Influence of aging and hemorrhage injury on Sirt1 expression: Possible role of myc-Sirt1 regulation in mitochondrial function

Trauma–hemorrhage (T–H) causes hypoxia and organ dysfunction. Mitochondrial dysfunction is a major factor for cellular injury due to T–H. Aging also has been known to cause progressive mitochondrial dysfunction. In order to study the effect of aging on T–H-induced mitochondrial dysfunction, we recently developed a rodent mitochondrial genechip with probesets representing mitochondrial and nuclear genes contributing to mitochondrial structure and function. Using this chip we recently identified signature mitochondrial genes altered following T–H in 6 and 22 month old rats; augmented expression of the transcription factor c-myc was the most pronounced. Based on reports of c-myc-IL6 collaboration and c-myc-Sirt1 negative regulation, we further investigated the expression of these regulatory factors with respect to aging and injury. Rats of ages 6 and 22 months were subjected to T–H or sham operation and left ventricular tissues were tested for cytosolic cytochrome c, mtDNA content, Sirt1 and mitochondrial biogenesis factors Foxo1, Ppara and Nrf-1. We observed increased cardiac cytosolic cytochrome c (sham vs T–H, p < 0.03), decreased mitochondrial DNA content (sham vs T–H, p < 0.05), and decreased Sirt1 expression (sham vs TH, p < 0.05) following T–H and with progressing age. Additionally, expression of mitochondrial biogenesis regulating transcription factors Foxo1 and Nrf-1 was also decreased with T–H and aging. Based upon these observations we conclude that Sirt1 expression is negatively modulated by T–H causing downregulation of mitochondrial biogenesis. Thus, induction of Sirt1 is likely to produce salutary effects following T–H induced injury and hence, Sirt1 may be a potential molecular target for translational research in injury resolution.

► Severe hemorrhage causes cardiac mitochondrial dysfunction. ► Aging exacerbates mitochondrial functional alteration due to hemorrhage. ► We observed increased release of cytochrome c from mitochondria to cytosol with aging and injury. ► We found a decrease in Sirt1 expression following hemorrhage. ► Coupled with our previous observation that c-Myc is upregulated following hemorrhage, our hypothesis is that c-Myc-Sirt1 regulation is important in mitochondrial function following hemorrhage injury.