Key result
Homozygous K280N TNNT2 mutation increases tension cost ~35%, which wild-type troponin exchange reverses.
Why the study?
Cardiac remodeling during HCM development can mask the pathogenic impact of mutations, requiring discrimination between mutation-induced and disease-related changes in myofilament function.
Does the homozygous K280N TNNT2 mutation alter cross-bridge kinetics and increase the energetic cost of tension generation in human hypertrophic cardiomyopathy?
Does the homozygous K280N TNNT2 mutation alter cross-bridge kinetics and increase the energetic cost of tension generation in human hypertrophic cardiomyopathy?
The homozygous K280N mutation in TNNT2 directly alters cross-bridge kinetics and impairs sarcomere energetics, supporting the hypothesis that inefficient ATP utilization plays a central role in HCM pathogenesis.
Answers are grounded in this paper and cite their sources.
Implicates sarcomeric energetics in HCM pathogenesis; leaves open whether modulating cross-bridge kinetics alters human disease progression.
Hypertrophic cardiomyopathy (HCM) is a genetic form of left ventricular hypertrophy, primarily caused by mutations in sarcomere proteins. The cardiac remodeling that occurs as the disease develops can mask the pathogenic impact of the mutation. Here, to discriminate between mutation-induced and disease-related changes in myofilament function, we investigate the pathogenic mechanisms underlying HCM in a patient carrying a homozygous mutation (K280N) in the cardiac troponin T gene (TNNT2), which results in 100% mutant cardiac troponin T. We examine sarcomere mechanics and energetics in K280N-isolated myofibrils and demembranated muscle strips, before and after replacement of the endogenous troponin. We also compare these data to those of control preparations from donor hearts, aortic stenosis patients (LVHao), and HCM patients negative for sarcomeric protein mutations (HCMsmn). The rate constant of tension generation following maximal Ca2+ activation (kACT) and the rate constant of isometric relaxation (slow kREL) are markedly faster in K280N myofibrils than in all control groups. Simultaneous measurements of maximal isometric ATPase activity and Ca2+-activated tension in demembranated muscle strips also demonstrate that the energy cost of tension generation is higher in the K280N than in all controls. Replacement of mutant protein by exchange with wild-type troponin in the K280N preparations reduces kACT, slow kREL, and tension cost close to control values. In donor myofibrils and HCMsmn demembranated strips, replacement of endogenous troponin with troponin containing the K280N mutant increases kACT, slow kREL, and tension cost. The K280N TNNT2 mutation directly alters the apparent cross-bridge kinetics and impairs sarcomere energetics. This result supports the hypothesis that inefficient ATP utilization by myofilaments plays a central role in the pathogenesis of the disease.
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Piroddi et al. (2018) studied Hypertrophic cardiomyopathy (HCM) (n=24). Homozygous K280N TNNT2 mutation vs. Controls (donor hearts, aortic stenosis, and sarcomere mutation-negative HCM) was evaluated on Tension cost (μmol L-1 s-1 / kN m-2) (p=<0.05). The homozygous K280N TNNT2 mutation accelerated cross-bridge kinetics and increased the energetic cost of tension generation compared to controls, an impairment that was reversed by wild-type troponin exchange.
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