Moreover, adeno-associated virus-mediated exogenous expression of several MTMR2 isoforms ameliorates the myopathic phenotype owing to MTM1 loss, with increased muscle force, reduced myofiber atrophy, and reduction of the intracellular disorganization hallmarks associated with myotubular myopathy.
These results indicate that strategies aiming at increasing MTMR2 expression levels in skeletal muscle may be beneficial in the treatment of myotubular myopathy.
X-linked recessive myotubular myopathy is associated with overexpression of vimentin and desmin, fetal intermediate filaments that attach to nuclear, mitochondrial, and inner sarcolemmal membranes and Z-bands of sarcomeres to preserve the morphologic organization of the myotube.
X-linked recessive myotubular myopathy is associated with overexpression of vimentin and desmin, fetal intermediate filaments that attach to nuclear, mitochondrial, and inner sarcolemmal membranes and Z-bands of sarcomeres to preserve the morphologic organization of the myotube.
Finally, we identify abnormalities in the tubulo-reticular network in muscle from myotubularin zebrafish morphants and correlate these changes with abnormalities in T-tubule organization in biopsies from patients with myotubular myopathy.
Skeletal muscle deficiency in the 3-phosphoinositide (PtdInsP) phosphatase myotubularin (MTM1) causes myotubular myopathy which is associated with severe depression of voltage-activated sarcoplasmic reticulum Ca<sup>2+</sup> release through ryanodine receptors.
This finding suggests that at least some unresolved cases of myotubular myopathy are due to duplications in MTM1, and that array-CGH should be considered when MTM1 sequencing is unrevealing.
These data demonstrate for the first time a role for MTM1 in the production of PtdIns(5)P in mammalian cells, suggesting that the lack of transformation of phosphatidylinositol 3,5-bisphosphate into PtdIns(5)P might be an important component in the etiology of myotubular myopathy.
Moreover, adeno-associated virus-mediated exogenous expression of several MTMR2 isoforms ameliorates the myopathic phenotype owing to MTM1 loss, with increased muscle force, reduced myofiber atrophy, and reduction of the intracellular disorganization hallmarks associated with myotubular myopathy.
Myotubularin, the gene mutated in myotubular myopathy, functions as a lipid phosphatase with specificity for PtdIns(3)P. It is now apparent that there is an increasing family of proteins that are defined by their significant homology with myotubularin.
This work highlights an important physiological function of catalytically inactive phosphatases in the pathophysiology of myotubular myopathy and suggests a novel therapeutic approach through identification of drugs that could stabilize the myotubularin-MTMR12 complex and hence ameliorate this disorder.