Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation

Norbert Frey, Derk Frank, Stefanie Lippl, Christian Kuhn, Harald Kögler, Tomasa Barrientos, Claudia Rohr, Rainer Will, Oliver J. Müller, Hartmut Weiler, Rhonda Bassel-Duby, Hugo A. Katus, Eric N. Olson

Research output: Contribution to journalArticle

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Abstract

The composition of skeletal muscle, in terms of the relative number of slow- and fast-twitch fibers, is tightly regulated to enable an organism to respond and adapt to changing physical demands. The phosphatase calcineurin and its downstream targets, transcription factors of the nuclear factor of activated T cells (NFAT) family, play a critical role in this process by promoting the formation of slow-twitch, oxidative fibers. Calcineurin binds to calsarcins, a family of striated muscle-specific proteins of the sarcomeric Z-disc. We show here that mice deficient in calsarcin-2, which is expressed exclusively by fast-twitch muscle and encoded by the myozenin 1 (Myoz1) gene, have substantially reduced body weight and fast-twitch muscle mass in the absence of an overt myopathic phenotype. Additionally, Myoz1 KO mice displayed markedly improved performance and enhanced running distances in exercise studies. Analysis of fiber type composition of calsarcin-2-deficient skeletal muscles showed a switch toward slow-twitch, oxidative fibers. Reporter assays in cultured myoblasts indicated an inhibitory role for calsarcin-2 on calcineurin, and Myoz1 KO mice exhibited both an excess of NFAT activity and an increase in expression of regulator of calcineurin 1-4 (RCAN1-4), indicating enhanced calcineurin signaling in vivo. Taken together, these results suggest that calsarcin-2 modulates exercise performance in vivo through regulation of calcineurin/NFAT activity and subsequent alteration of the fiber type composition of skeletal muscle.

Original languageEnglish (US)
Pages (from-to)3598-3608
Number of pages11
JournalJournal of Clinical Investigation
Volume118
Issue number11
DOIs
StatePublished - Nov 3 2008

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NFATC Transcription Factors
Calcineurin
Skeletal Muscle
Muscles
Striated Muscle
Muscle Proteins
Myoblasts
Skeletal Muscle Fibers
Running
Transcription Factors
Body Weight
Phenotype
Genes

ASJC Scopus subject areas

  • Medicine(all)

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Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation. / Frey, Norbert; Frank, Derk; Lippl, Stefanie; Kuhn, Christian; Kögler, Harald; Barrientos, Tomasa; Rohr, Claudia; Will, Rainer; Müller, Oliver J.; Weiler, Hartmut; Bassel-Duby, Rhonda; Katus, Hugo A.; Olson, Eric N.

In: Journal of Clinical Investigation, Vol. 118, No. 11, 03.11.2008, p. 3598-3608.

Research output: Contribution to journalArticle

Frey, N, Frank, D, Lippl, S, Kuhn, C, Kögler, H, Barrientos, T, Rohr, C, Will, R, Müller, OJ, Weiler, H, Bassel-Duby, R, Katus, HA & Olson, EN 2008, 'Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation', Journal of Clinical Investigation, vol. 118, no. 11, pp. 3598-3608. https://doi.org/10.1172/JCI36277
Frey, Norbert ; Frank, Derk ; Lippl, Stefanie ; Kuhn, Christian ; Kögler, Harald ; Barrientos, Tomasa ; Rohr, Claudia ; Will, Rainer ; Müller, Oliver J. ; Weiler, Hartmut ; Bassel-Duby, Rhonda ; Katus, Hugo A. ; Olson, Eric N. / Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation. In: Journal of Clinical Investigation. 2008 ; Vol. 118, No. 11. pp. 3598-3608.
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