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Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function
Maria Papadaki, … , David M. Warshaw, Jonathan A. Kirk
Maria Papadaki, … , David M. Warshaw, Jonathan A. Kirk
Published October 18, 2018
Citation Information: JCI Insight. 2018;3(20):e121264. https://doi.org/10.1172/jci.insight.121264.
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Research Article Cardiology Cell biology

Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function

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Abstract

Patients with diabetes are at significantly higher risk of developing heart failure. Increases in advanced glycation end products are a proposed pathophysiological link, but their impact and mechanism remain incompletely understood. Methylglyoxal (MG) is a glycolysis byproduct, elevated in diabetes, and modifies arginine and lysine residues. We show that left ventricular myofilament from patients with diabetes and heart failure (dbHF) exhibited increased MG modifications compared with nonfailing controls (NF) or heart failure patients without diabetes. In skinned NF human and mouse cardiomyocytes, acute MG treatment depressed both calcium sensitivity and maximal calcium-activated force in a dose-dependent manner. Importantly, dbHF myocytes were resistant to myofilament functional changes from MG treatment, indicating that myofilaments from dbHF patients already had depressed function arising from MG modifications. In human dbHF and MG-treated mice, mass spectrometry identified increased MG modifications on actin and myosin. Cosedimentation and in vitro motility assays indicate that MG modifications on actin and myosin independently depress calcium sensitivity, and mechanistically, the functional consequence requires actin/myosin interaction with thin-filament regulatory proteins. MG modification of the myofilament may represent a critical mechanism by which diabetes induces heart failure, as well as a therapeutic target to avoid the development of or ameliorate heart failure in these patients.

Authors

Maria Papadaki, Ronald J. Holewinski, Samantha Beck Previs, Thomas G. Martin, Marisa J. Stachowski, Amy Li, Cheavar A. Blair, Christine S. Moravec, Jennifer E. Van Eyk, Kenneth S. Campbell, David M. Warshaw, Jonathan A. Kirk

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Figure 6

Methylglyoxal reduces actin-myosin functional interaction when regulated by calcium.

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Methylglyoxal reduces actin-myosin functional interaction when regulated...
(A) Cosedimentation between actin and myosin S1 fragment (S1), shown by mean ± SEM and linear regression, was unaffected by treatment with 100 μM methylglyoxal (MG) (n = 5). (B) Representative cosedimentation of myosin S1 fragment (S1) and native thin filaments (NTFs) is shown (inset above, n = 3) at 0.145 μM calcium and individual data points before (black) and after (red) 100 μM MG treatment (dashed lines connect the same sample before and after treatment) and mean ± SEM. *P < 0.05 by 2-way repeated-measures ANOVA and Holm-Sidak post hoc test. (C) Fraction moving for NTFs at different calcium concentrations in the in vitro motility assay (n = 4–5 at each concentration) (mean ± SEM). (D) NTF fraction moving at 0.175 μM calcium where either myosin (red), NTFs (green), or both (blue) were treated with 1 μM, 10, μM, or 100 μM MG (n = 5 per group) (mean ± SEM). *P < 0.05 for MG treatment (for all 3 groups) by 2-way repeated-measures ANOVA and Holm-Sidak post hoc test. (E) Individual data points as well as corresponding mean ± SEM for NTF fraction moving as in D.

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