[HTML][HTML] Phosphatase-dead myotubularin ameliorates X-linked centronuclear myopathy phenotypes in mice

L Amoasii, DL Bertazzi, H Tronchère, K Hnia… - 2012 - journals.plos.org
L Amoasii, DL Bertazzi, H Tronchère, K Hnia, G Chicanne, B Rinaldi, BS Cowling, A Ferry
2012journals.plos.org
Myotubularin MTM1 is a phosphoinositide (PPIn) 3-phosphatase mutated in X-linked
centronuclear myopathy (XLCNM; myotubular myopathy). We investigated the involvement
of MTM1 enzymatic activity on XLCNM phenotypes. Exogenous expression of human MTM1
in yeast resulted in vacuolar enlargement, as a consequence of its phosphatase activity.
Expression of mutants from patients with different clinical progression and determination of
PtdIns3 P and PtdIns5 P cellular levels confirmed the link between vacuolar morphology and …
Myotubularin MTM1 is a phosphoinositide (PPIn) 3-phosphatase mutated in X-linked centronuclear myopathy (XLCNM; myotubular myopathy). We investigated the involvement of MTM1 enzymatic activity on XLCNM phenotypes. Exogenous expression of human MTM1 in yeast resulted in vacuolar enlargement, as a consequence of its phosphatase activity. Expression of mutants from patients with different clinical progression and determination of PtdIns3P and PtdIns5P cellular levels confirmed the link between vacuolar morphology and MTM1 phosphatase activity, and showed that some disease mutants retain phosphatase activity. Viral gene transfer of phosphatase-dead myotubularin mutants (MTM1C375S and MTM1S376N) significantly improved most histological signs of XLCNM displayed by a Mtm1-null mouse, at similar levels as wild-type MTM1. Moreover, the MTM1C375S mutant improved muscle performance and restored the localization of nuclei, triad alignment, and the desmin intermediate filament network, while it did not normalize PtdIns3P levels, supporting phosphatase-independent roles of MTM1 in maintaining normal muscle performance and organelle positioning in skeletal muscle. Among the different XLCNM signs investigated, we identified only triad shape and fiber size distribution as being partially dependent on MTM1 phosphatase activity. In conclusion, this work uncovers MTM1 roles in the structural organization of muscle fibers that are independent of its enzymatic activity. This underlines that removal of enzymes should be used with care to conclude on the physiological importance of their activity.
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