Abstract P400: Treatment With The AMPK Agonist AICAR Alleviates Age-associated Cardiac Defects In The Mouse By Distinct Sex-specific Mechanisms

Heart failure is a major cause of mortality in the elderly. Features of cardiac aging include diastolic dysfunction and interstitial fibrosis with sex-specific differences. We treated old male and female mice (21 months-old) 3 times a week for 3 months with the AMPK agonist 5-aminoimidazole-4-carboxamide ribonucleoside (AICAR, 0.166 mg/g BW). We previously reported that AICAR normalizes the aged fibroblast phenotype. In a longitudinal study, we found that AICAR attenuates the age-associated increase in left atrial volume, an indirect indicator of diastolic dysfunction, in female AICAR-treated mice (-29% ±5%) but not in males (-7% ±6%). Cardiac fibroblasts from AICAR-treated mice expressed decreased pro-collagen levels by 42% (mean fluorescence intensity, P=0.0003 for females, and P=0.05 for males). Cardiac fibroblasts cultured on decellularized cardiac matrices also had a reduced expression of pro-collagen when treated with AICAR (0.5mM, 7 days). Myocardial hydroxyproline level (an indicator of total collagen content) was reduced in female hearts (from 0.83 ± 0.07 in controls to 0.48 ± 0.05 in AICAR-treated, P=0.006). Female cells also exhibited a reduced expression of periostin after treatment (by 65%, P=0.02). By contrast, age-matched control males had a lower cardiac level of hydroxyproline (-65%, P=0.0002) and periostin (-45%, P=0.0004) than females, and were not affected by the treatment. Accumulation of defective mitochondria is a hallmark of aging. Since AICAR can favor mitophagy, we isolated mitochondrial fractions from the hearts of old mice undergoing treatment. We found that AICAR decreased Parkin level in the small mitochondria fraction (0.75±0.09, P=0.028) in males, but no significant change was found between the groups of females. The reduction of Parkin may suggest improved clearance of defective mitochondria.For all experiments, we used 4-10 animals per group. One-way Anova or student’s T-test evaluated statistical significance. In conclusion, age-associated cardiac remodeling leads to distinct patterns between male and female mice. AICAR treatment can have sex-specific effects: it reduces fibrosis in females but may promote mitophagy in males, translating into an improvement of heart function via distinct mechanisms.