Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue Hum Mol Genet Année : 2013

Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy

M. W. Lawlor
  • Fonction : Auteur
D. Armstrong
  • Fonction : Auteur
M. G. Viola
  • Fonction : Auteur
J. J. Widrick
  • Fonction : Auteur
H. Meng
  • Fonction : Auteur
R. W. Grange
  • Fonction : Auteur
M. K. Childers
  • Fonction : Auteur
C. P. Hsu
  • Fonction : Auteur
M. O'Callaghan
  • Fonction : Auteur
C. R. Pierson
  • Fonction : Auteur
A. H. Beggs
  • Fonction : Auteur

Résumé

No effective treatment exists for patients with X-linked myotubular myopathy (XLMTM), a fatal congenital muscle disease caused by deficiency of the lipid phosphatase, myotubularin. The Mtm1delta4 and Mtm1 p.R69C mice model severely and moderately symptomatic XLMTM, respectively, due to differences in the degree of myotubularin deficiency. Contractile function of intact extensor digitorum longus (EDL) and soleus muscles from Mtm1delta4 mice, which produce no myotubularin, is markedly impaired. Contractile forces generated by chemically skinned single fiber preparations from Mtm1delta4 muscle were largely preserved, indicating that weakness was largely due to impaired excitation contraction coupling. Mtm1 p.R69C mice, which produce small amounts of myotubularin, showed impaired contractile function only in EDL muscles. Short-term replacement of myotubularin with a prototypical targeted protein replacement agent (3E10Fv-MTM1) in Mtm1delta4 mice improved contractile function and muscle pathology. These promising findings suggest that even low levels of myotubularin protein replacement can improve the muscle weakness and reverse the pathology that characterizes XLMTM.

Dates et versions

hal-02881184 , version 1 (25-06-2020)

Identifiants

Citer

M. W. Lawlor, D. Armstrong, M. G. Viola, J. J. Widrick, H. Meng, et al.. Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy. Hum Mol Genet, 2013, 22 (8), pp.1525-38. ⟨10.1093/hmg/ddt003⟩. ⟨hal-02881184⟩
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