Ca2+-independent alterations in diastolic sarcomere length and relaxation
kinetics in a mouse model of lipotoxic diabetic cardiomyopathy.
Authors Flagg TP, Cazorla O, Remedi MS, Haim TE, Tones MA, Bahinski A, Numann RE, Kovacs
A, Schaffer JE, Nichols CG, Nerbonne JM
Submitted By Jean Schaffer on 3/31/2010
Status Published
Journal Circulation research
Year 2009
Date Published 1/2/2009
Volume : Pages 104 : 95 - 103
PubMed Reference 19023131
Abstract Previous studies demonstrated increased fatty acid uptake and metabolism in
MHC-FATP transgenic mice that overexpress fatty acid transport protein (FATP)1
in the heart under the control of the alpha-myosin heavy chain (alpha-MHC)
promoter. Doppler tissue imaging and hemodynamic measurements revealed diastolic
dysfunction, in the absence of changes in systolic function. The experiments
here directly test the hypothesis that the diastolic dysfunction in MHC-FATP
mice reflects impaired ventricular myocyte contractile function. In vitro
imaging of isolated adult MHC-FATP ventricular myocytes revealed that mean
diastolic sarcomere length is significantly (P<0.01) shorter than in wild-type
(WT) cells (1.79+/-0.01 versus 1.84+/-0.01 microm). In addition, the relaxation
rate (dL/dt) is significantly (P<0.05) slower in MHC-FATP than WT myocytes
(1.58+/-0.09 versus 1.92+/-0.13 microm/s), whereas both fractional shortening
and contraction rates are not different. Application of 40 mmol/L
2,3-butadionemonoxime (a nonspecific ATPase inhibitor that relaxes actin-myosin
interactions) increased diastolic sarcomere length in both WT and MHC-FATP
myocytes to the same length, suggesting that MHC-FATP myocytes are partially
activated at rest. Direct measurements of intracellular Ca(2+) revealed that
diastolic [Ca(2+)](i) is unchanged in MHC-FATP myocytes and the rate of calcium
removal is unexpectedly faster in MHC-FATP than WT myocytes. Moreover, diastolic
sarcomere length in MHC-FATP and WT myocytes was unaffected by removal of
extracellular Ca(2+) or by buffering of intracellular Ca(2+) with the Ca(2+)
chelator BAPTA (100 micromol/L), indicating that elevated intracellular Ca(2+)
does not underlie impaired diastolic function in MHC-FATP ventricular myocytes.
Functional assessment of skinned myocytes, however, revealed that myofilament
Ca(2+) sensitivity is markedly increased in MHC-FATP, compared with WT,
ventricular cells. In addition, biochemical experiments demonstrated increased
expression of the beta-MHC isoform in MHC-FATP, compared with WT ventricles,
which likely contributes to the slower relaxation rate observed in MHC-FATP
myocytes. Collectively, these data demonstrate that derangements in lipid
metabolism in MHC-FATP ventricles, which are similar to those observed in the
diabetic heart, result in impaired diastolic function that primarily reflects
changes in myofilament function, rather than altered Ca(2+) cycling.

Investigators with authorship
Jean SchafferWashington University in St Louis


Dnahc8dynein, axon, heavy chain 8
Pax1paired box gene 1