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Altered fast- and slow-twitch muscle fibre characteristics in female mice with a (S248F) knock-in mutation of the brain neuronal nicotinic acetylcholine receptor

Abstract

We generated a mouse line with a missense mutation (S248F) in the gene (CHRNA4) encoding the α4 subunit of neuronal nicotinic acetylcholine receptor (nAChR). Mutant mice demonstrate brief nicotine induced dystonia that resembles the clinical events seen in patients with the same mutation. Drug-induced dystonia is more pronounced in female mice, thus our aim was to determine if the S248F mutation changed the properties of fast- and slow-twitch muscle fibres from female mutant mice. Reverse transcriptase-PCR confirmed CHRNA4 gene expression in the brain but not skeletal muscles in normal and mutant mice. Ca2+ and Sr2+ force activation curves were obtained using skinned muscle fibres prepared from slow-twitch (soleus) and fast-twitch (EDL) muscles. Two significant results were found: (1) the (pCa50 − pSr50) value from EDL fibres was smaller in mutant mice than in wild type (1.01 vs. 1.30), (2) the percentage force produced at pSr 5.5 was larger in mutants than in wild type (5.76 vs. 0.24%). Both results indicate a shift to slow-twitch characteristics in the mutant. This conclusion is supported by the identification of the myosin heavy chain (MHC) isoforms. Mutant EDL fibres expressed MHC I (usually only found in slow-twitch fibres) as well as MHC IIa. Despite the lack of spontaneous dystonic events, our findings suggest that mutant mice may be having subclinical events or the mutation results in a chronic alteration to muscle neural input.

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Acknowledgments

This study was supported by a project grant from the National Health and Medical Research Council (NHMRC). J.D. is a NHMRC practitioner fellow. Authors would like to thank Jim Massalas (Howard Florey Institute) for his assistance with the S248F mouse strain and Prof. George Stephenson (La Trobe University) for helpful suggestions and critically reading the manuscript.

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Correspondence to David J. Cannata.

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Cannata, D.J., Finkelstein, D.I., Gantois, I. et al. Altered fast- and slow-twitch muscle fibre characteristics in female mice with a (S248F) knock-in mutation of the brain neuronal nicotinic acetylcholine receptor. J Muscle Res Cell Motil 30, 73–83 (2009) doi:10.1007/s10974-009-9177-x

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Keywords

  • Ca2+/Sr2+-activation
  • Dystonia
  • Nicotinic acetylcholine receptor
  • S248F mutation
  • Skinned muscle fibre