Titre :
|
Mouse model of LMNA-congenital muscular dystrophy show severe skeletal and cardiac muscle maturation defects associated with major metabolic defects leading to early death : Acte de colloque : 4ème colloque international de Myologie (9-13 mai 2011; Lille (France))
|
contenu dans :
|
|
Auteurs :
|
Renou L ;
Papadopoulos A ;
Beuvin M ;
Lacene E ;
Arimura T ;
Gruenbaum Y ;
Bonne G
|
Type de document :
|
Article
|
Editeur :
|
AFM-TELETHON, 2011
|
Pages :
|
p. 12
|
Langues:
|
Anglais
|
Mots-clés :
|
colloque
;
dystrophie musculaire congénitale
;
épidémiologie
;
facteur de transcription
;
gène LMNA
;
hypoglycémie
;
modèle animal
;
muscle squelettique
;
régulation métabolique
;
tissu adipeux
|
Résumé :
|
LMNA gene encodes for lamins A/C, ubiquitous proteins of the nuclear envelope in post-mitotic cells. Lamin A/C are thought to have structural but also essential regulatory roles in various signalization pathways by interactions with transcription factors such as Sterol Regulatory Element Binding Protein 1 (SREBP-1). LMNA mutations are responsible for more than 10 different disorders affecting various tissues in isolated or systemic fashion. Among those the LMNA-related congenital muscular dystrophy (L-CMD) is characterized by early onset of muscle weakness and joins contractures. To get insight on the disease pathophysiology, we reproduce in mice the Lmna Lys32 deletion found in L-CMD patients.Homozygous mice are born with expected Mendelian ratios but shortly after birth developed general growth retardation and died within the 2nd week of life with severe hypoglycemia. This is associated with a 80% decrease of mutated lamins A/C expression, despite normal mRNA levels. In vitro formation of lamin filaments of C elegans homologous mutant revealed altered dimerization of mutant lamins. Analysis of mouse organs revealed a maturation defect of skeletal and cardiac muscle but also of organs involved in the lipid and glucose storage and release (pancreas, white adipose tissue). Considering the involvement of SREBP-1 in the maturation of white adipose tissue and pancreas and its role in glucose release from glycogen storage in the liver, we checked the activation of this pathway and the expression of its target genes in affected tissues. Our data showed an upregulation of mature SREBP-1 in liver. Mature SREBP-1 and mutated lamins A/C were essentially aggregated in the nucleoplasm.Thus the deletion of Lys32 localized in the dimerization domain, destabilizes the mutated proteins that are partly degraded. Decreased protein level plus abnormally dimerized lamin A/C may modify the multiple lamin A/C interactions with as consequence abnormal SREBP-1 signaling inducing major metabolic defects leading to mouse death.
|