Mice lacking calsarcin-1 are sensitized to calcineurin signaling and show accelerated cardiomyopathy in response to pathological biomechanical stress.
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.
Frey
Norbert
N
Department of Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390-9148, USA. norbert.frey@med.uni-heidelberg.de
Barrientos
Tomasa
T
Shelton
John M
JM
Frank
Derk
D
Rütten
Hartmut
H
Gehring
Doris
D
Kuhn
Christian
C
Lutz
Matthias
M
Rothermel
Beverly
B
Bassel-Duby
Rhonda
R
Richardson
James A
JA
Katus
Hugo A
HA
Hill
Joseph A
JA
Olson
Eric N
EN
D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D001696:Biomechanical Phenomena; D019703:Calcineurin / Q000378:metabolism*; D065095:Calcineurin Inhibitors; D009202:Cardiomyopathies / Q000378:metabolism*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D017931:DNA Primers; D004268:DNA-Binding Proteins; D004452:Echocardiography; D005786:Gene Expression Regulation; D006321:Heart / Q000187:drug effects / Q000254:growth & development; D007150:Immunohistochemistry; D047908:Intracellular Signaling Peptides and Proteins; D007545:Isoproterenol / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D008854:Microscopy, Electron; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics / Q000494:pharmacology; D018482:Muscle, Skeletal / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D009206:Myocardium / Q000378:metabolism / Q000648:ultrastructure; D010805:Physical Conditioning, Animal; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012518:Sarcomeres / Q000378:metabolism; D015398:Signal Transduction; D013312:Stress, Physiological / Q000378:metabolism; D001616:beta-Galactosidase
D000318:Adrenergic beta-Agonists; D065095:Calcineurin Inhibitors; D002352:Carrier Proteins; D017931:DNA Primers; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; C108612:RCAN1 protein, human; D019703:Calcineurin; D001616:beta-Galactosidase; D007545:Isoproterenol