Sarcomere thin filament regulatory isoforms. Evidence of a dominant effect of slow skeletal troponin I on cardiac contraction.
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 Ca(2+) 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.
Metzger
Joseph M
JM
Department of Physiology, School of Medicine, University of Michigan, Ann Arbor, Michigan 48109-0622, USA. metzgerj@umich.edu
Michele
Daniel E
DE
Rust
Elizabeth M
EM
Borton
Andrea R
AR
Westfall
Margaret V
MV
D000494:Allosteric Regulation; D000818:Animals; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D005260:Female; D019084:Fluorescent Antibody Technique, Indirect; D006321:Heart / Q000187:drug effects / Q000502:physiology; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology*; D009206:Myocardium / Q000166:cytology; D020033:Protein Isoforms / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000502:physiology*; D014335:Tropomyosin / Q000502:physiology; D019210:Troponin I / Q000502:physiology*; D020107:Troponin T / Q000502:physiology*
D020033:Protein Isoforms; D014335:Tropomyosin; D019210:Troponin I; D020107:Troponin T; D002118:Calcium