Abstract
BackgroundBranched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. We, therefore, determined if cardiac BCAA accumulation occurs in patients with dilated cardiomyopathy (DCM), due to an impaired catabolism of BCAA, and if stimulating cardiac BCAA oxidation can improve cardiac function in mice with heart failure.MethodFor human cohorts of DCM and control, both male and female patients of ages between 22 and 66 years were recruited with informed consent from University of Alberta hospital. Left ventricular biopsies were obtained at the time of transplantation. Control biopsies were obtained from non-transplanted donor hearts without heart disease history. To determine if stimulating BCAA catabolism could lessen the severity of heart failure, C57BL/6J mice subjected to a transverse aortic constriction (TAC) were treated between 1 to 4-week post-surgery with either vehicle or a stimulator of BCAA oxidation (BT2, 40 mg/kg/day).ResultEchocardiographic data showed a reduction in ejection fraction (54.3 ± 2.3 to 22.3 ± 2.2%) and an enhanced formation of cardiac fibrosis in DCM patients when compared to the control patients. Cardiac BCAA levels were dramatically elevated in left ventricular samples of patients with DCM. Hearts from DCM patients showed a blunted insulin signalling pathway, as indicated by an increase in P-IRS1ser636/639 and its upstream modulator P-p70S6K, but a decrease in its downstream modulators P-AKT ser473 and in P-GSK3β ser9. Cardiac BCAA oxidation in isolated working hearts was significantly enhanced by BT2, compared to vehicle, following either acute or chronic treatment. Treatment of TAC mice with BT2 significantly improved cardiac function in both sham and TAC mice (63.0 ± 1.8 and 56.9 ± 3.8% ejection fraction respectively). Furthermore, P-BCKDH and BCKDK expression was significantly decreased in the BT2 treated groups.ConclusionWe conclude that impaired cardiac BCAA catabolism and insulin signaling occur in human heart failure, while enhancing BCAA oxidation can improve cardiac function in the failing mouse heart.
Highlights
Branched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart
The objectives of this study were to determine whether cardiac BCAA catabolism is defective in patients with dilated cardiomyopathy (DCM), and whether this occurs in conjunction with an impaired cardiac insulin signaling along with an activation of the mammalian target of rapamycin (mTOR) pathway
Patients with DCM have elevated levels of cardiac BCAA and an impaired BCAA catabolic pathway To explore the potential association between heart failure and BCAA, cardiac BCAA levels and the key enzymes for BCAA catabolism were assessed in failing human explanted hearts with DCM (Fig. 2a)
Summary
Branched chain amino acids (BCAA) can impair insulin signaling, and cardiac insulin resistance can occur in the failing heart. While altering BCAA oxidation is unlikely to directly compete with the use of other cardiac energy substrates, it still has the potential to alter cardiac BCAA levels This is important as the accumulation of BCAAs can activate mammalian target of rapamycin (mTOR) [10] and impair insulin signaling, due to its ability to phosphorylate IRS1 via directly activating p70S6K through mTOR [1, 11,12,13]. A decrease in cardiac BCAA oxidation has the potential to increase cardiac BCAA levels, which may activate mTOR signaling and reduce cardiac insulin sensitivity It remains unclear whether cardiac insulin signaling is impaired along with a decreased BCAA catabolism and activation of mTOR pathway in human failing hearts
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