Branched-chain amino acids promote thrombocytopoiesis by activating mTOR signaling

Background: Megakaryocyte differentiation and platelet production disorders are the main causes of thrombocythemia and thrombocytopenia and lead to thrombosis or hemorrhage. Branched-chain amino acids (BCAAs) are essential nutrients that regulate important metabolic signals. BCAA administration could also increase platelet activation and promote the risk of thrombosis.Objectives: To unveil the role of BCAAs in thrombocytopoiesis. Methods: BCAA-fed mice and megakaryocyte/platelet-specific branched-chain alpha-keto acid dehydrogenase E1 alpha subunit-deficient mice were used to study the role of BCAAs in thrombocytopoiesis. Results: In this study, we found that BCAA diet could facilitate megakaryocyte differentiation and platelet production. Meanwhile, megakaryocyte/platelet-specific branched-chain alpha-keto acid dehydrogenase E1 alpha subunit-deficient mice developed thrombocythemia, which was mainly caused by the excessive differ-entiation of megakaryocytes and proplatelet biogenesis. Moreover, the use of BT2, the agonist of BCAA catabolism, could affect proplatelet formation (PPF) and megakaryocyte polyploidization, as well as ameliorating the thrombocythemia of BCAA-fed mice. Conclusion: We found that deficiency in BCAA catabolism led to the activation of p70S6K/mammalian target of rapamycin (mTOR) signaling, megakaryocyte over differentiation, and the acceleration of PPF. Activating BCAA metabolism with BT2 could inhibit mTOR signaling, reduce PPF, and ameliorate thrombocythemia in BCAA-fed mice. Therefore, this study reveals a novel role of BCAAs in megakaryocyte differen-tiation and platelet production, suggesting that targeting BCAA-mediated p70S6K/ mTOR signaling may be a potential strategy for the treatment of thrombocytopenia or thrombocythemia.