Abstract 2273: Mitochondrial Dysfunction Predisposes to Heart Failure in a Mouse Model of Accelerated Aging
Heart failure prevalence increases dramatically with aging, but it is unclear whether aging itself has intrinsic effects, or simply increases the time for diseases such as hypertension to take effect. In the absence of disease, aged hearts are increased in size, but have normal function. Mitochondrial DNA (mtDNA) mutations also increase with aging in humans, and may contribute to the aging process in the heart. To test this hypothesis, we used previously generated mice homozygous for a defective proof-reading mtDNA polymerase (mtmut). Mtmut mice have 4 –5-fold more mtDNA mutations than wild-type (WT) mice and exhibit multiple features of premature aging including early mortality. We evaluated mtmut mice aged 16 weeks, before the development of overt pathologies, at baseline and after transverse aortic constriction (TAC) and compared them with WT littermates. At baseline, mtmut mouse hearts had a 24.5% increase in LV diameter compared with WT (p<0.05), without a significant difference in systolic function or normalized heart weight. As in human aging, mtmut hearts displayed a decrease in mitochondrial function as measured by complex I activity compared with WT (Complex I/Complex V 0.270±0.002 mtmut vs 0.417±0.017, p < 0.05). Gene expression analysis revealed that ERR-α expression was increased 2-fold at baseline in mtmut hearts compared with WT (p< 0.05), with no change in the expression of PGC-1α, PPARα, TFAM, NRF-1 or NRF-2. Following TAC, mtmut mice were more likely to develop heart failure than WT (OR 4.41, 1.5– 6.9, p<0.05), with a mean fractional shortening 1 week after TAC of 28.9±9.3% vs 47.7±12.4% in WT (p<0.05). This decrease in systolic function occurred without a significant difference in hypertrophic response to TAC, and there was no difference in apoptosis, fibrosis, or tissue inflammation at 1 or 4 weeks after TAC. These data demonstrate that mtDNA mutation is sufficient to recapitulate phenotypes seen in aging human hearts at baseline. In addition, accelerated heart failure after similar biomechanical stress in this model suggests that heart failure with aging may reflect intrinsic effects of the aging process itself. Mtmut mice should provide a useful model for investigation of the mechanisms of aging-related cardiac biology and heart failure.