Abstract 210: Progressive Mitochondrial Protein Acetylation and Microsteatosis is Associated with Diastolic Dysfunction in a Hypertrophic Cardiomyopathy Model

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Abstract

We tested the hypothesis that increased mitochondrial protein acetylation is associated with impaired fatty acid metabolism and diastolic dysfunction in Friedreich’s Ataxia (FRDA). FRDA results from deficiency of the mitochondrial protein, frataxin (FXN), and causes hypertrophic cardiomyopathy. FRDA hearts show decreased ATP production. We previously showed that FXN loss results in loss of activity of the NAD+-dependent mitochondrial deacetylase, sirtuin 3 (SIRT3), and cardiac mitochondrial protein hyperacetylation in a mouse model of FRDA. Long-chain and medium chain acyl CoA dehydrogenases (LCAD, MCAD) are targets of SIRT3, suggesting that abnormal acetylation may alter fatty acid metabolism. A cardiac specific mouse model with conditional deletion of FXN in heart and skeletal muscle (FXN MCK-Cre-/-) was compared to healthy controls (FXNfl/fl). Mice underwent echocardiogram and left heart catheterization in vivo at age 30 and 65 days. Heart lysate was examined for overall lysine acetylation at ages 30, 45 and 70 days, and acetylated LCAD and MCAD. Myocardial cells were stained with oil red to detect lipids. Hearts of FXN MCK-Cre-/- animals showed mitochondrial hyperacetylation, increased LCAD and MCAD acetylation, and microsteatosis compared to controls. Diastolic dysfunction was evident in FXN MCK-Cre-/- at day 65 by increased mitral valve E/A ratios and IVRT (p<0.04 and p<0.03, respectively, n=7), prolonged tau, and decreased -dP/dt (p<0.02 and p <0.03, respectively, n=6). Cardiac mechanics at day 65 showed systolic failure with reduced EF and FS (p<0.002 and p<0.003, respectively, n=7). Comparison of FXN deficient mice and controls at day 65 trended toward flattened ESPVR and left shifted EDPVR curves, but differences were not significant. Early diastolic dysfunction was evident at day 30 in FXN MCK-Cre-/- by high E/A ratio and EDP compared to day 65 controls (p <0.03, n=7, and p<0.03, n=6, respectively). We conclude that progressive mitochondrial protein acetylation and abnormal fatty acid metabolism is associated with early diastolic dysfunction and later systolic failure. This metabolic dysregulation and pathophysiology may share characteristics with other metabolic heart disorders, such as diabetes and metabolic syndrome.

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