Nature Medicine10, 1336 - 1343 (2004)
Published online: 14 November 2004; | doi:10.1038/nm1132
Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress
Norbert Frey1, 2, 7, Tomasa Barrientos1, 6, 7, John M Shelton5, 6, Derk Frank2, Hartmut Rütten4, Doris Gehring4, Christian Kuhn2, Matthias Lutz2, Beverly Rothermel5, Rhonda Bassel-Duby1, James A Richardson3, Hugo A Katus2, Joseph A Hill1, 5, 6
& Eric N Olson1, 6
1
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9148, USA.
2
Department of Internal Medicine III University of Heidelberg, IFN410, 69120 Heidelberg, Germany.
3
Pathology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9072, USA.
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.
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated.
