Abstract P233: PPARα-Sirt1 Complex Mediates Metabolic Adaptation in Response to Starvation in the Heart
Minimizing nutritional usage is believed to be important for prolonging survival time in organisms under starvation conditions such as fasting and hibernation. The heart is a major organ that constantly consumes nutrition coupling with mitochondrial ATP production. However, it remains unknown how mitochondrial gene expression is regulated in the heart during starvation conditions. We have previously shown that a PPARα-Sirt1 complex mediates downregulation of mitochondrial gene expression in the failing heart. Since both PPARα and Sirt1 are crucial regulators in physiological fasting responses, we hypothesized that the same mechanism is involved in the physiological fasting response in the heart. To investigate this hypothesis, heterozygous knockout PPARα (PPARα+/-) and Sirt1 (Sirt1+/-) mice were subjected to 24 hours fasting. Several mitochondrial genes, such as Sdha and Atp5g1, were downregulated following fasting in wild type (WT) mice, but this downregulation was at least partly prevented in PPARα+/- and Sirt1+/- mice, suggesting that PPARα and Sirt1 play an important role in fasting-induced downregulation of mitochondrial gene expression in the heart. After fasting, cardiac systolic function was slightly reduced in WT mice, but this response was not induced in PPARα+/- and Sirt1+/- mice (ejection fraction (%): Fed WT 74, Fasted WT 68*, Fed PPARα+/- 76, Fasted PPARα+/- 75, Fed Sirt1+/- 74, Fasted Sirt1+/- 74, p<0.05 vs Fed WT). Weight loss after 24 hours fasting increased in PPARα+/- mice, compared to WT mice (Body weight reduction (%): WT 9, PPARα+/- 14*, p<0.05 vs WT). Under an isolated working mouse heart model with nutrient free perfusion buffer, spontaneous beating terminated earlier in hearts isolated from PPARα+/- and Sirt1+/- mice than in hearts from WT mice (Beating time (minutes): WT 63, PPARα+/- 37*, Sirt1+/- 36*, p<0.05 vs WT). Glucose deprivation-induced cell death was cooperatively prevented by overexpression of PPARα and Sirt1 in primary cultured myocytes (Cell survival rate (%): control 54, PPARα 75*, Sirt1 60, PPARα with Sirt1 94*, PPARα with Sirt1 knockdown 52, p<0.05 vs control). These results suggest that PPARα and Sirt1 are crucial regulators of adaptation to starvation in the heart.
- © 2011 by American Heart Association, Inc.