Amino acids‐induced cardiac protection by promoting mitochondrial function via mTOR and Opa‐1 signaling

Abstract

ObjectsAmino acids, especially branched chain amino acids (BCAAs), have important regulatory roles in protein synthesis. Recently studies revealed that BCAAs protect against ischemia/reperfusion (I/R) injury. We studied the signaling pathway and mitochondrial function affecting a cardiac preconditioning of BCAAs.MethodsCardiac myocytes were isolated by cardiac retrograde aortic perfusion and collagenase and were subjected to simulated ischemia and cell death was quantified. Immunoblot and real time PCR were performed as biochemical assay and mitochondrial function was assessed using Seahorse XF cell Mito test.ResultsIn myocytes undergoing simulated I/R, BCAA treatment significantly preserved cell viability (71.7 ± 2.7% vs. 34.5 ± 1.6%, respectively, p < 0.0001), whereas rapamycin prevented this BCAA‐induced cardioprotective effect (43.5 ± 3.4% vs. BCAA, p < 0.0001). To elucidate the mechanism, we assessed changes in the mitochondrial fusion regulators Opa‐1, Mfn‐1, and Mfn‐2. BCAA treatment increased expression of Opa‐1, but not Mfn‐1 or Mfn‐2. Enhanced mitochondrial fusion also improved mitochondrial function including oxygen consumption rate.ConclusionsBCAA acutely regulates mitochondrial metabolism in cardiomyocytes and increased mitochondrial fusion, Opa‐1, and the Akt‐mTOR pathway, offering a novel target for prevention and treatment of coronary disease.Support or Funding InformationThis study was supported by Japan Society of Promotion Science #19K09353 to YMT.