| 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.
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