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

Nicole Stupka, David R. Plant, Jonathan D. Schertzer, Tennent M. Emerson, Rhonda Bassel-Duby, Eric N. Olson, Gordon S. Lynch

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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 (mdxCnA*) 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. 2006 The Authors. Journal compilation

Original languageEnglish (US)
Pages (from-to)645-656
Number of pages12
JournalJournal of Physiology
Volume575
Issue number2
DOIs
StatePublished - Sep 2006

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Inbred mdx Mouse
Calcineurin
Skeletal Muscle
Muscles
Wounds and Injuries
Utrophin
Albumins
Isometric Contraction
Myosin Heavy Chains
Muscle Contraction

ASJC Scopus subject areas

  • Physiology

Cite this

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.

In: Journal of Physiology, Vol. 575, No. 2, 09.2006, p. 645-656.

Research output: Contribution to journalArticle

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. In: Journal of Physiology. 2006 ; Vol. 575, No. 2. pp. 645-656.
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abstract = "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 (mdxCnA*) 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. 2006 The Authors. Journal compilation",
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AB - 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 (mdxCnA*) 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. 2006 The Authors. Journal compilation

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