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

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 tib...

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Main Authors: Stupka, Nicole, Plant, David R, Schertzer, Jonathan D, Emerson, Tennent M, Bassel-Duby, Rhonda, Olson, Eric N, Lynch, Gordon S
Formato: Artigo
Idioma:English
Publicado em: Blackwell Science Inc 2006
Assuntos:
Skeletal Muscle and Exercise
Acesso em linha:https://ncbi.nlm.nih.gov/pmc/articles/PMC1819459/
https://ncbi.nlm.nih.gov/pubmed/16793906
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1113/jphysiol.2006.108472
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spelling pubmed-18194592007-09-01 Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice Stupka, Nicole Plant, David R Schertzer, Jonathan D Emerson, Tennent M Bassel-Duby, Rhonda Olson, Eric N Lynch, Gordon S J Physiol Skeletal Muscle and Exercise 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 mdx CnA* muscles. The proportion of albumin-positive fibres was significantly less in control and injured muscles from mdx CnA* mice than from mdx mice. Compared with mdx mice, mean fibre cross-sectional area was 50% less in muscles from mdx CnA* mice. Furthermore, muscles from mdx CnA* 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 mdx CnA* 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. Blackwell Science Inc 2006-09-01 2006-06-22 /pmc/articles/PMC1819459/ /pubmed/16793906 http://dx.doi.org/10.1113/jphysiol.2006.108472 Text en © 2006 The Authors. Journal compilation © 2006 The Physiological Society
institution US National Library of Medicine
collection PubMed Central
language English
format Article
topic Skeletal Muscle and Exercise
spellingShingle Skeletal Muscle and Exercise
Stupka, Nicole
Plant, David R
Schertzer, Jonathan D
Emerson, Tennent M
Bassel-Duby, Rhonda
Olson, Eric N
Lynch, Gordon S
Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice
description 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 mdx CnA* muscles. The proportion of albumin-positive fibres was significantly less in control and injured muscles from mdx CnA* mice than from mdx mice. Compared with mdx mice, mean fibre cross-sectional area was 50% less in muscles from mdx CnA* mice. Furthermore, muscles from mdx CnA* 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 mdx CnA* 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.
author Stupka, Nicole
Plant, David R
Schertzer, Jonathan D
Emerson, Tennent M
Bassel-Duby, Rhonda
Olson, Eric N
Lynch, Gordon S
author_facet Stupka, Nicole
Plant, David R
Schertzer, Jonathan D
Emerson, Tennent M
Bassel-Duby, Rhonda
Olson, Eric N
Lynch, Gordon S
author_sort Stupka, Nicole
title Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice
title_short Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice
title_full Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice
title_fullStr Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice
title_full_unstemmed Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice
title_sort activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice
publisher Blackwell Science Inc
publisher_facet Blackwell Science Inc
publishDate 2006
url https://ncbi.nlm.nih.gov/pmc/articles/PMC1819459/
https://ncbi.nlm.nih.gov/pubmed/16793906
https://ncbi.nlm.nih.govhttp://dx.doi.org/10.1113/jphysiol.2006.108472
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