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- W52679319 abstract "It has recently been reported that impaired PI3K signaling leads to cardiac mitochondrial dysfunction and that cardiac insulin receptor deficiency impairs cardiac growth. Signaling from insulin and insulin-like growth factor 1 receptors to PI3K is mediated by insulin receptor substrates (IRS) 1 and 2. Our objective was to determine the contribution of IRS isoforms on cardiac structure, mitochondrial and contractile function. For this purpose we generated mice with cardiomyocyte-specific deletion of IRS1 (CIRS1KO) or IRS2 (CIRS2KO) or IRS1 + IRS2 (CIRS12KO). While the single KOs had normal survival, CIRS12KO mice died from heart failure within the first eleven weeks of life. At the age of 8 weeks, heart weight-to-tibia length ratios, HW/TL were reduced by 11% (p<0.05) in CIRS1KO versus WT. ADP-stimulated mitochondrial oxygen consumption (V-ADP) was decreased by 22% (p<0.05) and ATP synthesis by 16% (p<0.05) in saponin-permeabilized cardiac fibers using pyruvate as substrate but not with palmitoyl carnitine (PC) or glutamate. In contrast, HW/TL was unchanged in CIRS2KO at the age of 8 weeks and was increased at the age of 14 weeks (+7%, p<0.05). Similarly, ADP-stimulated respirations were reduced in CIRS2KO at both ages by −21% and −16% respectively, (p < 0.05) only with pyruvate as substrate. In contrast, CIRS12KO developed dilated cardiomyopathy at the age of 4 weeks (LVDs + 18.9%, LVPWd −12.7%, LVPWs −21.4%, FS −36.7%, EF −26.3%, p<0.05). Histology revealed myofibrillar loss and disarray and increased fibrosis. Using stereology, cardiomyocyte nuclei per area was reduced by 27% and cardiomyocyte cross-sectional area was increased by 33% (both, p<0.05). Using pyruvate, PC or glutamate as substrates, V-ADP and ATP-synthesis rates were reduced by 33– 41%. Transcriptional analysis revealed a coordinate downregulation (by 40 – 60%) of PDK4 and PDH subunits, FAO and OXPHOS genes that were associated with a 35% reduction in expression of PGC-1β. At the protein level, expression of the complex II subunit, succinate-ubiquinol oxidoreductase was reduced by −51% (p<0.01). These data identify a critical role for IRS-mediated signaling in the regulation mitochondrial gene and protein expression, mitochondrial function and cardiomyocyte survival." @default.
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- W52679319 date "2008-10-28" @default.
- W52679319 modified "2023-09-26" @default.
- W52679319 title "Abstract 3559: Insulin Receptor Substrates (IRS) Signaling are Essential Regulators of Mitochondrial Function and Cardiomyocyte Survival" @default.
- W52679319 doi "https://doi.org/10.1161/circ.118.suppl_18.s_444-b" @default.
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