Constitutive activation of mTOR pathway by leucine causes heart hypertrophy which can be blocked by rapamycin

Abstract

Mitochondrial branched chain aminotransferase (BCATm) KO mice fed an amino acid diet containing intermediate levels of branched chain amino acids (BCAA) to prevent toxicity and wild type mice fed an amino acid diet with normal levels of the BCAA were studied. To determine the mTOR specific effects of constitutively high concentration of BCAA in the blood, BCATm KO and wild type mice were fed diets with and without encapsulated rapamycin. Following thirteen days of feeding, the mice were sacrificed without fasting. The plasma levels of BCAAs were found to be higher in the KO mice without any effect by rapamycin. Despite higher concentration of leucine, food intake was higher for the KO mice suggesting that chronically high leucine levels cannot suppress food intake. BCATm KO mice exhibited heart but not skeletal muscle hypertrophy which was prevented by dietary rapamycin. In addition, feeding the KO mice with a diet containing rapamycin resulted in increased activity. Rapamycin feeding had no effect on heart size of the wild type mice although mouse activity was reduced. Western blotting showed the activation of mTOR signaling pathway in KO mice. Our results suggest that leucine induced protein synthesis through the activation of mTOR that leads to growth is tissue dependent and leucine alone is insufficient to induce skeletal muscle hypertrophy. (Support Ajinomoto and Virginia Tech)