Skeletal troponin C reduces contractile sensitivity to acidosis in cardiac myocytes from transgenic mice

Joseph M. Metzger, Michael S. Parmacek, Eliav Barr, Krystyna Pasyk, Wan In Lin, Karen L. Cochrane, Loren J. Field, Jeffrey M. Leiden

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Abstract

Depressed contractile function plays a primary role in the pathophysiology of acute myocardial ischemia. Intracellular acidification is an important factor underlying the inhibition offeree production in the ischemic myocardium. The effect of acidosis to depress contractility is markedly greater in cardiac as compared to skeletal muscle; however, the molecular basis of this difference in sensitivity to acidosis is not clearly understood. In this report, we describe transgenic mice that express the fast skeletal isoform of troponin C (sTnC) in cardiac muscle. In permeabilized single cardiac myocytes the shift in the midpoint of the tension-pCa relationship (i.e., pCa50, where pCa is -log[Ca2+]) due to lowering pH from 7.00 to 6.20 was 1.27 ± 0.03 (n = 7) pCa units in control cardiac TnC (cTnC) expressing myocytes and 0.96 ± 0.04 (n = 11) pCa unit in transgenic cardiac myocytes (P < 0.001). The effect of pH to alter maximum Ca2+-activated tension was unchanged by TnC isoforms in these cardiac myocytes. In a reciprocal experiment, contractile sensitivity to acidosis was increased in fast skeletal muscle fibers following extraction of endogenous sTnC and reconstitution with purified cTnC in vitro. Our findings demonstrate that TnC plays an important role in determining the profound sensitivity of cardiac muscle to acidosis and identify cTnC as a target for therapeutic interventions designed to modify ischemia-induced myocardial contractile dysfunction.

Original languageEnglish (US)
Pages (from-to)9036-9040
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume90
Issue number19
DOIs
StatePublished - Oct 1 1993

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