TY - JOUR
T1 - The giant protein titin regulates the length of the striated muscle thick filament
AU - Tonino, Paola
AU - Kiss, Balazs
AU - Strom, Josh
AU - Methawasin, Mei
AU - Smith, John E.
AU - Kolb, Justin
AU - Labeit, Siegfried
AU - Granzier, Henk
N1 - Funding Information:
Dr. Granzier is the Allan and Alfie Norville Endowed Chair. We are grateful to our lab members Xiangdang Liu, Xiaoqun Zhou, Chandra Saripalli, Maya Adler, Yaeren Her-nandez, and Alexander Gasch, the University of Arizona Genetic Engineering of Mouse Model and the Mouse Phenotyping Core Facilities. We are grateful to Dr Carol Gregorio for the I103 antibody and Dr Samantha Harris for the cMyBP-C (C5-C7) antibody. Funding was by Foundation Leducq (TNE-13CVD04) and National Institutes of Health Grants HL062881, HL118524, and HL115988. We dedicate this study to Dr Károly (Charles) Trombitás, a pioneer in electron microscopy on titin and a continued source of inspiration.
Publisher Copyright:
© 2017 The Author(s).
PY - 2017/12/1
Y1 - 2017/12/1
N2 - The contractile machinery of heart and skeletal muscles has as an essential component the thick filament, comprised of the molecular motor myosin. The thick filament is of a precisely controlled length, defining thereby the force level that muscles generate and how this force varies with muscle length. It has been speculated that the mechanism by which thick filament length is controlled involves the giant protein titin, but no conclusive support for this hypothesis exists. Here we show that in a mouse model in which we deleted two of titin's C-zone super-repeats, thick filament length is reduced in cardiac and skeletal muscles. In addition, functional studies reveal reduced force generation and a dilated cardiomyopathy (DCM) phenotype. Thus, regulation of thick filament length depends on titin and is critical for maintaining muscle health.
AB - The contractile machinery of heart and skeletal muscles has as an essential component the thick filament, comprised of the molecular motor myosin. The thick filament is of a precisely controlled length, defining thereby the force level that muscles generate and how this force varies with muscle length. It has been speculated that the mechanism by which thick filament length is controlled involves the giant protein titin, but no conclusive support for this hypothesis exists. Here we show that in a mouse model in which we deleted two of titin's C-zone super-repeats, thick filament length is reduced in cardiac and skeletal muscles. In addition, functional studies reveal reduced force generation and a dilated cardiomyopathy (DCM) phenotype. Thus, regulation of thick filament length depends on titin and is critical for maintaining muscle health.
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U2 - 10.1038/s41467-017-01144-9
DO - 10.1038/s41467-017-01144-9
M3 - Article
C2 - 29051486
AN - SCOPUS:85031899890
VL - 8
JO - Nature Communications
JF - Nature Communications
SN - 2041-1723
IS - 1
M1 - 1041
ER -