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The Effect of Methylglyoxal (MGO) on the Cardiac Myofilament
Author(s) -
Papadaki Maria,
Holewinski Ronald,
Stachowski Marisa,
Kirk Jonathan
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.843.10
Subject(s) - myofilament , methylglyoxal , chemistry , myocyte , biophysics , calcium , myosin , myofibril , biochemistry , medicine , endocrinology , biology , organic chemistry , enzyme
Methylglyoxal (MGO), a byproduct of glycolysis and a reactive carbonyl species (RCS), is significantly elevated in diabetes. MGO adds post‐translational modifications by reacting with arginine and lysine residues to form irreversible carbonyl adducts. At basal concentrations, MGO is removed by glyoxal‐1 (GLO‐1), but at concentrations observed in diabetes, GLO‐1 cannot meet the demands and MGO modifications can accumulate. In the heart, MGO has been previously found to act on the ryanodine receptor and SERCA to depress calcium transients, and other proteins to induce cardiomyocyte apoptosis. However, the effect of MGO on the cardiac myofilament has never been studied. The aim of this study is to characterize the structural and functional effects of MGO on the myofilament. Skinned myocytes were isolated from ~100 μg of mouse left ventricle heart tissue, skinned using 0.3% Triton for 20 minutes and force‐Ca 2+ relationships were measured. 20 minute exposure to 100 μM MGO reduced the myocyte maximal calcium activated force (F max ) by 12 ± 4 % (n = 8, p = 0.048) and Ca 2+ sensitivity by 45 ± 11 % (n = 8, p = 0.02). With 10 μM MGO, Ca 2+ sensitivity was decreased by 67 ± 17 % (n = 9, p<0.01) but there was no effect on F max . Using mass spectrometry, we identified MGO modifications on several myofilament proteins in mouse myocytes treated with MGO including actin, myosin and myosin essential light chain. In a pilot study, using immunoprecipitation assay we were able to detect similar MGO modifications on myofilament proteins from human diabetic cardiomyopathy tissue that were not present in control hearts (n = 2/group). Our data show that these modifications would have significant implications on myofilament function in patients suffering from diabetic cardiomyopathy and other diseases affecting glucose metabolism. Support or Funding Information This project is supported by American Heart Association