A myopathy-related actin mutation increases contractile function
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A myopathy-related actin mutation increases contractile function. / Lindqvist, Johan; Pénisson-Besnier, Isabelle; Iwamoto, Hiroyuki; Li, Meishan; Yagi, Naoto; Ochala, Julien.
I: Acta Neuropathologica, Bind 123, Nr. 5, 05.2012, s. 739-746.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - A myopathy-related actin mutation increases contractile function
AU - Lindqvist, Johan
AU - Pénisson-Besnier, Isabelle
AU - Iwamoto, Hiroyuki
AU - Li, Meishan
AU - Yagi, Naoto
AU - Ochala, Julien
PY - 2012/5
Y1 - 2012/5
N2 - 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 alphaactin). 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.
AB - 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 alphaactin). 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.
KW - ACTA1 mutation
KW - Actin
KW - Force
KW - Myosin cross-bridge
KW - Nemaline myopathy
KW - Skeletal muscle
UR - http://www.scopus.com/inward/record.url?scp=84862803390&partnerID=8YFLogxK
U2 - 10.1007/s00401-012-0962-z
DO - 10.1007/s00401-012-0962-z
M3 - Journal article
C2 - 22358459
AN - SCOPUS:84862803390
VL - 123
SP - 739
EP - 746
JO - Acta Neuropathologica
JF - Acta Neuropathologica
SN - 0001-6322
IS - 5
ER -
ID: 245664006