Deletion of BCATm increases insulin-stimulated glucose oxidation in the heart

Backgrounds: Branched chain amino acid (BCAA) oxidation is impaired in cardiac insulin resistance, leading to the accumulation of BCAAs and the first products of BCAA oxidation, the branched chain ketoacids. However, it is not clear whether it is the BCAAs, BCKAs or both that are mediating cardiac insulin resistance. To determine this, we produced mice with a cardiac-specific deletion of BCAA aminotransferase (BCATm(-/-)), the first enzyme in the BCAA oxidation pathway that is responsible for converting BCAAs to BCKAs. Methods: Eight-week-old BCATm cardiac specific knockout (BCATm(-/-)) male mice and their alpha-MHC (myosin heavy chain) - Cre expressing wild type littermates (WT-Cre(+/+)) received tamoxifen (50 mg/kg i.p. 6 times over 8 days). At 16-weeks of age, cardiac energy metabolism was assessed in isolated working hearts. Results: BCATm(-/-) mice have decreased cardiac BCAA oxidation rates, increased cardiac BCAAs and a reduction in cardiac BCKAs. Hearts from BCATm(-/-) mice showed an increase in insulin stimulation of glucose oxidation and an increase in p-AKT. To determine the impact of reversing these events, we perfused isolated working mice hearts with high levels of BCKAs, which completely abolished insulin-stimulated glucose oxidation rates, an effect associated with decreased p-AKT and inactivation of pyruvate dehydrogenase (PDH), the rate-limiting enzyme in glucose oxidation. Conclusion: This implicates the BCKAs, and not BCAAs, as the actual mediators of cardiac insulin resistance and suggests that lowering cardiac BCKAs can be used as a therapeutic strategy to improve insulin sensitivity in the heart. (C) 2021 Elsevier Inc. All rights reserved.

Automated summary

The study found that cardiac-specific deletion of BCAA aminotransferase in mice led to decreased BCAA oxidation rates, increased BCAA levels, and reduced BCKA levels in the heart, while showing an increase in insulin stimulation of glucose oxidation. This suggests that BCKAs, rather than BCAAs, are the mediators of cardiac insulin resistance.