{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T02:01:16Z","timestamp":1790128876614,"version":"4.0.1"},"reference-count":70,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2018,8,30]],"date-time":"2018-08-30T00:00:00Z","timestamp":1535587200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"the Takeda Science Foundation and the Japan Ministry of Education, Science, and Culture","award":["17 K10137"],"award-info":[{"award-number":["17 K10137"]}]},{"name":"the Takeda Science Foundation and the Japan Ministry of Education, Science, and Culture","award":["15 K09115"],"award-info":[{"award-number":["15 K09115"]}]},{"name":"the Takeda Science Foundation and the Japan Ministry of Education, Science, and Culture","award":["26350879"],"award-info":[{"award-number":["26350879"]}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["J cachexia sarcopenia muscle"],"published-print":{"date-parts":[[2018,10]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background<\/jats:title><jats:p>Exercise intolerance is a common clinical feature and is linked to poor prognosis in patients with heart failure (HF). Skeletal muscle dysfunction, including impaired energy metabolism in the skeletal muscle, is suspected to play a central role in this intolerance, but the underlying mechanisms remain elusive. Lysine acetylation, a recently identified post\u2010translational modification, has emerged as a major contributor to the derangement of mitochondrial metabolism. We thus investigated whether mitochondrial protein acetylation is associated with impaired skeletal muscle metabolism and lowered exercise capacity in both basic and clinical settings of HF.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We first conducted a global metabolomic analysis to determine whether plasma acetyl\u2010lysine is a determinant factor for peak oxygen uptake (peak VO<jats:sub>2<\/jats:sub>) in HF patients. We then created a murine model of HF (<jats:italic>n<\/jats:italic>\u00a0=\u00a011) or sham\u2010operated (<jats:italic>n<\/jats:italic>\u00a0=\u00a011) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry\u2010based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in <jats:italic>in vitro<\/jats:italic> studies.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>The metabolomic analysis verified that acetyl\u2010lysine was the most relevant metabolite that was negatively correlated with peak VO<jats:sub>2<\/jats:sub> (r = \u22120.81, <jats:italic>P<\/jats:italic> &lt; 0.01). At 4\u00a0weeks post\u2010myocardial infarction HF, a treadmill test showed lowered work (distance\u00a0\u00d7\u00a0body weight) and peak VO<jats:sub>2<\/jats:sub> in the HF mice compared with the sham\u2010operated mice (11\u00a0\u00b1\u00a01 vs. 23\u00a0\u00b1\u00a01\u00a0J, <jats:italic>P<\/jats:italic> &lt; 0.01; 143\u00a0\u00b1\u00a05 vs. 159\u00a0\u00b1\u00a03\u00a0mL\/kg\/min, <jats:italic>P<\/jats:italic> = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham\u2010operated mice (<jats:italic>P<\/jats:italic> = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid \u03b2\u2010oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (\u03b2\u2010hydroxyacyl CoA dehydrogenase) activity and fatty acid\u2010driven mitochondrial respiration were reduced in the HF mice. This alteration was associated with a decreased expression of mitochondrial deacetylase, Sirtuin 3, because silencing of Sirtuin 3 in cultured skeletal muscle cells resulted in increased mitochondrial acetylation and reduced \u03b2\u2010hydroxyacyl CoA dehydrogenase activity.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Enhanced mitochondrial protein acetylation is associated with impaired FAO in skeletal muscle and reduced exercise capacity in HF. Our results indicate that lysine acetylation is a crucial mechanism underlying deranged skeletal muscle metabolism, suggesting that its modulation is a potential approach for exercise intolerance in HF.<\/jats:p><\/jats:sec>","DOI":"10.1002\/jcsm.12322","type":"journal-article","created":{"date-parts":[[2018,8,31]],"date-time":"2018-08-31T03:40:11Z","timestamp":1535686811000},"page":"844-859","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure"],"prefix":"10.1002","volume":"9","author":[{"given":"Masaya","family":"Tsuda","sequence":"first","affiliation":[{"name":"Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine Hokkaido University  Sapporo 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