Functional effects of the DCM mutant Gly159Asp troponin C in skinned muscle fibres.
We recently reported a dilated cardiomyopathy (DCM) causing mutation in a novel disease gene, TNNC1, which encodes cardiac troponin C (TnC). We have determined how this mutation, Gly159Asp, affects contractile regulation when incorporated into muscle fibres. Endogenous troponin in rabbit skinned psoas fibres was partially replaced by recombinant human cardiac troponin containing either wild-type or Gly159Asp TnC. We measured both the force-pCa relationship of these fibres and the activation rate using the caged-Ca(2+) compound nitrophenyl-EGTA. Gly159Asp TnC had no significant effect on either the Ca(2+) sensitivity or cooperativity of force generation when compared to wild type. However, the mutation caused a highly significant (ca. 50%) decrease in the rate of activation. This study shows that whilst not affecting the force-pCa relationship, the mutation Gly159Asp causes a significant decrease in the rate of force production and a change in the relationship between the rate of force production and generated force. In vivo, this mutation may cause both a slowing of force generation and reduction in total systolic force. This represents a novel mechanism by which a cardiomyopathy-causing mutation can affect contractility.
Preston
Laura C
LC
Department of Physiology, University of Oxford, Oxford, UK.
Lipscomb
Simon
S
Robinson
Paul
P
Mogensen
Jens
J
McKenna
William J
WJ
Watkins
Hugh
H
Ashley
Chris C
CC
Redwood
Charles S
CS
D008841:Actin Cytoskeleton / Q000502:physiology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002311:Cardiomyopathy, Dilated / Q000235:genetics* / Q000473:pathology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology*; D017354:Point Mutation; D016658:Psoas Muscles / Q000166:cytology / Q000502:physiology*; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D019209:Troponin C / Q000235:genetics* / Q000494:pharmacology
D011994:Recombinant Proteins; D019209:Troponin C; D002118:Calcium