Published online before print July 5, 2007, doi: 10.1161/CIRCRESAHA.106.145557
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Submitted on November 29, 2006
Revised on June 19, 2007
Accepted on June 25, 2007
Cardiac Transgenic and Gene Transfer Strategies Converge to Support an Important Role for Troponin I in Regulating Relaxation in Cardiac Myocytes
So-ichiro Yasuda ;
From the Department of Molecular and Integrative Physiology (S.Y., P.C., J.M.M.), University of Michigan, Ann Arbor; and Children’s Hospital (S.S., J.R.), Cincinnati, Ohio.
* To whom correspondence should be addressed. E-mail: metzgerj{at}umich.edu.
Elucidating the relative roles of cardiac troponin I (cTnI) and phospholamban (PLN) in 
-adrenergic-mediated hastening of cardiac relaxation has been challenging and controversial. To test the hypothesis that -adrenergic phosphorylation of cTnI has a prominent role in accelerating cardiac myocyte relaxation performance we used transgenic (Tg) mice bearing near complete replacement of native cTnI with a -adrenergic phospho-mimetic of cTnI whereby tandem serine codons 23/24 were converted to aspartic acids (cTnI S23/24D). Adult cardiac myocytes were isolated and contractility determined at physiological temperature under unloaded and loaded conditions using micro-carbon fibers. At baseline, cTnI S23/24D myocytes had significantly faster relaxation times relative to controls, and isoproterenol stimulation (Iso) had only a small effect to further speed relaxation in cTnI S23/24D myocytes (delta Iso: 7.2 ms) relative to the maximum Iso effect (31.2 ms) in control. The Ca2+ transient decay rate was similarly accelerated by Iso in Tg and nontransgenic (Ntg) myocytes. Gene transfer of cTnI S23/24D to myocytes in primary culture showed comparable findings. Gene transfer of cTnI with both serines 23/24 converted to alanines (cTnI S23/24A), or gene transfer of slow skeletal TnI, both of which lack PKA phosphorylation sites, significantly blunted Iso-mediated enhanced relaxation compared with controls. Gene transfer of wild-type cTnI had no effect on relaxation. These findings support a key role of cTnI in myocyte relaxation and highlight a direct contribution of the myofilaments in modulating the dynamics of myocardial performance.
Key words: contraction • calcium • heart
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