Antagonistic control of active surface integrins by myotubularin and phosphatidylinositol 3-kinase C2β in a myotubular myopathy model

Abstract

X-linked centronuclear myopathy (XLCNM) is a severe human disease without existing therapies caused by mutations in the phosphoinositide 3-phosphatase MTM1. Loss of MTM1 function is associated with muscle fiber defects characterized by impaired localization of β-integrins and other components of focal adhesions. Here we show that defective focal adhesions and reduced active β-integrin surface levels in a cellular model of XLCNM are rescued by loss of phosphatidylinositiol 3-kinase C2β (PI3KC2β) function. Inactivation of the Mtm1 gene impaired myoblast differentiation into myotubes and resulted in reduced surface levels of active β1-integrins as well as corresponding defects in focal adhesions. These phenotypes were rescued by concomitant genetic loss of Pik3c2b or pharmacological inhibition of PI3KC2β activity. We further demonstrate that a hitherto unknown role of PI3KC2β in the endocytic trafficking of active β1-integrins rather than rescue of phosphatidylinositol 3-phosphate levels underlies the ability of Pik3c2b to act as a genetic modifier of cellular XLCNM phenotypes. Our findings reveal a crucial antagonistic function of MTM1 and PI3KC2β in the control of active β-integrin surface levels, thereby providing a molecular mechanism for the adhesion and myofiber defects observed in XLCNM. They further suggest specific pharmacological inhibition of PI3KC2β catalysis as a viable treatment option for XLCNM patients.

MTM1-mediated production of phosphatidylinositol 5-phosphate fuels the formation of podosome-like protrusions regulating myoblast fusion

“…This may be attributed to an ectopic localization of MTM1 within the nucleus, where phosphoinositides have been demonstrated to regulate myogenic gene expression ( 20 ). All of these results validate the Mtm1 -KO cell line as a cellular model and position MTM1 as a critical enzyme in myoblast differentiation as recently reported ( 21 ).…”

Inactivating the lipid kinase activity of PI3KC2β is sufficient to rescue myotubular myopathy in mice

“…Overall, we hypothesize that inactivation of PI3KC2β kinase activity normalizes PtdIns3P homeostasis, mTORC1 activity and β1 integrin trafficking, leading to the amelioration of cellular defects and rescue of the muscle structure and function. This is in line with some recent findings in cells supporting the notion that PI3KC2β controls integrin turnover ( 37 ).…”