation and glycogen synthesis; in the last decade, many studies have focused on insulin resistance and mitochondrial dysfunction, but fewer had critically examined the alternation between complete oxidation and macromolecular deposits (as glycogen or fat stores). We analyzed here lasting effects of insulin on muscle metabolism in connection with mitochondrial nitric oxide. Insulin substantially increases downstream Akt2 phosphorylation and translocation to mitochondria determining in situ phosphorylation and allosteric activation of mtNOS, and reduced O2 uptake. Directly nNOS and Akt2 siRNAs electroporated to gastrocnemius-muscle hampered the ability of insulin to inhibit respiration. We therefore accomplished an in vivo comparative metabolic condition in which nNOS-mtNOS-deficient muscles increase glucose and O2 utilization and reciprocally restrict glycogen-synthesis. Thus, phospho-mtNOS results a mitochondrial effector of phophoinositide-3-kinase/insulin pathway that links oxidative to intermediary metabolism; therefore, persistent mtNOS activation could be important in the progression of hyperinsulinemic diabetic metabolic syndrome.