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.