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Dystrophin‐ and MLP‐deficient mouse hearts: marked differences in morphology and function, but similar accumulation of cytoskeletal proteins
Author(s) -
Wilding James R.,
Schneider Jürgen E.,
Sang A. Elizabeth,
Davies Kay E.,
Neubauer Stefan,
Clarke Kieran
Publication year - 2005
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.04-1731fje
Subject(s) - dystrophin , utrophin , desmin , medicine , dilated cardiomyopathy , heart failure , ejection fraction , cardiomyopathy , endocrinology , cytoskeleton , cardiology , biology , duchenne muscular dystrophy , chemistry , vimentin , immunohistochemistry , genetics , cell
In humans, cytoskeletal dystrophin and muscle LIM protein (MLP) gene mutations can cause dilated cardiomyopathy, yet these mutations may have different effects in mice, owing to increased accumulation of other, compensatory cytoskeletal proteins. Consequently, we characterized left‐ventricular (LV) morphology and function in vivo using high‐resolution cine‐ magnetic resonance imaging (MRI) in 2‐ to 3‐month old dystrophin‐deficient ( mdx ) and MLP‐ null mice, and their respective controls. LV passive stiffness was assessed in isolated, perfused hearts, and cytoskeletal protein levels were determined using Western blot analyses. In mdx mouse hearts, LV‐to‐body weight ratio, cavity volume, ejection fraction, stroke volume, and cardiac output were normal. However, MLP‐null mouse hearts had 1.2‐fold higher LV‐to‐body weight ratios ( P <0.01), 1.5‐fold higher end‐diastolic volumes ( P <0.01), and decreased ejection fraction compared with controls (25% vs. 66%, respectively, P <0.01), indicating dilated cardiomyopathy and heart failure. In both models, isolated, perfused heart end‐diastolic pressure–volume relationships and passive left‐ventricular stiffness were normal. Hearts from both models accumulated desmin and β‐tubulin, mdx mouse hearts accumulated utrophin and MLP, and MLP‐null mouse hearts accumulated dystrophin and syncoilin. Although the increase in MLP and utrophin in the mdx mouse heart was able to compensate for the loss of dystrophin, accumulation of desmin, syncoilin and dystrophin were unable to compensate for the loss of MLP, resulting in heart failure.