A myopathy-related actin mutation increases contractile function

作者：Lindqvist Johan; Penisson Besnier Isabelle; Iwamoto Hiroyuki; Li Meishan; Yagi Naoto; Ochala Julien^*

来源：Acta Neuropathologica, 2012, 123(5): 739-746.

DOI：10.1007/s00401-012-0962-z

• Nemaline myopathy
• ACTA1 mutation
• Skeletal muscle
• Force
• Actin
• Myosin cross-bridge

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.

• 出版日期2012-5