Skeletal troponin C reduces contractile sensitivity to acidosis in cardiac myocytes from transgenic mice.
Depressed contractile function plays a primary role in the pathophysiology of acute myocardial ischemia. Intracellular acidification is an important factor underlying the inhibition of force 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 Ca(2+)-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.
Metzger
J M
JM
Department of Physiology, University of Michigan, School of Medicine, Ann Arbor 48109.
Parmacek
M S
MS
Barr
E
E
Pasyk
K
K
Lin
W I
WI
Cochrane
K L
KL
Field
L J
LJ
Leiden
J M
JM
D000138:Acidosis / Q000503:physiopathology*; D000818:Animals; D001483:Base Sequence; D002118:Calcium / Q000494:pharmacology; D002478:Cells, Cultured; D015870:Gene Expression; D006321:Heart / Q000187:drug effects / Q000502:physiology*; D006863:Hydrogen-Ion Concentration; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009132:Muscles / Q000502:physiology*; D009200:Myocardial Contraction / Q000502:physiology*; D017202:Myocardial Ischemia / Q000503:physiopathology; D009206:Myocardium / Q000648:ultrastructure; D009218:Myosins / Q000235:genetics; D009838:Oligodeoxyribonucleotides; D011401:Promoter Regions, Genetic; D014336:Troponin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D019209:Troponin C
D009838:Oligodeoxyribonucleotides; D014336:Troponin; D019209:Troponin C; D009218:Myosins; D002118:Calcium