Dystrophin- and MLP-deficient mouse hearts: marked differences in morphology and function, but similar accumulation of cytoskeletal proteins.
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 beta-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.
Wilding
James R
JR
Department of Physiology, University of Oxford, Oxford, England, UK.
Schneider
Jürgen E
JE
Sang
A Elizabeth
AE
Davies
Kay E
KE
Neubauer
Stefan
S
Clarke
Kieran
K
D000818:Animals; D001342:Autonomic Nervous System Diseases / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D009202:Cardiomyopathies / Q000473:pathology; D003598:Cytoskeletal Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D016189:Dystrophin / Q000172:deficiency* / Q000502:physiology; D004562:Electrocardiography / Q000379:methods; D005355:Fibrosis / Q000235:genetics / Q000517:prevention & control; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology; D006321:Heart / Q000033:anatomy & histology* / Q000502:physiology*; D060588:LIM Domain Proteins; D008264:Macrophages / Q000378:metabolism; D019028:Magnetic Resonance Imaging, Cine / Q000379:methods; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D009124:Muscle Proteins / Q000172:deficiency* / Q000502:physiology; D009205:Myocarditis / Q000209:etiology / Q000235:genetics / Q000517:prevention & control; D009206:Myocardium / Q000737:chemistry* / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000235:genetics; D009569:Nitric Oxide / Q000096:biosynthesis / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000235:genetics; D052248:Nitric Oxide Synthase Type I; D019076:Transgenes / Q000235:genetics
D003598:Cytoskeletal Proteins; D016189:Dystrophin; D060588:LIM Domain Proteins; D009124:Muscle Proteins; D009419:Nerve Tissue Proteins; C090114:cysteine and glycine-rich protein 3; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; C496321:Nos1 protein, mouse