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Usage Information

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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Usage data is cumulative from February 2022 through February 2023.

Usage JCI PMC
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PDF 103 56
Figure 201 1
Table 57 0
Supplemental data 28 4
Citation downloads 45 0
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Total Views 1,358
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