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

Nature Medicine volume 5, pages 1413–1417 (1999)Cite this article

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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References

  1. Watkins, H., Seidman, J.G. & Seidman, C.E. Familial hypertrophic cardiomyopathy: a genetic model of cardiac hypertrophy. Hum. Mol. Genet. 4, 1721–1727 (1995).

    Article  CAS  Google Scholar 

  2. Bonne, G., Carrier, L., Richard, P., Hainque, B. & Schwartz, K. Familial hypertrophic cardiomyopathy: from mutations to functional defects. Circ. Res. 83, 580–593 (1998).

    Article  CAS  Google Scholar 

  3. Thierfelder, L. et al. α-tropomyosin and cardiac troponin T mutations cause hypertrophic cardiomyopathy: a disease of the sarcomere. Cell. 77, 701–712 (1994).

    Article  Google Scholar 

  4. Nakajima-Taniguchi, C., Matsui, H., Nagata, S., Kishimoto, T. & Yamauchi-Takihara, K. Novel missense mutation in α-tropomyosin gene found in Japanese patients with hypertrophic cardiomyopathy. J. Mol. Cell. Cardiol. 27, 2053–2058 (1995).

    Article  CAS  Google Scholar 

  5. Yamauchi-Takihara, K. et al. Clinical implications of hypertrophic cardiomyopathy associated with mutations in the α-tropomyosin gene. Heart 76, 63–65 (1996).

    Article  CAS  Google Scholar 

  6. Tobacman, L.S. Thin filament-mediated regulation of cardiac contraction. Annu. Rev. Physiol. 58, 447–481 (1996).

    Article  CAS  Google Scholar 

  7. Watkins, H. et al. Characteristics and prognostic implications of myosin missense mutations in familial hypertrophic cardiomyopathy. N. Engl. J. Med. 326, 1108–1114 (1992).

    Article  CAS  Google Scholar 

  8. Epstein, N.D., Cohn, G.M., Cyran, F. & Fananapazir, L. Differences in clinical expression of hypertrophic cardiomyopathy associated with two distinct mutations in the β-myosin heavy chain gene. Circulation 86, 345–352 (1992).

    Article  CAS  Google Scholar 

  9. Watkins, H. et al. Mutations in the genes for cardiac troponin T and α-tropomyosin in hypertrophic cardiomyopathy. N. Eng. J. Med. 332, 1058–1064 (1995).

    Article  CAS  Google Scholar 

  10. Westfall, M.V., Rust, E.M., Albayya, F. & Metzger, J.M. Adenovirus mediated myofilament gene transfer into adult cardiac myocytes. Meth. Cell. Biol. 52, 307–322 (1997).

    Article  CAS  Google Scholar 

  11. Rust, E.M., Westfall, M.V. & Metzger, J.M. Stability of the contractile assembly and Ca2+ activated tension in adenovirus infected adult cardiac myocytes. Mol. Cell. Biochem. 181, 143–155 (1998).

    Article  CAS  Google Scholar 

  12. Michele, D.E., Albayya, F.P. & Metzger, J.M. Thin filament protein dynamics in fully differentiated adult cardiac myocytes: toward a model of sarcomere maintenance. J. Cell Biol. 145, 1483–1495 (1999).

    Article  CAS  Google Scholar 

  13. Martin, A.F. Turnover of cardiac troponin subunits. J. Biol. Chem. 256, 964–968 (1981).

    CAS  PubMed  Google Scholar 

  14. White, S.P., Cohen, C. & Phillips, G.N. Structure of co-crystals of tropomyosin and troponin. Nature 325, 826–828 (1987).

    Article  CAS  Google Scholar 

  15. Golitsina, N. et al. Effects of two familial hypertrophic cardiomyopathy causing mutations on α-tropomyosin structure and function. Biochemistry 36, 4637–4642 (1997); erratum: 38, 3850 (1999).

    Article  CAS  Google Scholar 

  16. McLachlan, A.D. & Stewart, M. Tropomyosin coiled-coil interactions: evidence for an unstaggered structure. J. Mol. Biol. 98, 293–304 (1975).

    Article  CAS  Google Scholar 

  17. McKillop. D.F.A. & Geeves, M.A. Regulation of the interaction between actin and myosin subfragment 1: evidence for three states of the thin filament. Biophys. J. 65, 693–701 (1993).

    Article  CAS  Google Scholar 

  18. Coviello, D.A. et al. Clinical features of hypertrophic cardiomyopathy caused by a mutation of a "hot spot" in the alpha-tropomyosin gene. J. Am. Coll. Cardiol. 29, 635–640 (1997).

    Article  CAS  Google Scholar 

  19. Thierfelder, L. et al. A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2. Proc. Natl. Acad. Sci. USA 90, 6720–6274 (1993).

    Article  Google Scholar 

  20. Muthuchamy, M. et al. Mouse model of a familial hypertrophic cardiomyopathy mutation in α-tropomyosin manifests cardiac dysfunction. Circ. Res. 85, 47–56 (1999).

    Article  CAS  Google Scholar 

  21. Bing, W. et al. Effects of two hypertrophic cardiomyopathy mutations in α-tropomyosin, Asp175Asn and Glu180Gly, on Ca2+ regulation of thin filament motility. Biochem. Biophys. Res. Comm. 236, 760–764 (1997).

    Article  CAS  Google Scholar 

  22. Bottinelli, R. et al. A mutant tropomyosin that causes hypertrophic cardiomyopathy is expressed in vivo and associated with an increased calcium sensitivity. Circ. Res. 82, 106–115 (1998).

    Article  CAS  Google Scholar 

  23. Rust, E.M., Albayya, F.P. & Metzger, J.M. Identification of a contractile deficit in adult cardiac myocytes expressing hypertrophic cardiomyopathy-associated mutant troponin T proteins. J. Clin. Invest. 103, 1459–1467 (1999).

    Article  CAS  Google Scholar 

  24. MacLeod, A.R. & Gooding, C. Human hTmα gene: expression in muscle and non-muscle tissue. Mol. Cell. Biol. 8, 433–440 (1988).

    Article  CAS  Google Scholar 

  25. Metzger, J. M. et al. Skeletal troponin C reduces contractile sensitivity to acidosis in cardiac myocytes from transgenic mice. Proc. Natl. Acad. Sci. USA 90, 9036–9040 (1993).

    Article  CAS  Google Scholar 

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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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  1. Department of Physiology, University of Michigan, 7730 Med Sci II, 1150 W. Medical Center Drive, Ann Arbor, 48109, Michigan, USA

    Daniel E. Michele, Faris P. Albayya & Joseph M. Metzger

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  1. Daniel E. Michele
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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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