Computational simulation of hypertrophic cardiomyopathy mutations in troponin I: influence of increased myofilament calcium sensitivity on isometric force, ATPase and [Ca2+]i.
Familial hypertrophic cardiomyopathy (FHC) is an inherited disease that is characterized by ventricular hypertrophy, cardiac arrhythmias and increased risk of premature sudden death. FHC is caused by autosomal-dominant mutations in genes for a number of sarcomeric proteins; many mutations in Ca(2+)-regulatory proteins of the cardiac thin filament are associated with increased Ca(2+) sensitivity of myofilament function. Computational simulations were used to investigate the possibility that these mutations could affect the Ca(2+) transient and mechanical response of a myocyte during a single cardiac cycle. We used existing experimental data for specific mutations of cardiac troponin I that exhibit increased Ca(2+) sensitivity in physiological and biophysical assays. The simulated Ca(2+) transients were used as input for a three-dimensional half-sarcomere biomechanical model with filament compliance to predict the resulting force. Mutations with the highest Ca(2+) affinity (lowest K(m)) values, exhibit the largest decrease in peak Ca(2+) assuming a constant influx of Ca(2+) into the cytoplasm; they also prolong Ca(2+) removal but have little effect on diastolic Ca(2+). Biomechanical model results suggest that these cTnI mutants would increase peak force despite the decrease in peak [Ca(2+)](i). There is a corresponding increase in net ATP hydrolysis, with no change in tension cost (ATP hydrolyzed per unit of time-integrated tension). These simulations suggest that myofilament-initiated hypertrophic signaling could be associated with decreased [Ca(2+)](i), increased stress/strain, and/or increased ATP flux.
Kataoka
Aya
A
Department of Biological Science, Florida State University, Tallahassee, FL 32306, USA.
Hemmer
Carolyn
C
Chase
P Bryant
PB
D008841:Actin Cytoskeleton / Q000201:enzymology / Q000378:metabolism*; D000251:Adenosine Triphosphatases / Q000378:metabolism*; D001696:Biomechanical Phenomena; D002118:Calcium / Q000378:metabolism* / Q000502:physiology; D024741:Cardiomyopathy, Hypertrophic, Familial / Q000201:enzymology / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D003198:Computer Simulation; D006801:Humans; D008954:Models, Biological; D009200:Myocardial Contraction / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics; D019210:Troponin I / Q000235:genetics* / Q000502:physiology
D019210:Troponin I; D000251:Adenosine Triphosphatases; D002118:Calcium