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.