R-92L and R-92W mutations in cardiac troponin T lead to distinct energetic phenotypes in intact mouse hearts.
It is now known that the flexibility of the troponin T (TnT) tail determines thin filament conformation and hence cross-bridge cycling properties, expanding the classic structural role of TnT to a dynamic role regulating sarcomere function. Here, using transgenic mice bearing R-92W and R-92L missense mutations in cardiac TnT known to alter the flexibility of the TnT tropomyosin-binding domain, we found mutation-specific differences in the cost of contraction at the whole heart level. Compared to age- and gender-matched sibling hearts, mutant hearts demonstrate greater ATP utilization measured using (31)P NMR spectroscopy as decreases in [ATP] and [PCr] and |DeltaG(~ATP)| at all workloads and profound systolic and diastolic dysfunction at all energetic states. R-92W hearts showed more severe energetic abnormalities and greater contractile dysfunction than R-92L hearts. The cost of increasing contraction was abnormally high when [Ca(2+)] was used to increase work in mutant hearts but was normalized with supply of the beta-adrenergic agonist dobutamine. These results show that R-92L and R-92W mutations in the TM-binding domain of cardiac TnT alter thin filament structure and flexibility sufficiently to cause severe defects in both whole heart energetics and contractile performance, and that the magnitude of these changes is mutation specific.
He
Huamei
H
NMR Laboratory for Physiological Chemistry, Division of Cardiovascular Medicine, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Javadpour
Maryam M
MM
Latif
Farhana
F
Tardiff
Jil C
JC
Ingwall
Joanne S
JS
D000255:Adenosine Triphosphate / Q000737:chemistry / Q000378:metabolism; D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000818:Animals; D004280:Dobutamine / Q000494:pharmacology; D006321:Heart / Q000502:physiology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D051379:Mice; D009154:Mutation; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism; D010641:Phenotype; D012518:Sarcomeres / Q000378:metabolism; D013816:Thermodynamics; D020107:Troponin T / Q000235:genetics* / Q000502:physiology*
D000318:Adrenergic beta-Agonists; D020107:Troponin T; D004280:Dobutamine; D000255:Adenosine Triphosphate