Endotoxin (LPS) and
sepsis decrease
mammalian target of rapamycin (mTOR) activity in skeletal muscle, thereby reducing
protein synthesis. Our study tests the hypothesis that inhibition of
branched-chain amino acid (BCAA) catabolism, which elevates circulating BCAA and stimulates mTOR, will blunt the LPS-induced decrease in
muscle protein synthesis. Wild-type (WT) and mitochondrial branched-chain
aminotransferase (BCATm) knockout mice were studied 4 h after Escherichia coli LPS or saline. Basal skeletal muscle
protein synthesis was increased in knockout mice compared with WT, and this change was associated with increased eukaryotic
initiation factor (eIF)-4E binding protein-1 (4E-BP1) phosphorylation,
eIF4E.
eIF4G binding, 4E-BP1.raptor binding, and
eIF3.raptor binding without a change in the mTOR.raptor complex in muscle. LPS decreased
muscle protein synthesis in WT mice, a change associated with decreased 4E-BP1 phosphorylation as well as decreased formation of
eIF4E.
eIF4G, 4E-BP1.raptor, and
eIF3.raptor complexes. In BCATm knockout mice given LPS,
muscle protein synthesis only decreased to values found in vehicle-treated WT control mice, and this ameliorated LPS effect was associated with a coordinate increase in 4E-BP1.raptor,
eIF3.raptor, and 4E-BP1 phosphorylation. Additionally, the LPS-induced increase in muscle
cytokines was blunted in BCATm knockout mice, compared with WT animals. In a separate study, 7-day survival and muscle mass were increased in BCATm knockout vs. WT mice after polymicrobial
peritonitis. These data suggest that elevating blood BCAA is sufficient to ameliorate the catabolic effect of LPS on skeletal muscle
protein synthesis via alterations in
protein-
protein interactions within mTOR complex-1, and this may provide a survival advantage in response to
bacterial infection.