MLP-deficient mice exhibit a disruption of cardiac cytoarchitectural organization, dilated cardiomyopathy, and heart failure.
MLP is a LIM-only protein of terminally differentiated striated muscle cells, where it accumulates at actin-based structures involved in cytoarchitecture organization. To assess its role in muscle differentiation, we disrupted the MLP gene in mice. MLP (-/-) mice developed dilated cardiomyopathy with hypertrophy and heart failure after birth. Ultrastructural analysis revealed dramatic disruption of cardiomyocyte cytoarchitecture. At birth, these hearts were not hypertrophic, but already abnormally soft, with cell-autonomous and MLP-sensitive alterations in cytoarchitecture. Thus, MLP promotes proper cardiomyocyte cytoarchitecture, whose perturbation can lead to dilated cardiomyopathy. In vivo analysis revealed that MLP-deficient mice reproduce the morphological and clinical picture of dilated cardiomyopathy and heart failure in humans, providing the first model for this condition in a genetically manipulatable organism.
Arber
S
S
Friedrich Miescher Institute, Basel, Switzerland.
Hunter
J J
JJ
Ross
J
J
Hongo
M
M
Sansig
G
G
Borg
J
J
Perriard
J C
JC
Chien
K R
KR
Caroni
P
P
D000818:Animals; D006332:Cardiomegaly / Q000209:etiology / Q000235:genetics / Q000473:pathology; D002311:Cardiomyopathy, Dilated / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility; D006801:Humans; D060588:LIM Domain Proteins; D051379:Mice; D018345:Mice, Knockout; D009124:Muscle Proteins / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D009210:Myofibrils / Q000378:metabolism; D010641:Phenotype
D060588:LIM Domain Proteins; D009124:Muscle Proteins; C090114:cysteine and glycine-rich protein 3