Fiber type–specific changes in Sestrin/GATOR2/mTORC1 signaling pathway in denervated rat skeletal muscle

In vitro studies have shown that Sestrin, a leucine sensor, inhibits the mechanistic/mammalian target of rapamycin complex 1 (mTORC1) by binding to the GTPase-activating proteins toward Rags 2 (GATOR2). This study aimed to investigate the in vivo effects of denervation and acute leucine ingestion on the Sestrin/GATOR2/mTORC1 signaling pathway in fast-twitch plantaris and slow-twitch soleus muscles (PM and SM, respectively). Unilateral PM and SM in rats underwent denervation-induced disuse for 7 days. Rats received L-leucine 1 h before muscle excision. Muscle weight was reduced by approximately 30% and 40% in the denervated PM and SM, respectively. Denervation increased the ratio of phosphorylated S6K1 to total S6K1 (an indicator of mTORC1 activation) in the PM, but decreased it in the SM. Regarding Sestrin that binds to GATOR2, the denervated PM exhibited increased Sestrin1 and Sestrin2 levels, whereas the denervated SM showed decreased Sestrin1 levels. Denervation also increased the levels of Sestrin2, leucyl-tRNA synthetase 1, RagA, and Rheb in the PM and decreased the levels of Sestrin1, secretion associated ras-related GTPase 1b, RagD, and Rheb in the SM. Sestrin function as a leucine sensor was preserved in both denervated muscles. These results indicate that denervation-induced changes in the Sestrin/GATOR2/mTORC1 signaling pathway are fiber type–specific and suggest that some proteins involved in this pathway may help mitigate muscle atrophy.