Unilateral isometric contraction induces REDD1 and suppresses insulin-stimulated mTORC1 and protein synthesis in non-contracted muscle of male mice.

Skeletal muscle hypertrophy is promoted by mechanical loading and is associated with activation of mTORC1 signaling. While REDD1, a stress-responsive inhibitor of mTORC1, is typically downregulated in contracting muscle, we previously reported that unilateral isometric contraction increases REDD1 expression in the contralateral non-contracted muscle. The functional significance of this response remains unclear. This study tested whether REDD1 induction in non-contracted muscle attenuates anabolic signaling under insulin-stimulated conditions. Male C57BL/6J mice underwent unilateral isometric contraction of the right gastrocnemius via percutaneous electrical stimulation. Insulin was administered systemically to stimulate mTORC1 signaling and protein synthesis. Western blotting was used to assess REDD1 protein levels and phosphorylation of mTORC1 downstream targets and Akt. REDD1 protein was significantly elevated in non-contracted muscle following contraction. This was accompanied by reduced insulin-stimulated phosphorylation of S6K1 and 4E-BP1, as well as decreased puromycin incorporation, indicating suppressed protein synthesis. Insulin-stimulated Akt phosphorylation was unchanged, suggesting that the suppression occurred downstream or independently of Akt. These findings demonstrate that isometric contraction can impair insulin-stimulated mTORC1 signaling and protein synthesis in non-contracted muscle in male mice, potentially via REDD1 induction.