Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice

Stupka, Nicole, Plant, David R., Schertzer, Jonathon D., Emerson, Tennent, Bassel-Duby, Rhonda, Olson, Eric N. and Lynch, Gordon S. 2006, Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice, Journal of physiology, vol. 575, no. 2, pp. 645-656, doi: 10.1113/jphysiol.2006.108472.

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Title Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice
Author(s) Stupka, NicoleORCID iD for Stupka, Nicole
Plant, David R.
Schertzer, Jonathon D.
Emerson, Tennent
Bassel-Duby, Rhonda
Olson, Eric N.
Lynch, Gordon S.
Journal name Journal of physiology
Volume number 575
Issue number 2
Start page 645
End page 656
Publisher Wiley-Blackwell
Place of publication London, England
Publication date 2006-06-22
ISSN 0022-3751
Summary Utrophin expression is regulated by calcineurin and up-regulating utrophin can decrease the susceptibility of dystrophic skeletal muscle to contraction-induced injury. We overexpressed the constitutively active calcineurin-A α in skeletal muscle of mdx dystrophic mice (mdx CnA*) and examined the tibialis anterior muscle to determine whether the presence of activated calcineurin promotes resistance to muscle damage after lengthening contractions. Two stretches (10 s apart) of 40% strain relative to muscle fibre length were initiated from the plateau of a maximal isometric tetanic contraction. Muscle damage was assessed 1, 5 and 15 min later by the deficit in maximum isometric force and by quantifying the proportion of muscle fibres staining positive for intracytoplasmic albumin. The force deficit at all time points after the lengthening contractions was approximately 80% in mdx muscles and 30% in mdxCnA* muscles. The proportion of albumin-positive fibres was significantly less in control and injured muscles from mdxCnA* mice than from mdx mice. Compared with mdx mice, mean fibre cross-sectional area was 50% less in muscles from mdxCnA* mice. Furthermore, muscles frommdxCnA* mice exhibited a higher proportion of fibres expressing the slow(er) myosin heavy chain (MyHC) I and IIa isoforms, prolonged contraction and relaxation times, lower absolute and normalized maximum forces, and a clear leftward shift of the frequency–force relationship with greater force production at lower stimulation frequencies. These are structural and functional markers of a slower muscle phenotype. Taken together, our findings show that muscles from mdxCnA* mice have a smaller mean fibre cross-sectional area, a greater sarcolemmal to cytoplasmic volume ratio, and an increase in utrophin expression, promoting an attenuated susceptibility to contraction-induced injury. We conclude that increased calcineurin activity may confer functional benefits to dystrophic skeletal muscles.
Language eng
DOI 10.1113/jphysiol.2006.108472
Field of Research 060110 Receptors and Membrane Biology
Socio Economic Objective 970106 Expanding Knowledge in the Biological Sciences
HERDC Research category C1.1 Refereed article in a scholarly journal
Copyright notice ©2006, The Authors
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Document type: Journal Article
Collections: Institute for Technology Research and Innovation
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Created: Mon, 28 Sep 2009, 17:23:18 EST by Nicole Stupka

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