Skeletal muscle protein balance in mTOR heterozygous mice in response to endotoxin and leucine

Abstract

We assessed the role of mTOR in regulating muscle protein synthesis in wild‐type (WT) and mTOR heterozygous (+/−) mice under basal conditions, and in response to endotoxin (LPS) and/or leucine. Lean body mass was decreased in mTOR+/− vs WT mice. Gastrocnemius weight was decreased in mTOR+/− mice due in part to a reduced rate of basal protein synthesis. LPS decreased muscle protein synthesis in WT and mTOR+/− mice to the same extent. Changes in protein synthesis in mTOR+/− mice under basal and LPS‐stimulated conditions were associated with reduced 4E‐BP1 and S6K1 phosphorylation. LPS also decreased PRSA40 phosphorylation and increased phosphorylation of raptor and IRS‐1 (Ser307) to the same extent in WT and mTOR+/− mice. Muscle atrogin‐1 and MuRF1 mRNAs were elevated in mTOR+/− mice under basal conditions implying increased proteolysis, and the LPS‐induced increase in these atrogenes was comparable between groups. Differences in basal muscle protein balance were not due to differences in plasma insulin or IGF‐I, nor to tissue TNFα, IL‐6 or NOS2. LPS impaired leucine's ability to increase muscle 4E‐BP1 and S6K1 phosphorylation in WT mice and this leucine resistance was exacerbated in mTOR+/− mice. Our data support the contention that sepsis‐induced reductions in mTOR activity are central in regulating skeletal muscle mass under basal conditions and especially in response to nutrient stimulation. (GM38032)