Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress

Norbert Frey, Tomasa Barrientos, John M. Shelton, Derk Frank, Hartmut Rütten, Doris Gehring, Christian Kuhn, Matthias Lutz, Beverly A Rothermel, Rhonda S Bassel-Duby, James A Richardson, Hugo A. Katus, Joseph A Hill, Eric N Olson

Research output: Contribution to journalArticle

164 Citations (Scopus)

Abstract

Signaling by the calcium-dependent phosphatase calcineurin profoundly influences the growth and gene expression of cardiac and skeletal muscle. Calcineurin binds to calsarcins, a family of muscle-specific proteins of the sarcomeric Z-disc, a focal point in the pathogenesis of human cardiomyopathies. We show that calsarcin-1 negatively modulates the functions of calcineurin, such that calcineurin signaling was enhanced in striated muscles of mice that do not express calsarcin-1. As a consequence of inappropriate calcineurin activation, mice with a null mutation in calsarcin-1 showed an excess of slow skeletal muscle fibers. The absence of calsarcin-1 also activated a hypertrophic gene program, despite the absence of hypertrophy, and enhanced the cardiac growth response to pressure overload. In contrast, cardiac adaptation to other hypertrophic stimuli, such as chronic catecholamine stimulation or exercise, was not affected. These findings show important roles for calsarcins as modulators of calcineurin signaling and the transmission of a specific subset of stress signals leading to cardiac remodeling in vivo.

Original languageEnglish (US)
Pages (from-to)1336-1343
Number of pages8
JournalNature Medicine
Volume10
Issue number12
DOIs
StatePublished - Dec 2004

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Calcineurin
Cardiomyopathies
Muscle
Calcium Signaling
Striated Muscle
Muscle Proteins
Skeletal Muscle Fibers
Cardiomegaly
Growth
Gene expression
Modulators
Catecholamines
Myocardium
Skeletal Muscle
Genes
Chemical activation
Calcium
Gene Expression
Pressure
Mutation

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Medicine(all)

Cite this

Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress. / Frey, Norbert; Barrientos, Tomasa; Shelton, John M.; Frank, Derk; Rütten, Hartmut; Gehring, Doris; Kuhn, Christian; Lutz, Matthias; Rothermel, Beverly A; Bassel-Duby, Rhonda S; Richardson, James A; Katus, Hugo A.; Hill, Joseph A; Olson, Eric N.

In: Nature Medicine, Vol. 10, No. 12, 12.2004, p. 1336-1343.

Research output: Contribution to journalArticle

Frey, Norbert ; Barrientos, Tomasa ; Shelton, John M. ; Frank, Derk ; Rütten, Hartmut ; Gehring, Doris ; Kuhn, Christian ; Lutz, Matthias ; Rothermel, Beverly A ; Bassel-Duby, Rhonda S ; Richardson, James A ; Katus, Hugo A. ; Hill, Joseph A ; Olson, Eric N. / Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress. In: Nature Medicine. 2004 ; Vol. 10, No. 12. pp. 1336-1343.
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