The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Proceedings of the National Academy of Sciences of the United States of America Année : 2002

The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice

Anna Buj-Bello
Vincent Laugel
  • Fonction : Auteur
Nadia Messaddeq
  • Fonction : Auteur
Hala Zahreddine
  • Fonction : Auteur
Jocelyn Laporte
  • Fonction : Auteur
Jean-François Pellissier
  • Fonction : Auteur
Jean-Louis Mandel
  • Fonction : Auteur

Résumé

Myotubularin is a ubiquitously expressed phosphatase that acts on phosphatidylinositol 3-monophosphate [PI(3)P], a lipid implicated in intracellular vesicle trafficking and autophagy. It is encoded by the MTM1 gene, which is mutated in X-linked myotubular myopathy (XLMTM), a muscular disorder characterized by generalized hypotonia and muscle weakness at birth leading to early death of most affected males. The disease was proposed to result from an arrest in myogenesis, as the skeletal muscle from patients contains hypotrophic fibers with centrally located nuclei that resemble fetal myotubes. To understand the physiopathological mechanism of XLMTM, we have generated mice lacking myotubularin by homologous recombination. These mice are viable, but their lifespan is severely reduced. They develop a generalized and progressive myopathy starting at around 4 weeks of age, with amyotrophy and accumulation of central nuclei in skeletal muscle fibers leading to death at 6–14 weeks. Contrary to expectations, we show that muscle differentiation in knockout mice occurs normally. We provide evidence that fibers with centralized myonuclei originate mainly from a structural maintenance defect affecting myotubularin-deficient muscle rather than a regenerative process. In addition, we demonstrate, through a conditional gene-targeting approach, that skeletal muscle is the primary target of murine XLMTM pathology. These mutant mice represent animal models for the human disease and will be a valuable tool for understanding the physiological role of myotubularin.

Dates et versions

hal-04481797 , version 1 (28-02-2024)

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Citer

Anna Buj-Bello, Vincent Laugel, Nadia Messaddeq, Hala Zahreddine, Jocelyn Laporte, et al.. The lipid phosphatase myotubularin is essential for skeletal muscle maintenance but not for myogenesis in mice. Proceedings of the National Academy of Sciences of the United States of America, 2002, 99 (23), pp.15060-15065. ⟨10.1073/pnas.212498399⟩. ⟨hal-04481797⟩
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