F110I and R278C troponin T mutations that cause familial hypertrophic cardiomyopathy affect muscle contraction in transgenic mice and reconstituted human cardiac fibers.
We have studied the physiological effects of the troponin T (TnT) F110I and R278C mutations associated with familial hypertrophic cardiomyopathy (FHC) in humans. Three to four-month-old transgenic (Tg) mice expressing F110I-TnT and R278C-TnT did not develop significant hypertrophy or ventricular fibrosis even after chronic exercise challenge. The F110I mutation impaired acute exercise tolerance, whereas R278C did not. Skinned papillary muscle fibers from transgenic mice expressing F110I-TnT demonstrated increased Ca(2+) sensitivity of force and ATPase activity, and likewise an increased Ca(2+) sensitivity of force was observed in F110I-TnT-reconstituted human cardiac muscle preparations. In contrast, no changes in force or the ATPase-pCa dependencies were observed in transgenic R278C fibers or in human fibers reconstituted with the R278C-TnT mutant. The maximal level of force development was dramatically decreased in both transgenic mice. However, the maximal ATPase was not different (R278C-TnT) or only slightly less (F110I-TnT) than that of non-Tg and WT-Tg littermates. Consequently, their ratios of ATPase/force (energy cost) at all Ca(2+) concentrations were dramatically higher compared with non-Tg and WT-Tg fibers. This increase in energy cost most likely results from a decrease in force per myosin cross-bridge, because forcing all cross-bridges into the force generating state by substitution of MgADP for MgATP in maximum contracting solutions resulted in the same increase in maximal force (15%) in all transgenic and non-transgenic preparations. The combination of increased Ca(2+) sensitivity and energy cost in the F110I hearts may be responsible for the greater severity of this phenotype compared with the R278C mutation.
Hernandez
Olga M
OM
Department of Pharmacology, Georgetown University Medical Center, Washington, D. C. 20057, USA.
Szczesna-Cordary
Danuta
D
Knollmann
Björn C
BC
Miller
Todd
T
Bell
Michael
M
Zhao
Jiaju
J
Sirenko
Syevda G
SG
Diaz
Zoraida
Z
Guzman
Georgianna
G
Xu
Yuanyuan
Y
Wang
Ying
Y
Kerrick
W Glenn L
WG
Potter
James D
JD
D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000235:genetics*; D004719:Endomyocardial Fibrosis / Q000378:metabolism / Q000473:pathology; D015444:Exercise; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009119:Muscle Contraction / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D009154:Mutation / Q000235:genetics*; D009206:Myocardium / Q000378:metabolism*; D010641:Phenotype; D013550:Swimming; D020107:Troponin T / Q000235:genetics / Q000502:physiology*
D020107:Troponin T; D000255:Adenosine Triphosphate; D000251:Adenosine Triphosphatases; D002118:Calcium