Plasticity of cardiac titin/connectin in heart development
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Many sarcomeric proteins in the myocardium alter their isoform pattern during perinatal development to adjust to the intensified pump function of the postnatal heart. These changes also involve the giant protein titin/connectin. Here we show by low-percentage polyacrylamide-gel electrophoresis that developmentally regulated switching of cardiac titin/connectin size occurs in the hearts of mouse, rat, pig, and chicken. Mammalian hearts express, well before birth, large foetal (∼3.7 MDa) N2BA-titin/connectin isoform but no N2B-isoform (3.0 MDa). During perinatal heart development the 3.7-MDa N2BA-isoform is replaced by a mix of smaller isoforms. At birth a plethora of intermediate-size N2BA-isoforms appears together with the N2B-isoform. In postnatal heart development the larger-size N2BA-isoforms disappear and smaller-size N2BA-isoforms are upregulated, whereas the proportion of N2B-titin/connectin increases to species-specific adult levels. The time courses of isoform switching are faster in small than in large mammals. Titin/connectin isoform switching also takes place in developing chicken hearts, but the largest embryonic isoform found here was less than 3.4 MDa. At hatching, various smaller-size isoforms appeared and within a week the adult expression pattern was established representing a major 3.0-MDa isoform and a minor 3.15-MDa isoform. The ratio between the two adult isoforms differed between the left ventricle and the right atrium. The perinatal changes toward smaller cardiac titin/connectin isoforms in mammals and chicken greatly increase the myofibrillar passive tension of postnatal hearts. Plasticity of titin/connectin at approximately the time of birth thus affects myocardial mechanics but could also be an important factor in developmentally regulated assembly and signalling processes.
KeywordsWild Boar Passive Tension Nebulin Chicken Heart Cardiac Titin
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We would like to thank Dr. Uta Opitz for continuous encouragement and the former members of the Linke lab in Heidelberg for their excellent work, which the present study is built upon. We gratefully acknowledge financial support of the Deutsche Forschungsgemeinschaft (grants Li 690/2-3, Li 690/6-2, SFB 629).
- Bang ML, Centner T, Fornoff F, Geach AJ, Gotthardt M, McNabb M, Witt CC, Labeit D, Gregorio CC, Granzier H, Labeit S (2001) The complete gene sequence of titin, expression of an unusual approximately 700-kDa titin isoform, and its interaction with obscurin identify a novel Z-line to I-band linking system. Circ Res 89:1065–1072PubMedGoogle Scholar
- Freiburg A, Trombitas K, Hell W, Cazorla O, Fougerousse F, Centner T, Kolmerer B, Witt C, Beckmann JS, Gregorio CC, Granzier H, Labeit S (2000) Series of exon-skipping events in the elastic spring region of titin as the structural basis for myofibrillar elastic diversity.Circ Res 86:1114–1121PubMedGoogle Scholar
- Fürst DO, Osborn M, Nave R, Weber K (1988) The organization of titin filaments in the half-sarcomere revealed by monoclonal antibodies in immunoelectron microscopy: a map of ten nonrepetitive epitopes starting at the Z line extends close to the M line. J Cell Biol 106:1563–1572PubMedCrossRefGoogle Scholar
- Itoh Y, Suzuki T, Kimura S, Ohashi K, Higuchi H, Sawada H, Shimizu T, Shibata M, Maruyama K (1988) Extensible and less-extensible domains of connectin filaments in stretched vertebrate skeletal muscle sarcomeres as detected by immunofluorescence and immunoelectron microscopy using monoclonal antibodies. J Biochem 104:504–508PubMedGoogle Scholar
- Lompré AM, Nadal-Ginard B, Mahdavi V (1984) Expression of the cardiac ventricular α- and ß-myosin heavy chain genes is developmentally and hormonally regulated. J Biol Chem 260:6437–6446Google Scholar
- Maruyama K, Matsubara S, Natori R, Nonomura Y, Kimura S, Ohashi K, Murakami F, Handa S, Eguchi G (1977a) Connectin, an elastic protein of muscle: characterization and function. J Biochem (Tokyo) 82:317–337Google Scholar
- Maruyama K, Murakami F, Ohashi K (1977b) Connectin, an elastic protein of muscle. Comparative Biochemistry. J Biochem (Tokyo) 82:339–345Google Scholar
- Reiser PJ, Westfall MV, Schiaffino S, Solaro RJ (1994) Tension production and thin-filament protein isoforms in developing rat myocardium. Am J Physiol Heart Circ Physiol 267:H1589–H1596Google Scholar