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- W2889168199 abstract "BACKGROUND 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-translational 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. METHODS We first conducted a global metabolomic analysis to determine whether plasma acetyl-lysine is a determinant factor for peak oxygen uptake (peak VO2 ) in HF patients. We then created a murine model of HF (n = 11) or sham-operated (n = 11) mice with or without limited exercise capacity by ligating a coronary artery, and we tested the gastrocnemius tissues by using mass spectrometry-based acetylomics. A causative relationship between acetylation and the activity of a metabolic enzyme was confirmed in in vitro studies. RESULTS The metabolomic analysis verified that acetyl-lysine was the most relevant metabolite that was negatively correlated with peak VO2 (r = -0.81, P < 0.01). At 4 weeks post-myocardial infarction HF, a treadmill test showed lowered work (distance × body weight) and peak VO2 in the HF mice compared with the sham-operated mice (11 ± 1 vs. 23 ± 1 J, P < 0.01; 143 ± 5 vs. 159 ± 3 mL/kg/min, P = 0.01; respectively). As noted, the protein acetylation of gastrocnemius mitochondria was 48% greater in the HF mice than the sham-operated mice (P = 0.047). Acetylproteomics identified the mitochondrial enzymes involved in fatty acid β-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (β-hydroxyacyl CoA dehydrogenase) activity and fatty acid-driven 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 β-hydroxyacyl CoA dehydrogenase activity. CONCLUSIONS 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." @default.
- W2889168199 created "2018-09-07" @default.
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- W2889168199 date "2018-08-30" @default.
- W2889168199 modified "2023-10-16" @default.
- W2889168199 title "Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure" @default.
- W2889168199 cites W1511815964 @default.
- W2889168199 cites W1673932087 @default.
- W2889168199 cites W1890886324 @default.
- W2889168199 cites W1939296385 @default.
- W2889168199 cites W1971400039 @default.
- W2889168199 cites W1972616589 @default.
- W2889168199 cites W1983076149 @default.
- W2889168199 cites W1991209451 @default.
- W2889168199 cites W1993534779 @default.
- W2889168199 cites W1998636725 @default.
- W2889168199 cites W2023657018 @default.
- W2889168199 cites W2035655653 @default.
- W2889168199 cites W2037457417 @default.
- W2889168199 cites W2039380477 @default.
- W2889168199 cites W2048672285 @default.
- W2889168199 cites W2051033597 @default.
- W2889168199 cites W2052751736 @default.
- W2889168199 cites W2054800877 @default.
- W2889168199 cites W2063222671 @default.
- W2889168199 cites W2064437293 @default.
- W2889168199 cites W2074602210 @default.
- W2889168199 cites W2078786918 @default.
- W2889168199 cites W2079709085 @default.
- W2889168199 cites W2082740501 @default.
- W2889168199 cites W2082937995 @default.
- W2889168199 cites W2086668012 @default.
- W2889168199 cites W2087407895 @default.
- W2889168199 cites W2087714970 @default.
- W2889168199 cites W2094916097 @default.
- W2889168199 cites W2096960190 @default.
- W2889168199 cites W2098014021 @default.
- W2889168199 cites W2100205653 @default.
- W2889168199 cites W2101175755 @default.
- W2889168199 cites W2101914549 @default.
- W2889168199 cites W2103836263 @default.
- W2889168199 cites W2106569666 @default.
- W2889168199 cites W2108049767 @default.
- W2889168199 cites W2109874388 @default.
- W2889168199 cites W2117415612 @default.
- W2889168199 cites W2118634943 @default.
- W2889168199 cites W2120240698 @default.
- W2889168199 cites W2124407942 @default.
- W2889168199 cites W2128606426 @default.
- W2889168199 cites W2130837272 @default.
- W2889168199 cites W2133864810 @default.
- W2889168199 cites W2144708423 @default.
- W2889168199 cites W2145139856 @default.
- W2889168199 cites W2153930165 @default.
- W2889168199 cites W2159430439 @default.
- W2889168199 cites W2160688542 @default.
- W2889168199 cites W2162460759 @default.
- W2889168199 cites W2171000032 @default.
- W2889168199 cites W219187680 @default.
- W2889168199 cites W2275107142 @default.
- W2889168199 cites W2302220243 @default.
- W2889168199 cites W2409263517 @default.
- W2889168199 cites W2483702483 @default.
- W2889168199 cites W2510316798 @default.
- W2889168199 cites W2511955506 @default.
- W2889168199 cites W2590559911 @default.
- W2889168199 cites W2616216901 @default.
- W2889168199 cites W2735723295 @default.
- W2889168199 cites W2765244546 @default.
- W2889168199 cites W2771156760 @default.
- W2889168199 cites W381513395 @default.
- W2889168199 cites W75562585 @default.
- W2889168199 cites W925400678 @default.
- W2889168199 doi "https://doi.org/10.1002/jcsm.12322" @default.
- W2889168199 hasPubMedCentralId "https://www.ncbi.nlm.nih.gov/pmc/articles/6204592" @default.
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