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A myopathy-related actin mutation increases contractile function

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Abstract

Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20–25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Despite increasing clinical and scientific interest, the contractile consequences of these subtle amino acid substitutions remain obscure. To decipher them, in the present study, we originally recorded and analysed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibres with a particular peptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an unexpected cascade of molecular and cellular events. During contraction, p.Phe352Ser greatly enhances the strain of individual cross-bridges. Paradoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by altering the rate of myosin head attachment to actin monomers. Overall, at the cell level, these divergent mechanisms conduct to an improved steady-state force production. Such results provide new surprising scientific insights and crucial information for future therapeutic strategies.

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Acknowledgments

The authors are grateful to Dr P. Marcorelles for the electron microscopy study; Y. Hedström, C. Dumez and I. Viau for excellent technical assistance. The authors also would like to thank Prof. N.G. Laing and Dr. K. Nowak for the genetic analysis, Dr. M. Lorenz for providing the Actomyosin model. This study was supported by grants from the Swedish Research Council and from and Harald och Greta Jeanssons Stiftelse to J.O and was performed under approval of the SPring-8 Proposal Review Committee (2011A1042).

Conflict of interest

The authors declare no conflict of interest.

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Authors and Affiliations

  1. Department of Neuroscience, Clinical Neurophysiology, Uppsala University, Entrance 85, 3rd Floor, 751 85, Uppsala, Sweden

    Johan Lindqvist, Meishan Li & Julien Ochala

  2. Département de Neurologie, CHU d’Angers, Centre de référence des maladies neuromusculaires, 49933, Angers, France

    Isabelle Pénisson-Besnier

  3. Japan Synchrotron Radiation Research Institute, 1-1-1 Kouto, Sayo-cho, Sayo-gun, Hyogo, 679-6198, Japan

    Hiroyuki Iwamoto & Naoto Yagi

Authors
  1. Johan Lindqvist
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  2. Isabelle Pénisson-Besnier
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  3. Hiroyuki Iwamoto
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  4. Meishan Li
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  5. Naoto Yagi
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  6. Julien Ochala
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Corresponding author

Correspondence to Julien Ochala.

Additional information

The authors J. Lindqvist, I. Pénisson-Besnier and H. Iwamoto contributed equally to the present manuscript.

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Lindqvist, J., Pénisson-Besnier, I., Iwamoto, H. et al. A myopathy-related actin mutation increases contractile function. Acta Neuropathol 123, 739–746 (2012). https://doi.org/10.1007/s00401-012-0962-z

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  • DOI: https://doi.org/10.1007/s00401-012-0962-z

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