| First Author | Massana-Muñoz X | Year | 2023 |
| Journal | JCI Insight | Volume | 8 |
| Issue | 9 | PubMed ID | 36943412 |
| Mgi Jnum | J:341022 | Mgi Id | MGI:7489068 |
| Doi | 10.1172/jci.insight.151933 | Citation | Massana-Munoz X, et al. (2023) Inactivating the lipid kinase activity of PI3KC2beta is sufficient to rescue myotubular myopathy in mice. JCI Insight 8(9) |
| abstractText | Phosphoinositides (PIs) 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) PI3KC2beta (PI3KC2B) protein improved the phenotypes of an 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 PI3KC2beta kinase-dead mice, we show that the selective inactivation of PI3KC2beta 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 PI3KC2beta kinase activity did not rescue the histopathology of the BIN1 autosomal CNM mouse model. Overall, these findings support the development of specific PI3KC2beta kinase inhibitors to cure myotubular myopathy. |
