What question did this study set out to answer?

Determine the functional and contractile consequences of the familial hypertrophic cardiomyopathy-linked cardiac troponin T (I79N) mutation in a transgenic mouse model.

February 1, 2001Journal of Biological ChemistryOpen Access

Abnormal Contractile Function in Transgenic Mice Expressing a Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N) Mutation

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Why the study?

Does the I79N troponin T mutation alter contractile function in a transgenic mouse model of familial hypertrophic cardiomyopathy?

Population

Transgenic mouse lines expressing human cardiac troponin T mutation driven by a murine alpha-myosin heavy…

Comparison

Expression of familial hypertrophic… vs Wild type and/or nontransgenic mice

Design

Preclinical

Authors

TMTodd MillerUniversity of Miami DSDanuta SzczȩsnaUniversity of Miami PHPhilippe R. HousmansMayo Clinic in Arizona

Discussion

Member takes

Implication

I79N mutation alters contractility without hypertrophy in mice; hypothesis-generating for HCM mechanisms but requires human validation.

Key Points

Determine the functional and contractile consequences of the familial hypertrophic cardiomyopathy-linked cardiac troponin T (I79N) mutation in a transgenic mouse model.
Generated transgenic mouse lines expressing wild-type or I79N mutant human cardiac troponin T under the control of an alpha-myosin heavy chain promoter.
Assessed survival, cardiac hypertrophy under chronic exercise, calcium sensitivity, ATPase activity, and force kinetics in skinned muscle fibers.
Conducted computational simulations to model intact myocardial contractile mechanics, calcium exchange kinetics, and cross-bridge cycling rates.
Transgenic I79N mice exhibited normal survival and no cardiac hypertrophy even after chronic exercise, but demonstrated marked increases in Ca2+ sensitivity for force and ATPase activity.
Skinned mutant fibers showed reduced maximal force per cross-sectional area, lower ATPase activity, accelerated force activation and relaxation rates, and abolished pH-mediated Ca2+ sensitivity shifts.
Simulations predicted decreased Ca2+ off-rates from troponin C, elevated cross-bridge detachment rates, higher basal contractility, and increased resting tension in intact I79N myocardium.

Structured PICO

Does the I79N troponin T mutation alter contractile function in a transgenic mouse model of familial hypertrophic cardiomyopathy?

Population

Transgenic mouse lines expressing human cardiac troponin T (I79N) mutation driven by a murine alpha-myosin heavy chain promoter, and wild type/nontransgenic mice.

Intervention

Expression of familial hypertrophic cardiomyopathy-linked Troponin T (I79N) mutation

Comparator

Wild type and/or nontransgenic mice

Outcome

Cardiac contractile function, including Ca2+ sensitivity of ATPase activity and force, force activation/relaxation rates, and maximal forcesurrogate

The I79N troponin T mutation alters cardiac contractility by increasing Ca2+ sensitivity and altering force kinetics, which may contribute to mortality in familial hypertrophic cardiomyopathy despite the absence of overt hypertrophy.

Cite This Study

Miller et al. (2001) studied this question.

synapsesocial.com/papers/6a80c92a1ece0ba82ce188e6 https://doi.org/10.1074/jbc.m006746200

Topics

Cardiomyopathy

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Abnormal Contractile Function in Transgenic Mice Expressing a Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N) Mutation

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

Topics

Abnormal Contractile Function in Transgenic Mice Expressing a Familial Hypertrophic Cardiomyopathy-linked Troponin T (I79N) Mutation

Discussion

Member takes

Implication

Key Points

Structured PICO

Cite This Study

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