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Originally published In Press as doi:10.1074/jbc.M212601200 on January 27, 2003

J. Biol. Chem., Vol. 278, Issue 15, 13118-13123, April 11, 2003
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Sarcomere Thin Filament Regulatory Isoforms
EVIDENCE OF A DOMINANT EFFECT OF SLOW SKELETAL TROPONIN I ON CARDIAC CONTRACTION*

Joseph M. MetzgerDagger §, Daniel E. MicheleDagger , Elizabeth M. RustDagger , Andrea R. BortonDagger , and Margaret V. Westfall||

From the Departments of Dagger  Physiology and  Surgery, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109-0622

Thin filament proteins tropomyosin (Tm), troponin T (TnT), and troponin I (TnI) form an allosteric regulatory complex that is required for normal cardiac contraction. Multiple isoforms of TnT, Tm, and TnI are differentially expressed in both cardiac development and disease, but concurrent TnI, Tm, and TnT isoform switching has hindered assignment of cellular function to these transitions. We systematically incorporated into the adult sarcomere the embryonic/fetal isoforms of Tm, TnT, and TnI by using gene transfer. In separate experiments, greater than 90% of native TnI and 40-50% of native Tm or TnT were specifically replaced. The Ca2+ sensitivity of tension development was markedly enhanced by TnI replacement but not by TnT or Tm isoform replacement. Titration of TnI replacement from >90% to <30% revealed a dominant functional effect of slow skeletal TnI to modulate regulation. Over this range of isoform replacement, TnI, but not Tm or TnT embryonic isoforms, influenced calcium regulation of contraction, and this identifies TnI as a potential target to modify contractile performance in normal and diseased myocardium.

* This work is supported by grants from the National Institutes of Health and the American Heart Association (to J. M. M.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: Dept. of Physiology, 7730 Medical Science Bldg. II, University of Michigan, Ann Arbor, MI 48109-0622. Tel.: 734-763-0560; Fax: 734-647-6461; E-mail: metzgerj@umich.edu.

|| Recipient of a Scientist Development grant from the American Heart Association.

Copyright © 2003 by The American Society for Biochemistry and Molecular Biology, Inc.
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