BCAA hypercatabolism does not inhibit leucine stimulation of the mTOR pathway in skeletal muscle of mice deleted for BDK.

Abstract

Deletion of the kinase (BDK) that regulates the branched-chain ketoacid dehydrogenase complex results in growth retardation in mice starting at 2 weeks of age. By adulthood, BDK null mice are ~80% the size of wild type controls and hind-limb muscle weights are reduced 50%. However, between weaning and sexual maturity, neither rate of gain nor food intake differs between strains. To examine if the anabolic response to exogenous BCAA is blunted by loss of BDK, wild-type and null mice were given an oral bolus of L-leucine at 0, 25, 50 and 100% the amount (135 mg/100 g BW) reported to stimulate protein synthesis via activation of the mammalian target of rapamycin (mTOR) pathway in skeletal muscle. Blood and hind-limb muscles were collected 30 min later. Phosphorylation states of the translation factors 4E-BP1 and S6K1 were used as markers of mTOR activation. 4E-BP1 phosphorylation (γ-form/total), increased in wild type mice to 9, 13, and 18% following 25, 50 and 100% leucine doses, respectively. BDK null mice demonstrated a similar pattern, increasing to 11, 19 and 27% after the same leucine doses. S6K1 phosphorylation patterns (p-Thr389 and total) were also similar between mouse strains in response to leucine. Thus, muscle growth retardation in BDK null mice cannot be explained by reduced amplitude of mTOR signaling by leucine. It remains to be determined if leucine stimulation of mTOR dissipates more quickly in BDK null mice due to more rapid BCAA clearance.