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Investigating the Pathogenesis of MYH7 Mutation Gly823Glu in Familial Hypertrophic Cardiomyopathy using a Mouse Model
Published on: August 8, 2022
HCM-linked ∆160E cardiac troponin T mutation causes unique progressive structural and molecular ventricular
Rachel K Moore1, Lauren Tal Grinspan, Jesus Jimenez
1Department of Physiology and Biophysics, Albert Einstein College of Medicine, Yeshiva University, 1300 Morris Park Avenue, Ullmann, Room 316, Bronx, NY 10461, USA.
Insights
The cardiac troponin T (cTnT) Δ160E mutation causes hypertrophic cardiomyopathy (HCM) through sarcomere disruption and calcium handling defects. This leads to progressive ventricular remodeling and cardiac dysfunction in a dose-dependent manner.
Area of Science:
- Cardiovascular Biology
- Molecular Cardiology
- Genetic Diseases
Background:
- Hypertrophic cardiomyopathy (HCM) is a primary cardiac muscle disease and a leading cause of sudden cardiac death (SCD) in young individuals.
- Mutations in cardiac troponin T (cTnT) are frequently linked to HCM, with a significant proportion occurring in the TNT1 domain.
- The specific mechanism by which distal TNT1 mutations, like Δ160E, contribute to HCM pathogenesis remains poorly understood.
Purpose of the Study:
- To investigate the cellular and physiological effects of the cTnT Δ160E mutation.
- To elucidate the mechanism underlying the disease progression associated with this specific cTnT mutation.
- To determine the dose-dependent impact of the cTnT Δ160E mutation on cardiac structure and function.
Main Methods:
- Generation of two independent transgenic mouse lines with varying doses (30% and 70%) of the cTnT Δ160E mutant transgene.
- Assessment of cellular and sarcomeric architecture, ventricular remodeling, and myocyte mechanical function.
- Analysis of calcium handling, including calcium transients, sarcoplasmic reticulum calcium load, and SERCA2a activity.
- Evaluation of calcium regulatory protein abundance and phosphorylation.
- Whole heart physiological studies in isovolumic mode.
Main Results:
- Hearts from Δ160E transgenic mice exhibited dose-dependent disruption of cellular and sarcomeric architecture, alongside progressive ventricular remodeling.
- Isolated ventricular myocytes showed dosage-independent mechanical impairments but dose-dependent decreases in calcium transients.
- Calcium regulatory protein levels and phosphorylation were altered, correlating with calcium transient changes.
- Whole heart studies revealed dose-dependent cardiac dysfunction.
Conclusions:
- The cTnT Δ160E mutation induces HCM via a combination of direct sarcomeric disruption and significant dysregulation of cellular calcium homeostasis.
- These cellular defects lead to a unique and progressive pattern of ventricular remodeling and cardiac dysfunction.
- The severity of clinical manifestations is directly related to the dose of the mutant cTnT transgene.
Abstract:
Hypertrophic cardiomyopathy (HCM) is a primary disease of the cardiac muscle, and one of the most common causes of sudden cardiac death (SCD) in young people. Many mutations in cardiac troponin T (cTnT) lead to a complex form of HCM with varying degrees of ventricular hypertrophy and ~65% of all cTnT mutations occur within or flanking the elongated N-terminal TNT1 domain. Biophysical studies have predicted that distal TNT1 mutations, including Δ160E, cause disease by a novel, yet unknown mechanism as compared to N-terminal mutations. To begin to address the specific effects of this commonly observed cTnT mutation we generated two independent transgenic mouse lines carrying variant doses of the mutant transgene. Hearts from the 30% and 70% cTnT Δ160E lines demonstrated a highly unique, dose-dependent disruption in cellular and sarcomeric architecture and a highly progressive pattern of ventricular remodeling. While adult ventricular myocytes isolated from Δ160E transgenic mice exhibited dosage-independent mechanical impairments, decreased sarcoplasmic reticulum calcium load and SERCA2a calcium uptake activity, the observed decreases in calcium transients were dosage-dependent. The latter findings were concordant with measures of calcium regulatory protein abundance and phosphorylation state. Finally, studies of whole heart physiology in the isovolumic mode demonstrated dose-dependent differences in the degree of cardiac dysfunction. We conclude that the observed clinical severity of the cTnT Δ160E mutation is caused by a combination of direct sarcomeric disruption coupled to a profound dysregulation of Ca(2+) homeostasis at the cellular level that results in a unique and highly progressive pattern of ventricular remodeling.
