RT Journal Article
SR Electronic
T1 Myofilament Glycation in Diabetes Reduces Contractility by Inhibiting Tropomyosin Movement, is Rescued by cMyBPC Domains
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2021.06.09.447778
DO 10.1101/2021.06.09.447778
A1 Maria Papadaki
A1 Theerachat Kampaengsri
A1 Samantha K. Barrick
A1 Stuart G. Campbell
A1 Dirk von Lewinski
A1 Peter P. Rainer
A1 Samantha P. Harris
A1 Michael J. Greenberg
A1 Jonathan A. Kirk
YR 2021
UL http://biorxiv.org/content/early/2021/06/09/2021.06.09.447778.abstract
AB 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.Competing Interest StatementThe authors have declared no competing interest.AbbreviationsAGAminoguanidineAGEAdvanced Glycation EndproductscMyBPCcardiac myosin binding protein Cfmyosin binding rateFmaxmaximal calcium-activated forcegxbmyosin detachment rateHFHeart FailurekATP detachment rate constantKBblocked-to-closed rate transitionktrrate of force redevelopmentLVLeft VentricleMGMethylglyoxalOMOmecamtiv Mecarbil