calcium desensitization
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2021 ◽  
Author(s):  
Maria Papadaki ◽  
Theerachat Kampaengsri ◽  
Samantha K Barrick ◽  
Stuart A. Campbell ◽  
Samantha P Harris ◽  
...  

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 uM 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.



2019 ◽  
Vol 597 (5) ◽  
pp. 1227-1229
Author(s):  
Matthew J. Novello ◽  
MengQi Zhang ◽  
Hannah E. Snyder ◽  
Qi‐Tong Lin


PLoS ONE ◽  
2016 ◽  
Vol 11 (12) ◽  
pp. e0167681 ◽  
Author(s):  
Mohun Ramratnam ◽  
Guy Salama ◽  
Ravi K. Sharma ◽  
David Wen Rui Wang ◽  
Stephen H. Smith ◽  
...  


2016 ◽  
pp. 119-136
Author(s):  
Liangming Liu ◽  
Tao Li ◽  
Guangming Yang ◽  
Chenyang Duan




Critical Care ◽  
2013 ◽  
Vol 17 (5) ◽  
pp. R245 ◽  
Author(s):  
Alessio Rungatscher ◽  
Seth Hallström ◽  
Alice Giacomazzi ◽  
Daniele Linardi ◽  
Elisabetta Milani ◽  
...  


2013 ◽  
Vol 104 (2) ◽  
pp. 450a
Author(s):  
Benjamin R. Nixon ◽  
Shane D. Walton ◽  
Sean C. Little ◽  
Jonathan P. Davis ◽  
Brandon J. Biesiadecki


Shock ◽  
2012 ◽  
Vol 38 (2) ◽  
pp. 186-195 ◽  
Author(s):  
Zi-Gang Zhao ◽  
Chun-Yu Niu ◽  
Yan-Ling Wei ◽  
Yu-Ping Zhang ◽  
Yong-Hua Si ◽  
...  


Shock ◽  
2012 ◽  
Vol 37 (4) ◽  
pp. 415-423 ◽  
Author(s):  
Chun-Yu Niu ◽  
Zi-Gang Zhao ◽  
Yu-Ping Zhang ◽  
Zhi-Quan Liu ◽  
Jing Zhang


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