Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy. Hum Mol Genet 2013 Apr 15;22(8):1525-38
Date
01/12/2013Pubmed ID
23307925Pubmed Central ID
PMC3605830DOI
10.1093/hmg/ddt003Scopus ID
2-s2.0-84875766052 (requires institutional sign-in at Scopus site) 69 CitationsAbstract
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 Mtm1δ4 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 Mtm1δ4 mice, which produce no myotubularin, is markedly impaired. Contractile forces generated by chemically skinned single fiber preparations from Mtm1δ4 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 Mtm1δ4 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.
Author List
Lawlor MW, Armstrong D, Viola MG, Widrick JJ, Meng H, Grange RW, Childers MK, Hsu CP, O'Callaghan M, Pierson CR, Buj-Bello A, Beggs AHAuthor
Michael W. Lawlor MD, PhD Adjunct Professor in the Pathology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsDisease Models, Animal
Enzyme Replacement Therapy
Fatigue
Female
Humans
Mice
Muscle Weakness
Muscle, Skeletal
Muscles
Myopathies, Structural, Congenital
Protein Tyrosine Phosphatases, Non-Receptor
