The effect of cardiomyopathy mutation (R97L) in mouse cardiac troponin T on the muscle length-mediated recruitment of crossbridges is modified divergently by α- and β-myosin heavy chain

Archives of Biochemistry and Biophysics
Sampath K Gollapudi, Murali Chandra

Abstract

Hypertrophic cardiomyopathy mutations in cardiac troponin T (TnT) lead to sudden cardiac death. Augmented myofilament Ca(2+) sensitivity is a common feature in TnT mutants, but such observations fail to provide a rational explanation for severe cardiac phenotypes. To better understand the mutation-induced effect on the cardiac phenotype, it is imperative to determine the effects on dynamic contractile features such as the muscle length (ML)-mediated activation against α- and β-myosin heavy chain (MHC) isoforms. α- and β-MHC are not only differentially expressed in rodent and human hearts, but they also modify ML-mediated activation differently. Mouse analog of human TnTR94L (TnTR97L) or wild-type TnT was reconstituted into de-membranated muscle fibers from normal (α-MHC) and transgenic (β-MHC) mouse hearts. TnTR97L augmented myofilament Ca(2+) sensitivity by a similar amount in α- and β-MHC fibers. However, TnTR97L augmented the negative impact of strained crossbridges on other crossbridges (γ) by 22% in α-MHC fibers, but attenuated γ by 21% in β-MHC fibers. TnTR97L decreased the magnitude of ML-mediated recruitment of crossbridges (ER) by 37% in α-MHC fibers, but increased ER by 35% in β-MHC fibers. We provide a mechanistic ba...Continue Reading

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Citations

May 10, 2016·Archives of Biochemistry and Biophysics·Brandon J Biesiadecki
Oct 23, 2016·American Journal of Physiology. Heart and Circulatory Physiology·Alexis V MickelsonMurali Chandra
May 20, 2018·The Journal of General Physiology·Sherif M Reda, Murali Chandra
Aug 3, 2019·American Journal of Physiology. Heart and Circulatory Physiology·Sherif M Reda, Murali Chandra
Aug 27, 2017·American Journal of Physiology. Heart and Circulatory Physiology·Alexis V Mickelson, Murali Chandra

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