Journal article
Effects of R92 mutations in mouse cardiac troponin T are influenced by changes in myosin heavy chain isoform
Journal of molecular and cellular cardiology, Vol.53(4), pp.542-551
10/2012
Handle:
https://hdl.handle.net/2376/107779
PMCID: PMC3442937
PMID: 22884844
Abstract
One limitation in understanding how different familial hypertrophic cardiomyopathy (FHC)-related mutations lead to divergent cardiac phenotypes is that such mutations are often studied in transgenic (TG) mouse hearts which contain a fast cycling myosin heavy chain isoform (α-MHC). However, the human heart contains a slow cycling MHC isoform (β-MHC). Given the physiological significance of MHC-troponin interplay effects on cardiac contractile function, we hypothesized that cardiac troponin T (cTnT) mutation-mediated effects on contractile function depend on the type of MHC isoform present in the sarcomere. We tested our hypothesis using two variants of cTnT containing mutations at FHC hotspot R92 (R92L or R92Q), expressed against either an α-MHC or β-MHC background in TG mouse hearts. One finding from our study was that R92L attenuated the length-dependent increase in tension and abolished the length-dependent increase in myofilament Ca2+ sensitivity only when β-MHC was present. In addition, α- and β-MHC isoforms differentially affected how R92 mutations altered crossbridge (XB) recruitment dynamics. For example, the rate of XB recruitment was faster in R92L or R92Q fibers when β-MHC was present, but was unaffected when α-MHC was present. The R92Q mutation sped XB detachment in the presence of β-MHC, but not in the presence of α-MHC. R92Q affected the XB strain-dependent influence on XB recruitment dynamics, an effect not observed for R92L. Our findings have major implications for understanding not only the divergent effects of R92 mutations on cardiac phenotype, but also the distinct effects of MHC isoforms in determining the outcome of mutations in cTnT.
► We studied hypertrophic cardiomyopathy using fibers from transgenic mouse hearts. ► Cardiac troponin T (cTnT) mutations are studied against β-myosin heavy chain (MHC). ► The length-dependence of contractile activation was blunted by R92L against β-MHC. ► Contractile dynamics were differentially affected by R92Q or R92L against β-MHC. ► These findings aid in understanding human heart failure, where β-MHC predominates.
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Details
- Title
- Effects of R92 mutations in mouse cardiac troponin T are influenced by changes in myosin heavy chain isoform
- Creators
- Steven J Ford - Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology (VCAPP), Washington State University, Pullman, WA 99164, USARanganath Mamidi - Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology (VCAPP), Washington State University, Pullman, WA 99164, USAJesus Jimenez - Department of Physiology and Biophysics, Albert Einstein College of Medicine, Bronx, NY 10461, USAJil C Tardiff - Department of Internal Medicine, Sarver Heart Center, University of Arizona, Tucson, AZ 85724, USAMurali Chandra - Department of Veterinary and Comparative Anatomy, Pharmacology, and Physiology (VCAPP), Washington State University, Pullman, WA 99164, USA
- Publication Details
- Journal of molecular and cellular cardiology, Vol.53(4), pp.542-551
- Academic Unit
- Integrative Physiology and Neuroscience, Department of
- Publisher
- Elsevier Ltd
- Identifiers
- 99900547117601842
- Language
- English
- Resource Type
- Journal article