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. Previous study has suggested that BCAA administration could increase platelet activation and promote the risk of thrombosis.

OBJECTIVES: To unveil the role of BCAAs in thrombocytopoiesis.

METHODS: BCAA-diet mice and megakaryocyte/platelet-specific branched chain α-keto acid dehydrogenase E1α subunit (BCKDHA)-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 BCKDHA-deficient mice developed thrombocythemia, which was mainly caused by the excessive differentiation 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.

CONCLUSIONS: We found that deficiency in BCAA catabolism led to the activation of p70S6K/mTOR signaling, megakaryocyte over differentiation and the acceleration of PPF. Activating BCAA metabolism with BT2 could inhibit mTOR signaling, reduce PPF and ameliorate the thrombocythemia of BCAA-fed mice. Therefore, this study reveals a novel role of BCAAs in megakaryocyte differentiation and platelet production, suggesting that targeting BCAA-mediated p70S6K/mTOR signaling may be a potential strategy for the treatment of thrombocytopenia or thrombocythemia.