Control of muscle mitochondria by insulin entails activation of Akt2-mtNOS pathway: Imlpications for the metabolic syndrome

Abstract

Background: In the metabolic syndrome with hyperinsulinemia, mitachondrial inhibition facillitates muscle fat and glycogen accumulation and accelerates its progression. In the last decade, nitric oxide (NO) emerged as a typical mitochoridrial modulator by reversibly inhibiting citochrome oxidase and oxygen utilization. We wondered whether insulin-operated signaling pathways modulate mitochondrial respiration via NO, to alternatively release complete glucose oxidation to C02 and H2O or to drive glucose storage to glycogen. Methodology/Principal Findings: We illustrate here that NO produced by translocated , nNOS (mtNOS) is the insulin-signaling molecule that controls mitochondrial oxygen utilization, We evoke a hyperinsulinemic-normoglycemic non-invasive clamp by subcutaneously injecting adult male rats with long-lasting human insulin glargine that remains. stable in plasma by several hours. At a precise concentration, insulin increased phospho-Akt2 that translocates to mithondria and determines in situ phosphorylation and substantial cooperative mtNOS activation (+4-8 fold, P <05), which reciprocally restricted glycogen-synthesis by a half. Conclusions/Significance. These evidences show that after energy replenishtment, insulin depresses mitochondrial respiration in skeletal muscle via NO which permits substrates to be deposited as macromoleculeso; at discrete hyperinsulinemia, persistent mtNOS activation could contribute to mitochondrial dysfunctions with insulin resistance and obesity and therefore, to the progression of the metabolic syndrome. © 2008 Finocchietto et al.