Calsarcin-2 deficiency increases exercise capacity in mice through calcineurin/NFAT activation. J Clin Invest 2008 Nov;118(11):3598-608
Date
10/11/2008Pubmed ID
18846255Pubmed Central ID
PMC2564612DOI
10.1172/JCI36277Scopus ID
2-s2.0-55849135238 (requires institutional sign-in at Scopus site) 128 CitationsAbstract
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.
Author List
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 ENMESH terms used to index this publication - Major topics in bold
AnimalsCalcineurin
Carrier Proteins
Cell Line
Genes, Reporter
Mice
Mice, Knockout
Microfilament Proteins
Models, Biological
Muscle Fibers, Slow-Twitch
Muscle Proteins
Myoblasts
NFATC Transcription Factors
Physical Conditioning, Animal
