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The alpha and beta cardiac myosin he...

Yeshiva University.

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The alpha and beta cardiac myosin heavy chain isoforms direct mutation-specific effects on myofilament activation in Troponin-T related cardiomyopathies in vivo.

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	The alpha and beta cardiac myosin heavy chain isoforms direct mutation-specific effects on myofilament activation in Troponin-T related cardiomyopathies in vivo./
作者:	Rice, Ron.
面頁冊數:	159 p.
附註:	Adviser: Jil C. Tardiff.
Contained By:	Dissertation Abstracts International69-07B.
標題:	Biology, Animal Physiology. -
電子資源:	http://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=3325523
ISBN:	9780549767060

The alpha and beta cardiac myosin heavy chain isoforms direct mutation-specific effects on myofilament activation in Troponin-T related cardiomyopathies in vivo.
Rice, Ron.

The alpha and beta cardiac myosin heavy chain isoforms direct mutation-specific effects on myofilament activation in Troponin-T related cardiomyopathies in vivo. - 159 p.

Adviser: Jil C. Tardiff.

Thesis (Ph.D.)--Yeshiva University, 2009.

Myofilament activation couples myocellular Ca2+ rise to thin filament sliding. Within the sarcomere, Troponin-T plays a central role in myofilament activation. Naturally occurring mutations of Troponin-T impair activation of the myofilaments and negatively affect contraction. Our R92Q and R92L transgenic models of cTnT related Familial Hypertrophic Cardiomyopathy (FHC) demonstrate impaired contraction/relaxation patterns and Ca2+ handling as well as myocyte disarray and fetal gene expression. Myofilament activation is not a fully Ca2+ regulated process but is enhanced by the cooperative binding of strong myosin crossbridges to the thin filament. Myosin, therefore, plays a central role in myofilament activation. Human ventricles predominantly express the beta myosin heavy chain isoform while smaller mammals, such as rodents, predominantly express alpha. The beta/alpha composition increases in human heart failure although the functional meaning of this change is unclear. To understand the role of increased beta-MyHC expression in the setting of a cardiomyopathy, we developed novel double transgenic mouse models expressing the R92Q or R92L cTnT mutation with 80% beta-MyHC in the left ventricle (LV). We therefore made a primary change in myofilament composition by increasing the number of cycling beta crossbridges in the context of cTnT mutations. Impaired R92Q whole heart and myocellular contractility improved in beta-R92Q double transgenics. Mutation specific improvements in myocellular Ca2+ handling were also noted and believed to drive the changes in contractility. Central to these changes was improved sarcoplasmic reticulum (SR) myocellular Ca2+ loading in beta-R92Q and beta-R92L isolated myocytes. Whole heart and myocellular contractility in R92L was consistent with Non-Tg and remained the same in beta-R92L double transgenics. Impaired SERCA2a mediated Ca2+ uptake in R92Q ventricular homogenates was rescued in beta-R92Q and was correlated with increased phosphorylated phospholamban (P-PLB). Conversely, beta-R92L homogenates demonstrated decreased P-PLB and Ca2+ uptake as compared to R92L, which was similar to Non-Tg in both respects. These observations demonstrate that increased beta-MyHC in the context of a cardiomyopathy, caused by thin filament missense mutations, results in mutation specific improvements in Ca2+ handling and contractility. We suggest these changes occurred via synergism between primary myofilament effects as well as posttranslational modifications.

ISBN: 9780549767060Subjects--Topical Terms:

1017835
Biology, Animal Physiology.

The alpha and beta cardiac myosin heavy chain isoforms direct mutation-specific effects on myofilament activation in Troponin-T related cardiomyopathies in vivo.
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