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Direct, convergent hypersensitivity of calcium-activated force generation produced by hypertrophic cardiomyopathy mutant α-tropomyosins in adult cardiac myocytes

Abstract

Familial hypertrophic cardiomyopathy is a clinically and genetically diverse autosomal dominant disorder characterized by ventricular hypertrophy and myocyte disarray in the absence of known hypertrophic stimuli1,2. It has been linked to many cardiac contractile proteins, including four point mutations in α-tropomyosin3,4,5 (Tm). Here we use adenoviral-mediated gene transfer into adult cardiac myocytes in vitro to show that all four hypertrophic cardiomyopathy α-Tm proteins can be expressed and incorporated into normal sarcomeric structures in cardiac myocytes at similar levels as normal α-Tm proteins after 5–6 days in culture. Isometric force recordings of single cardiac myocytes demonstrated inappropriate increased force output at submaximal calcium concentration with a specific mutant allele hierarchy. These data indicate that the severity of direct calcium-sensitizing effect of mutations in α-Tm may predict the clinical severity of mutant α-Tm-associated hypertrophic cardiomyopathy.

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Figure 1: HCM mutant αTm structure and expression.
Figure 2: Indirect immunofluoresecence confocal three dimensional reconstructions of adult cardiac myocytes.
Figure 3: Calcium-activated force generation in single adult cardiac myocytes.

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Acknowledgements

This work was funded by grants from the National Institutes of Health and the American Heart Association to J.M. and National Institutes of Health training grants to D.M.. J.M. is an Established Investigator of the American Heart Association.

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Correspondence to Joseph M. Metzger.

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Michele, D., Albayya, F. & Metzger, J. Direct, convergent hypersensitivity of calcium-activated force generation produced by hypertrophic cardiomyopathy mutant α-tropomyosins in adult cardiac myocytes. Nat Med 5, 1413–1417 (1999). https://doi.org/10.1038/70990

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