title: Enzyme replacement therapy rescues weakness and improves muscle pathology in mice with X-linked myotubular myopathy.
abstract: 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.
authors: Division of Genetics and Program in Genomics, The Manton Center for Orphan Disease Research, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA.
authors: Michael W
authors: MW
authors: Lawlor
authors: Dustin
authors: D
authors: Armstrong
authors: Marissa G
authors: MG
authors: Viola
authors: Jeffrey J
authors: JJ
authors: Widrick
authors: Hui
authors: H
authors: Meng
authors: Robert W
authors: RW
authors: Grange
authors: Martin K
authors: MK
authors: Childers
authors: Cynthia P
authors: CP
authors: Hsu
authors: Michael
authors: M
authors: O'Callaghan
authors: Christopher R
authors: CR
authors: Pierson
authors: Anna
authors: A
authors: Buj-Bello
authors: Alan H
authors: AH
authors: Beggs
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D056947:Enzyme Replacement Therapy; D005221:Fatigue / Q000378:metabolism / Q000503:physiopathology; D005260:Female; D006801:Humans; D051379:Mice; D018908:Muscle Weakness / Q000235:genetics / Q000628:therapy; D018482:Muscle, Skeletal / Q000503:physiopathology; D009132:Muscles / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D020914:Myopathies, Structural, Congenital / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000628:therapy*; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000096:biosynthesis / Q000172:deficiency / Q000235:genetics*
chemical_list: D054558:Protein Tyrosine Phosphatases, Non-Receptor; C099588:myotubularin