Abstract| Volume 23, ISSUE 10, SUPPLEMENT , S72, October 2017

Protein Acetylation in Skeletal Muscle Impairs Mitochondrial Fatty Acid Oxidation and Limits Exercise Capacity in Post-Infarct Heart Failure in Mice

      Background: Exercise intolerance is a major clinical manifestation in heart failure (HF) patients, due largely to skeletal muscle (SKM) abnormalities. Lysine Acetylation is a reversible post-translational modification involved in regulating mitochondrial metabolic enzymes. We investigated whether mitochondrial acetylation in SKM could contribute to impaired fatty acid oxidation and exercise intolerance associated with HF. Methods and Results: MI was created in male C57BL/6J mice by ligating the left coronary artery (n = 7), and a sham operation was performed in other mice (n = 7). After 4 weeks, the work and peak oxygen uptake (VO2) was significantly reduced in MI mice compared to sham mice (work 11 ± 1 vs 23 ± 1 J; peak VO2 143 ± 5 vs 159 ± 3 mL⋅kg−1⋅min−1). Mitochondrial proteins that include TCA cycle enzymes, electron transport chain, and fatty acid β-oxidation enzymes such as enoyl-CoA hydratase and 3-ketoacyl-CoA thiolase were hyperacetylated in SKM from MI mice, in conjunction with a decrease in mitochondrial fatty acid respiratory capacity rates. In addition, metabolomic analysis revealed that plasma N6-acetyl-lysine level was increased in HF patients compared to controls (15.0 ± 3.2 × 10−5 vs 9.8 ± 2.4 × 10−5, P < .01) and negatively correlated with peak VO2 measured by cardiopulmonary exercise test (r2 = 0.52, P < .01). Conclusions: Mitochondrial acetylation is associated with impaired fatty acid oxidation and reduced exercise capacity in HF. These results provide a novel pathophysiological insight into the mechanism of exercise intolerance in HF.
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