Abstract 14367: Mitochondrial Protein Acetylation in Skeletal Muscle Was Associated With Exercise Intolerance in Heart Failure After Myocardial Infarction in Mice
Background: Exercise intolerance is a major clinical manifestation and an independent predictor of poor prognosis in heart failure (HF) patients, due largely to skeletal muscle abnormalities. Protein acetylation on lysine residues is one of post-translational modifications that have been recently emerged as an important mechanism involved in energy metabolism in the skeletal muscle. Here, we investigated the hypothesis that mitochondrial protein acetylation in skeletal muscle contributes to exercise intolerance and skeletal muscle abnormalities in an HF mouse model after creating myocardial infarction (MI). We also examined the association between plasma N6-acetyl-lysine level and exercise capacity in HF patients.
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 (distance x body weight) and peak oxygen uptake (VO2) evaluated by treadmill test with expired gas analysis, were significantly reduced in MI mice compared to sham mice (work 11±1 vs 23±1 J, p<0.05, and peak VO2 143±5 vs 159±3 mL/kg/min, p<0.05). Acetyl-lysine level of mitochondrial fraction assessed by Western blotting was increased in the skeletal muscle from MI mice. In association with these results, activities of citrate synthase, an enzyme of tricarboxylic acid cycle, and mitochondrial respiratory chain complexes were significantly decreased in the skeletal muscle from MI mice. In addition, metabolomic analysis of plasma sample from human patients with HF (n=10) and controls (n=5) were performed using capillary electrophoresis time-of-flight mass spectroscopy, and revealed that plasma N6-acetyl-lysine level was increased in HF patients compared to controls (15.0±3.2х10-5 vs. 9.8±2.4х10-5, p<0.01) and had a negative correlation with peak VO2 (r2=0.64, p<0.01).
Conclusions: Mitochondrial protein acetylation is associated with reduced exercise capacity and skeletal muscle abnormalities in HF. These results provide a novel pathophysiological insight into the mechanism of exercise intolerance with HF and also plasma N6-acetyl-lysine might be a new biomarker for exercise capacity in patients with HF.
Author Disclosures: M. Tsuda: None. S. Kinugawa: None. S. Takada: None. A. Fukushima: None. T. Yokota: None. W. Mizushima: None. T. Furihata: None. J. Matsumoto: None. T. Katayama: None. T. Nakajima: None. S. Maekawa: None. H. Nambu: None. R. Shirakawa: None. N. Kakutani: None. K. Okita: None. H. Tsutsui: Research Grant; Significant; Tanabe-Mitsubishi, Daiichi-Sankyo, Takeda, Boehriner-Ingelheim, Bayer. Honoraria; Modest; Boehriner-Ingelheim, Bayer, BMS, Takeda. Honoraria; Significant; MSD, Tanabe-Mitsubishi, Daiichi-Sankyo, Teijin.
- © 2016 by American Heart Association, Inc.