A myopathy-related actin mutation increases contractile function

Acta Neuropathol. 2012 May;123(5):739-46. doi: 10.1007/s00401-012-0962-z. Epub 2012 Feb 23.


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.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actins / genetics*
  • Humans
  • In Vitro Techniques
  • Male
  • Middle Aged
  • Muscle Contraction / genetics*
  • Muscle Fibers, Skeletal / pathology
  • Muscle, Skeletal / physiopathology
  • Mutation / genetics*
  • Myopathies, Nemaline / genetics*
  • Myopathies, Nemaline / physiopathology*
  • Myosin Heavy Chains / metabolism
  • Physical Stimulation
  • X-Ray Diffraction


  • Actins
  • Myosin Heavy Chains