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Am J Physiol Heart Circ Physiol (May 5, 2006). doi:10.1152/ajpheart.00114.2006
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Submitted on January 31, 2006
Accepted on May 3, 2006

Developmental changes in passive stiffness and myofilament Ca2+ sensitivity due to titin and troponin-I isoform switching are not critically triggered by birth

Martina Kruger1, Thomas Kohl2, and Wolfgang A. Linke1*

1 Physiology and Biophysics Unit, University of Muenster, Muenster, Germany
2 German Center for Fetal Surgery & Minimally-Invasive Therapy, University of Bonn, Bonn, Germany

* To whom correspondence should be addressed. E-mail: wlinke{at}uni-muenster.de.

The giant protein titin, a major contributor to myocardial mechanics, is expressed in two main cardiac isoforms: stiff N2B (3.0MDa) and more compliant N2BA (>3.2MDa). Fetal hearts of mice, rats, and pigs express a unique N2BA-isoform (~3.7MDa) but no N2B. Around birth the fetal N2BA-titin is replaced by smaller-size N2BA-isoforms and N2B, which predominates in adult hearts, stiffening their sarcomeres. Here we show that perinatal titin-isoform switching and corresponding passive-stiffness (STp) changes do not occur in the hearts of guinea-pig and sheep. In these species the shift toward "adult" proportions of N2B-isoform is almost completed by mid-gestation. The relative contributions of titin and collagen to STp were estimated in force measurements on skinned cardiac-muscle strips by selective titin proteolysis, leaving the collagen matrix unaffected. Titin-based STp contributed between 42% and 58% to total STp in late-fetal and adult sheep/guinea-pig, and adult rat. However, only ~20% of total STp was titin-based in late-fetal rat. Titin-borne passive tension and the proportion of titin-based STp generally scaled with the N2B-isoform percentage. The titin-isoform transitions were correlated to a switch in troponin-I (TnI) isoform expression. In rats, fetal ssTnI was replaced by adult cTnI shortly after birth, thereby reducing the Ca2+-sensitivity of force development. In contrast, guinea-pig and sheep co-expressed ssTnI and cTnI in fetal hearts and skinned fibers from guinea-pig showed almost no perinatal shift in Ca2+-sensitivity. We conclude that TnI-isoform and titin-isoform switching and corresponding functional changes during heart development are not initiated by birth, but are genetically programmed, species-specifically regulated, events.




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