title: Functional effects of the DCM mutant Gly159Asp troponin C in skinned muscle fibres.
abstract: 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.
authors.affiliation: Department of Physiology, University of Oxford, Oxford, UK.
authors.forename: Laura C
authors.initials: LC
authors.lastname: Preston
authors.forename: Simon
authors.initials: S
authors.lastname: Lipscomb
authors.forename: Paul
authors.initials: P
authors.lastname: Robinson
authors.forename: Jens
authors.initials: J
authors.lastname: Mogensen
authors.forename: William J
authors.initials: WJ
authors.lastname: McKenna
authors.forename: Hugh
authors.initials: H
authors.lastname: Watkins
authors.forename: Chris C
authors.initials: CC
authors.lastname: Ashley
authors.forename: Charles S
authors.initials: CS
authors.lastname: Redwood
mesh_terms: 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
chemical_list: D011994:Recombinant Proteins; D019209:Troponin C; D002118:Calcium