Stimulation of calcineurin Aα activity attenuates muscle pathophysiology in mdx dystrophic mice

Stupka, Nicole, Schertzer, Jonathon D., Bassel-Duby, Rhonda, Olson, Eric N. and Lynch, Gordon S. 2008, Stimulation of calcineurin Aα activity attenuates muscle pathophysiology in mdx dystrophic mice, American journal of physiology : regulatory, integrative and comparative physiology, vol. 294, no. 3, pp. 983-992.

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Title Stimulation of calcineurin Aα activity attenuates muscle pathophysiology in mdx dystrophic mice
Formatted title Stimulation of calcineurin Aα activity attenuates muscle pathophysiology in mdx dystrophic mice
Author(s) Stupka, Nicole
Schertzer, Jonathon D.
Bassel-Duby, Rhonda
Olson, Eric N.
Lynch, Gordon S.
Journal name American journal of physiology : regulatory, integrative and comparative physiology
Volume number 294
Issue number 3
Start page 983
End page 992
Total pages 10
Publisher American Physiological Society
Place of publication Bethesda, Md.
Publication date 2008-01-16
ISSN 0363-6119
1522-1490
Keyword(s) muscle regeneration
muscular dystrophy
skeletal muscle
muscle contraction
Summary Calcineurin activation ameliorates the dystrophic pathology of hindlimb muscles in mdx mice and decreases their susceptibility to contraction damage. In mdx mice, the diaphragm is more severely affected than hindlimb muscles and more representative of Duchenne muscular dystrophy. The constitutively active calcineurin A transgene (CnA) was overexpressed in skeletal muscles of mdx (mdx CnA*) mice to test whether muscle morphology and function would be improved. Contractile function of diaphragm strips and extensor digitorum longus and soleus muscles from adult mdx CnA* and mdx mice was examined in vitro. Hindlimb muscles from mdx CnA* mice had a prolonged twitch time course and were more resistant to fatigue. Because of a slower phenotype and a decrease in fiber cross-sectional area, normalized force was lower in fast- and slow-twitch muscles of mdx CnA* than mdx mice. In the diaphragm, despite a slower phenotype and a 35% reduction in fiber size, normalized force was preserved. This was likely mediated by the reduction in the area of the diaphragm undergoing degeneration (i.e., mononuclear cell and connective and adipose tissue infiltration). The proportion of centrally nucleated fibers was reduced in mdx CnA* compared with mdx mice, indicative of improved myofiber viability. In hindlimb muscles of mdx mice, calcineurin activation increased expression of markers of regeneration, particularly developmental myosin heavy chain isoform and myocyte enhancer factor 2A. Thus activation of the calcineurin signal transduction pathway has potential to ameliorate the mdx pathophysiology, especially in the diaphragm, through its effects on muscle degeneration and regeneration and endurance capacity.
Language eng
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
ERA Research output type C Journal article
HERDC collection year 2008
Copyright notice ©2008, American Physiological Society
Persistent URL http://hdl.handle.net/10536/DRO/DU:30019973

Document type: Journal Article
Collection: Institute for Technology Research and Innovation
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Created: Mon, 28 Sep 2009, 17:09:31 EST by Nicole Stupka

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