High glutamine suppresses osteogenesis through mTORC1-mediated inhibition of the mTORC2/AKT-473/RUNX2 axis

Activation of the key nutrient cellular sensors mTORC1 and mTORC2 directs the fate of mesenchymal stromal cells (MSCs). Here, we report that glutamine regulates crosstalk between mTOR complexes and lineage commitment of MSCs independent of glucose concentration. High glutamine-induced mTORC1 hyperactivation resulted in the suppression of mTORC2, which otherwise stabilizes RUNX2 via GSK3β inhibition through pAKT-473. Activation of GSK3β resulted in the ubiquitination of RUNX2, a key transcription factor for the osteogenic commitment of MSCs. However, low glutamine conditions inhibit mTORC1 hyperactivation followed by increased mTORC2 activation and RUNX2 stabilization. Under diabetic/high-glucose conditions, glutamine-triggered hyperactivation of mTORC1 resulted in mTORC2 suppression, and active GSK3β led to suppression of RUNX2. Activation of p-AMPK by metformin inhibits high glutamine-induced mTORC1 hyperactivation and rescues RUNX2 through the mTORC2/AKT-473 axis. Collectively, our study indicates the role of glutamine in modulating MSC fate through cross-talk between mTOR complexes by identifying a critical switch in signaling. It also shows the importance of glutamine in modulating molecular cues (mTORC1/p-70S6K/mTORC2/RUNX2) that are involved in driving diabetes-induced bone adipogenesis and other secondary complications.