Novel Functions Of Branched-chain Amino Acid Metabolism In Actue Myeloid Leukemia And Heart Failure

Branched-chain Amino Acid(BCAA),including leucine,isoleucine and valine,are essential amino acids with various functions in cells.Recent studies have revealed a significant association between BCAA metabolic reprogramming in multiple diseases,including cancer,metabolic disease and cardiovascular diseases.However,the causal relationship,underlying mechanisms between BCAA metabolic reprogramming and disease deveploment remain unkown,and the therapeutic potential of targeting BCAA reprogramming needs further exploration.Our study found expression of rate-limiting enzyme BCKDK was upregulated in acute myeloid leukemia(AML),and significantly associated with poor prognosis of AML patients.Further functional studies showed that BCKDK inhibition affected key regulators in cell cycle,induced G0/G1 arrest in AML(acute myeloid leukemia)cells,therefor inhibited AML cell proliferation.In contrast,overexpressing PP2 Cm phosphatase with opposite function with BCKDK,also inhibited AML cell proliferation.Mechanistic study showed that BCKDK inhibition downregulated cMyc protein level,and inhibited gene expression involving glycolysis driven by c-Myc.Additionally,reducing exogenous BCAA supply also downregulated c-Myc protein level,and inhibited glycolysis genes expression.Except for regulating cancer cell proliferation and metabolism,BCAA remodeling also played important roles in the development of heart failure.Under pathological condition,correcting BCAA catabolic defects by BCKDK inhibition improved myocardial mechanics both systole and diastole,therefor alleviated cardiac dysfunction and chamber dilation induced by pressure-overload in mouse heart.At molecular level,BCKDK inhibition was found upregulating genes expression involving fatty acid oxidation in both dysfunctional hearts and hypertrophic cardiomyocytes.In conclusion,our study demonstrated the important roles of BCAA metabolism in disease development of both AML and heart failure,and revealed potential underlying mechanisms,which providing strong rationale of founding new targets for AML and heart failure treatment.