Go to The Journal of Clinical Investigation
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Immunology
    • Metabolism
    • Nephrology
    • Oncology
    • Pulmonology
    • All ...
  • Videos
  • Collections
    • Resource and Technical Advances
    • Clinical Medicine
    • Reviews
    • Editorials
    • Perspectives
    • Top read articles
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • In-Press Preview
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Transfers
  • Advertising
  • Job board
  • Contact
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.
View: Text | PDF
Research Article Cardiology Cell biology

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

  • Text
  • PDF
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

×

Figure 2

Effect of methylglyoxal on mouse skinned myocyte function.

Options: View larger image (or click on image) Download as PowerPoint
Effect of methylglyoxal on mouse skinned myocyte function.
(A) Mean forc...
(A) Mean force as a function of calcium concentration and fitted curves for skinned myocytes before (open circles, black line) and after (open gray squares, gray dotted line) treatment with 10 μM methylglyoxal (MG) for 20 minutes (n = 9 per group). (B) Mean force as a function of calcium concentration and fitted curves for myocytes before (open circles, black line) and after (open gray squares, gray dotted line) treatment with 100 μM MG for 20 minutes (n = 9 per group). (C) All calculated values for individual myocytes and summary box plot before (black) and after (gray) 10 μM MG on maximal calcium-activated force (Fmax, left) and Ca2+ sensitivity (EC50, right). Individual myocytes before and after treatment are connected by dotted lines. (D) All individual calculated values and summary box plot showing the effect of 100 μM MG on Fmax and EC50. (E) Dose effect of 1–100 μM MG on Fmax and (F) EC50 of skinned mouse myocytes. *P < 0.05, **P < 0.01, ***P < 0.001 by paired t test (C and D) or 2-way repeated-measures ANOVA (E and F).

Copyright © 2023 American Society for Clinical Investigation
ISSN 2379-3708

Sign up for email alerts