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Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure

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Please use this identifier to cite or link to this item:http://hdl.handle.net/2115/73863

Title: Protein acetylation in skeletal muscle mitochondria is involved in impaired fatty acid oxidation and exercise intolerance in heart failure
Authors: Tsuda, Masaya Browse this author
Fukushima, Arata Browse this author →KAKEN DB
Matsumoto, Junichi Browse this author
Takada, Shingo Browse this author →KAKEN DB
Kakutani, Naoya Browse this author
Nambu, Hideo Browse this author
Yamanashi, Katsuma Browse this author
Furihata, Takaaki Browse this author →KAKEN DB
Yokota, Takashi Browse this author →KAKEN DB
Okita, Koichi Browse this author →KAKEN DB
Kinugawa, Shintaro Browse this author →KAKEN DB
Anzai, Toshihisa Browse this author →KAKEN DB
Keywords: Heart failure
Exercise intolerance
Lysine acetylation
Skeletal muscle metabolism
Fatty acid oxidation
Issue Date: Oct-2018
Publisher: John Wiley & Sons
Journal Title: Journal of cachexia, sarcopenia and muscle
Volume: 9
Issue: 5
Start Page: 844
End Page: 859
Publisher DOI: 10.1002/jcsm.12322
PMID: 30168279
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 (distancexbody weight) and peak VO2 in the HF mice compared with the sham-operated mice (111 vs. 23 +/- 1J, P < 0.01; 143 +/- 5 vs. 159 +/- 3mL/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-oxidation (FAO), the tricarboxylic acid cycle, and the electron transport chain as targets of acetylation. In parallel, the FAO enzyme (beta-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 -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.
Rights: https://creativecommons.org/licenses/by-nc/4.0/
Type: article
URI: http://hdl.handle.net/2115/73863
Appears in Collections:北海道大学病院 (Hokkaido University Hospital) > 雑誌発表論文等 (Peer-reviewed Journal Articles, etc)

Submitter: 福島 新

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