Journal
JCI INSIGHT
Volume 6, Issue 3, Pages -Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.144301
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Funding
- NIH [HL110349, 2T32DK007247-41, R01HL144778]
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One hallmark of impaired myocardial energetics in failing hearts is the downregulation of the creatine kinase (CK) system. A study found an inverse relationship between the activity and acetylation of CK muscle form (CKM) in human and mouse failing hearts, where hyperacetylation disrupted MM homodimer formation and reduced enzymatic activity. Deacetylation by sirtuin 2 improved dimer formation and restored CKM activity from failing heart tissue, suggesting a novel mechanism for improving high-energy phosphoryl transfer in heart failure.
A hallmark of impaired myocardial energetics in failing hearts is the downregulation of the creatine kinase (CK) system. In heart failure patients and animal models, myocardial phosphocreatine content and the flux of the CK reaction are negatively correlated with the outcome of heart failure. While decreased CK activity is highly reproducible in failing hearts, the underlying mechanisms remains elusive. Here, we report an inverse relationship between the activity and acetylation of CK muscle form (CKM) in human and mouse failing hearts. Hyperacetylation of recombinant CKM disrupted MM homodimer formation and reduced enzymatic activity, which could be reversed by sirtuin 2 treatment. Mass spectrometry analysis identified multiple lysine residues on the MM dimer interface, which were hyperacetylated in the failing hearts. Molecular modeling of CK MM homodimer suggested that hyperacetylat ion prevented dimer formation through interfering salt bridges within and between the 2 monomers. Deacetylation by sirtuin 2 reduced acetylation of the critical lysine residues, improved dimer formation, and restored CKM activity from failing heart tissue. These findings reveal a potentially novel mechanism in the regulation of CK activity and provide a potential target for improving high-energy phosphoryl transfer in heart failure.
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