18434328

pubmed:Citation

14

Myotubular myopathy (XLMTM, OMIM 310400) is a severe congenital muscular disease due to mutations in the myotubularin gene (MTM1) and characterized by the presence of small myofibers with frequent occurrence of central nuclei. Myotubularin is a ubiquitously expressed phosphoinositide phosphatase with a muscle-specific role in man and mouse that is poorly understood. No specific treatment exists to date for patients with myotubular myopathy. We have constructed an adeno-associated virus (AAV) vector expressing myotubularin in order to test its therapeutic potential in a XLMTM mouse model. We show that a single intramuscular injection of this vector in symptomatic Mtm1-deficient mice ameliorates the pathological phenotype in the targeted muscle. Myotubularin replacement in mice largely corrects nuclei and mitochondria positioning in myofibers and leads to a strong increase in muscle volume and recovery of the contractile force. In addition, we used this AAV vector to overexpress myotubularin in wild-type skeletal muscle and get insight into its localization and function. We show that a substantial proportion of myotubularin associates with the sarcolemma and I band, including triads. Myotubularin overexpression in muscle induces the accumulation of packed membrane saccules and presence of vacuoles that contain markers of sarcolemma and T-tubules, suggesting that myotubularin is involved in plasma membrane homeostasis of myofibers. This study provides a proof-of-principle that local delivery of an AAV vector expressing myotubularin can improve the motor capacities of XLMTM muscle and represents a novel approach to study myotubularin function in skeletal muscle.

http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-10417791, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-10790201, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-10802647, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-11001925, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-11175789, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-11259414, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-11302699, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-11595516, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-11711432, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-12118066, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-12183633, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-12467749, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-12554688, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-12707983, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-12890864, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-12925573, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-14500759, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-14722070, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-15528407, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-15731758, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-15735640, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-16042307, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-16103356, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-16227997, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-16361117, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-16501048, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-16787938, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-16824801, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-16828287, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-17164775, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-17376604, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-17426713, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-17537630, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-17636067, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-17651088, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-17932957, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-2357647, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-8544184, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-8640223, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-9008709, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-9499080, http://linkedlifedata.com/resource/pubmed/commentcorrection/18434328-9931531

http://linkedlifedata.com/resource/pubmed/journal/9208958

http://linkedlifedata.com/resource/pubmed/chemical/Protein Tyrosine Phosphatases..., http://linkedlifedata.com/resource/pubmed/chemical/myotubularin

Jul

pubmed-author:BeggsAlan HAH, pubmed-author:Buj-BelloAnnaA, pubmed-author:DanosOlivierO, pubmed-author:DenèflePatriceP, pubmed-author:DouarAnne-MarieAM, pubmed-author:DurandMurielM, pubmed-author:FougerousseFrançoiseF, pubmed-author:KretzChristineC, pubmed-author:MandelJean-LouisJL, pubmed-author:MessaddeqNadiaN, pubmed-author:MontusMarieM, pubmed-author:PiersonChristopher RCR, pubmed-author:SchultzPatrickP, pubmed-author:SchwabYannickY, pubmed-author:SpehnerDanièleD

15

NLM

2132-43

pubmed-meshheading:18434328-Animals, pubmed-meshheading:18434328-Mice, pubmed-meshheading:18434328-Homeostasis, pubmed-meshheading:18434328-Injections, Intramuscular, pubmed-meshheading:18434328-Female, pubmed-meshheading:18434328-Male