Massana-Muñoz, Xènia;
Goret, Marie;
Nattarayan, Vasugi;
Reiss, David;
Kretz, Christine;
Chicanne, Gaetan;
Payrastre, Bernard;
... Laporte, Jocelyn; + view all
(2023)
Inactivating the lipid kinase activity of PI3KC2β is sufficient to rescue myotubular myopathy in mice.
JCI Insight
, 8
(9)
, Article e151933. 10.1172/jci.insight.151933.
Preview |
PDF
151933.2-20230410120624-covered-e0fd13ba177f913fd3156f593ead4cfd.pdf - Published Version Download (21MB) | Preview |
Abstract
Phosphoinositides (PI) are membrane lipids that regulate signal transduction and vesicular trafficking. X-linked centronuclear myopathy (XLCNM), also called myotubular myopathy, results from loss-of-function mutations in the Mtm1 gene, which encodes the myotubularin phosphatidylinositol 3-phosphate (PtdIns3P) lipid phosphatase. No therapy for this disease is currently available. Previous studies showed that loss of expression of the class II phosphoinositide 3-kinase (PI3K) PI3K-C2β protein improved the phenotypes of a XLCNM mouse model. PI3Ks are well known to have extensive scaffolding functions and the importance of the catalytic activity of this PI3K for rescue remains unclear. Here, using PI3K-C2β kinase-dead mice, we show that the selective inactivation of PI3K-C2β kinase activity is sufficient to fully prevent muscle atrophy and weakness, histopathology, and sarcomere and triad disorganization in Mtm1 knockout mice. This rescue correlates with normalization of PtdIns3P level and mTORC1 activity, a key regulator of protein synthesis and autophagy. Conversely, lack of PI3K-C2β kinase activity did not rescue the histopathology of the BIN1 autosomal centronuclear myopathy mouse model. Overall, these findings support the development of specific PI3K-C2β kinase inhibitors to cure myotubular myopathy.
| Type: | Article |
|---|---|
| Title: | Inactivating the lipid kinase activity of PI3KC2β is sufficient to rescue myotubular myopathy in mice |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1172/jci.insight.151933 |
| Publisher version: | http://doi.org/10.1172/jci.insight.151933 |
| Language: | English |
| Additional information: | © 2023, Massana-Muñoz et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/). |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10169878 |
Archive Staff Only
 |
View Item |
