Abstract 3920: Metallothionein Transgene Prevents Insulin Resistant Induced Cardiac Contractile Dysfunction by Promoting Mitochondrial Biogenesis through Upregulation of Peroxisome Proliferator-activated Receptor gamma Coactivator-1 (PGC-1) alpha
Impaired mitochondrial biogenesis has been implicated in the pathogenesis of insulin resistance although its role in cardiac complications has not been examined. Enhanced oxidative stress under insulin resistant state may down-regulate mitochondrial biosynthesis in myocardium, which further contributes to cardiac contractile dysfunction. To test this hypothesis, we examined the impact of endogenous overexpression of the free radical scavenger metallothionein on insulin resistance-induced cardiac dysfunction and the potential mechanism involved with mitochondrial biogenesis. Wild type FVB mice and mice with cardiac overexpression of metallothionein (MT) were fed high fat diet for 20 weeks to induce obesity and whole body insulin resistance. Echocardiography revealed decreased ejection fraction, left ventricular dilation and increased ventricular mass in FVB mice following high fat feeding. Cardiomyocytes from insulin resistant mice exhibited contractile dysfunction characterized by depressed peak shortening, prolonged relaxation, and slowed Ca2+ clearance. Morphological analyses by transmission electron microscopy indicated that the mitochondrial density was significantly decreased, which was consistent with our result showing a reduction of mitochondrial DNA(mtDNA)in the insulin resistant myocardium. Western blot revealed that insulin resistance significantly increased pFoxO1, pFoxO3a, FoxO1 and FoxO3a levels in the heart without affecting Sir2 expression. However, the level of PGC-1α, the nuclear receptor coactivator regulating mitochondrial biosynthesis, was significantly down-regulated. Furthermore, our RT-PCR data suggested factors downstream of PGC-1 α, including nuclear respiratory factor 1(NRF1), nuclear respiratory factor 2(NRF2) and mitochondrial transcription factor A (mtTFA), were also decreased in diet-induced insulin resistant mouse hearts. Interestingly, all these high fat diet induced alterations with the exception of elevated pFoxO3a level were attenuated or ablated by MT transgene. Collectively, our data suggest a protective role of antioxidant against insulin resistant induced cardiac dysfunction, possibly through rescuing mitochondrial biogenesis by up-regulation of PGC-1 α.