Diabetes mellitus increases the risk of heart failure, but the mechanisms underlying this relationship are unclear. New research shows that, compared with muscle from nonfailing hearts, the heart muscle from patients with heart failure and diabetes has increased levels of post-translational modifications induced by the glycolysis by-product methylglyoxal (MG). “We further showed that MG modifications depress the function of the molecular motors of the heart, which could explain the increased risk of heart failure in patients with diabetes,” says lead investigator Jonathan Kirk.
Kirk and colleagues examined left ventricular samples of explanted and rejected donor hearts and found higher levels of MG modifications of the myofilaments in patients with diabetes and heart failure than in patients with nonfailing hearts or with heart failure but without diabetes. Ex vivo exposure to pathological MG levels reduced contractility and Ca2+ sensitivity in nonfailing cardiomyocytes from humans or mice, but cardiomyocytes from patients with diabetes were resistant to functional changes from MG treatment, suggesting that these cells had already been exposed to MG in vivo. Proteomic analysis of samples from patients with diabetes and heart failure and from MG-treated mice showed increased MG modifications on the myofilament proteins actin and myosin, but not on the thin-filament regulatory proteins tropomyosin and troponin complex. MG modifications on actin and myosin independently depressed thin-filament regulation, and the functional effects required the presence of Ca2+-regulated thin-filament proteins.
These findings highlight the potential of MG modifications as a therapeutic target to prevent or ameliorate heart failure in patients with diabetes. “Although MG modifications are irreversible, the myofilament is a highly tunable system,” notes Kirk. “We are interested in determining whether the detrimental effects of the MG modifications in patients with diabetes could be reversed using existing small molecules,” he adds.
Papadaki, M. et al. Diabetes with heart failure increases methylglyoxal modifications in the sarcomere, which inhibit function. JCI Insight https://doi.org/10.1172/jci.insight.121264 (2018)
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Fernández-Ruiz, I. A new link for heart failure and diabetes. Nat Rev Cardiol 16, 4 (2019). https://doi.org/10.1038/s41569-018-0121-x
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