Myofilament glycation in diabetes reduces contractility by inhibiting tropomyosin movement, is rescued by cMyBPC domains. (January 2022)

• Record Type: Journal Article
• Authors: Papadaki, Maria; Kampaengsri, Theerachat; Barrick, Samantha K.; Campbell, Stuart G.; von Lewinski, Dirk; Rainer, Peter P.; Harris, Samantha P.; Greenberg, Michael J.; Kirk, Jonathan A.
• Is Part Of: Journal of molecular and cellular cardiology. Volume 162(2022)
• Page Start: 1
• Page End: 9
• Publication Date: 2022-01
• Subjects: Myofilament glycation -- Diabetes -- myBPC C0C2 -- Tropomyosin; AG Aminoguanidine -- AGE Advanced Glycation Endproducts -- cMyBPC cardiac myosin binding protein C -- f myosin binding rate -- Fmax maximal calcium-activated force -- gxb myosin detachment rate -- HF Heart Failure -- k ATP detachment rate constant -- KB blocked-to-closed rate transition -- ktr rate of force redevelopment -- LV Left Ventricle -- MG Methylglyoxal -- OM Omecamtiv Mecarbil; Cardiology -- Periodicals; Heart Diseases -- Periodicals; Molecular Biology -- Periodicals; Cardiologie -- Périodiques; Cardiology; Electronic journals; Periodicals; 616.12
• DOI: 10.1016/j.yjmcc.2021.08.012
• Languages: English
• ISSNs: 0022-2828

Abstract

Abstract: Diabetes doubles the risk of developing heart failure (HF). As the prevalence of diabetes grows, so will HF unless the mechanisms connecting these diseases can be identified. Methylglyoxal (MG) is a glycolysis by-product that forms irreversible modifications on lysine and arginine, called glycation. We previously found that myofilament MG glycation causes sarcomere contractile dysfunction and is increased in patients with diabetes and HF. The aim of this study was to discover the molecular mechanisms by which MG glycation of myofilament proteins cause sarcomere dysfunction and to identify therapeutic avenues to compensate. In humans with type 2 diabetes without HF, we found increased glycation of sarcomeric actin compared to non-diabetics and it correlated with decreased calcium sensitivity. Depressed calcium sensitivity is pathogenic for HF, therefore myofilament glycation represents a promising therapeutic target to inhibit the development of HF in diabetics. To identify possible therapeutic targets, we further defined the molecular actions of myofilament glycation. Skinned myocytes exposed to 100 μM MG exhibited decreased calcium sensitivity, maximal calcium-activated force, and crossbridge kinetics. Replicating MG's functional affects using a computer simulation of sarcomere function predicted simultaneous decreases in tropomyosin's blocked-to-closed rate transition and crossbridge duty cycle were consistent with all experimental findings. Stopped-flow experiments and ATPase activity confirmed MG decreased the blocked-to-closed transition rate. Currently, no therapeutics target tropomyosin, so as proof-of-principal, we used a n-terminal peptide of myosin-binding protein C, previously shown to alter tropomyosin's position on actin. C0C2 completely rescued MG-induced calcium desensitization, suggesting a possible treatment for diabetic HF. Graphical abstract: Unlabelled Image Highlights: Diabetes is a major risk factor for the development of heart failure but the mechanisms are unknown. Human diabetics exhibited increased actin glycation compared to healthy subjects. Actin glycation correlated with reduced sarcomere calcium sensitivity. Myofilament glycation depresses function by inhibiting tropomyosin's movement on actin. Targeting this mechanism via a proof-of-concept in vitro therapy was able to rescue function.