Young MLP deficient mice show diastolic dysfunction before the onset of dilated cardiomyopathy.
Targeted deletion of cytoskeletal muscle LIM protein (MLP) in mice consistently leads to dilated cardiomyopathy (DCM) after one or more months. However, next to nothing is known at present about the mechanisms of this process. We investigated whether diastolic performance including passive mechanics and systolic behavior are altered in 2-week-old MLP knockout (MLPKO) mice, in which heart size, fractional shortening and ejection fraction are still normal. Right ventricular trabeculae were isolated from 2-week-old MLPKO and wildtype mice and placed in an apparatus that allowed force measurements and sarcomere length measurements using laser diffraction. During a twitch from the unloaded state at 1 Hz, MLPKO muscles relengthened to slack length more slowly than controls, although the corresponding force relaxation time was unchanged. Active developed stress at a diastolic sarcomere length of 2.00 microm was preserved in MLPKO trabeculae over a wide range of pacing frequencies. Force relaxation under the same conditions was consistently prolonged compared with wildtype controls, whereas time to peak and maximum rate of force generation were not significantly altered. Ca2+ content of the sarcoplasmic reticulum (SR) and the quantities of Ca2+ handling proteins were similar in both genotypes. In summary, young MLPKO mice revealed substantial alterations in passive myocardial properties and relaxation time, but not in most systolic characteristics. These results indicate that the progression to heart failure in the MLPKO model may be driven by diastolic myocardial dysfunction and abnormal passive properties rather than systolic dysfunction.
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093-0412, USA.
Ilka
I
Lorenzen-Schmidt
Bruno D
BD
Stuyvers
Henk E D J
HE
ter Keurs
Moto-o
MO
Date
Masahiko
M
Hoshijima
Kenneth R
KR
Chien
Andrew D
AD
McCulloch
Jeffrey H
JH
Omens
D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000503:physiopathology*; D003971:Diastole / Q000502:physiology*; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D012518:Sarcomeres / Q000502:physiology; D013599:Systole / Q000502:physiology
D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3