Résumé :
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Facioscapulohumeral muscular dystrophy (FSHD) is an inherited neuromuscular disorder affecting a characteristic pattern of muscles. The physiopathological mechanism has not been elucidated yet, but relies on the deletion of the D4Z4 repeat in the 4q subtelomeric region thus affecting expression of a panel of genes in FSHD patients. Indeed most studies focus on determining which genes are involved in FSHD disease and suggest implication of genes controling proliferation, differentiation and cell cycle progression. Besides, FSHD myoblasts present a proliferation defect in vitro. Aiming at better characterize this proliferation defect, we investigated in the present study the progression of FSHD myoblasts through the cell cycle. After cell synchronization, these myoblasts abnormally accumulated in the G0/G1 phase compared to control myoblasts. We revealed that this G0/G1 block in FSHD myoblasts results from the decreased CDK4 and CDK2 activities and, consequently, altered Rb phosphorylation state. In addition, expression of the cyclin-dependent kinase (CDK) inhibitors p21 and p57 are affected in FSHD myoblasts in comparison to control myoblasts: p21 is up-regulated during all the cell cycle phases and in contrast p57 is drastically diminished. Moreover, concerning the expression of p53 and MyoD, key proteins controling cell cycle progression, we found up-regulation of p53 and stabilized level of MyoD during the S phase in patient myoblasts compared to control myoblasts. Finally, focusing on the consequences of the p53 overexpression on FSHD myoblasts fate, we demonstrated that patient myoblasts are not apoptotic or necrotic, but enter an early senescent state. Altogether our data provide further insights in the physiopathology of FSHD disease, showing that dysregulation of several regulators involved in cell cycle control are responsible, after onset of engagement in the pathogenic mechanism of the disease, for withdrawal of FSHD myoblasts from the cell cycle and that these myoblasts are prematurely senescent.
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