title: Ca(2+) activation of myofilaments from transgenic mouse hearts expressing R92Q mutant cardiac troponin T.
abstract: The functional consequences of the R92Q mutation in cardiac troponin T (cTnT), linked to familial hypertrophic cardiomyopathy in humans, are not well understood. We have studied steady- and pre-steady-state mechanical activity of detergent-skinned fiber bundles from a transgenic (TG) mouse model in which 67% of the total cTnT in the heart was replaced by the R92Q mutant cTnT. TG fibers were more sensitive to Ca(2+) than nontransgenic (NTG) fibers [negative logarithm of half maximally activating molar Ca(2+) (pCa(50)) = 5.84 +/- 0.01 and 6.12 +/- 0.01 for NTG and TG fibers, respectively]. The shift in pCa(50) caused by increasing the sarcomere length from 1.9 to 2.3 microm was significantly higher for TG than for NTG fibers (DeltapCa(50) = 0.13 +/- 0.01 and 0.29 +/- 0.02 for NTG and TG fibers, respectively). The relationships between rate of ATP consumption and steady-state isometric tension were linear, and the slopes were the same in NTG and TG fibers. Rate of tension redevelopment was more sensitive to Ca(2+) in TG than in NTG fibers (pCa(50) = 5.71 +/- 0.02 and 6.07 +/- 0.02 for NTG and TG fibers, respectively). We concluded that overall cross-bridge cycling kinetics are not altered by the R92Q mutation but that altered troponin-tropomyosin interactions could be responsible for the increase in myofilament Ca(2+) sensitivity in TG myofilaments.
authors.affiliation: Department of Physiology and Biophysics and Cardiovascular Sciences Program, College of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
authors.forename: M
authors.initials: M
authors.lastname: Chandra
authors.forename: V L
authors.initials: VL
authors.lastname: Rundell
authors.forename: J C
authors.initials: JC
authors.lastname: Tardiff
authors.forename: L A
authors.initials: LA
authors.lastname: Leinwand
authors.forename: P P
authors.initials: PP
authors.lastname: De Tombe
authors.forename: R J
authors.initials: RJ
authors.lastname: Solaro
mesh_terms: D000138:Acidosis / Q000503:physiopathology; D008841:Actin Cytoskeleton / Q000378:metabolism*; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism* / Q000494:pharmacology; D003432:Cross-Linking Reagents / Q000378:metabolism; D003902:Detergents; D016259:Genes, myc / Q000235:genetics; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000502:physiology*; D009154:Mutation / Q000502:physiology; D011401:Promoter Regions, Genetic / Q000502:physiology; D020107:Troponin T / Q000235:genetics* / Q000378:metabolism*
chemical_list: D003432:Cross-Linking Reagents; D003902:Detergents; D020107:Troponin T; D000255:Adenosine Triphosphate; D002118:Calcium