Manipulation of the mouse genome by site-specific mutagenesis has been 
extensively used to study gene function and model human disorders. Mouse models 
of myotubular myopathy (XLMTM), a severe congenital muscular disorder due to 
loss-of-function mutations in the MTM1 gene, have been generated by homologous 
recombination and shown that myotubularin is essential for skeletal muscle. 
However, since the Mtm1 deletion occurred constitutively or shortly after birth 
in these mice, it is not known whether myotubularin is required during 
adulthood, an important issue in the context of not only muscle biology but also 
therapies. To delete the Mtm1 gene in adult muscle fibers, we constructed a 
recombinant adeno-associated vector (AAV) that expresses the Cre recombinase 
under the muscle-specific desmin promoter. We report that a single injection of 
this vector into muscles of 3-month-old Mtm1 conditional mice leads to a 
myotubular myopathy phenotype with myofiber atrophy, disorganization of 
organelle positioning, such as mitochondria and nuclei, T-tubule defects and 
severe muscle weakness. In addition, our results show that MTM1-related atrophy 
and dysfunction correlate with abnormalities in satellite cell number and 
markers of autophagy, protein synthesis and neuromuscular junction transmission. 
The expression level of atrogenes was also analyzed. Therefore, we provide a 
valuable tissue model that recapitulates the main features of the disease, and 
it is useful to study pathogenesis and evaluate therapeutic strategies. We 
establish the proof-of-concept that myotubularin is required for the proper 
function of skeletal muscle during adulthood, suggesting that therapies will be 
required for the entire life of XLMTM patients.