Repressors of mTORC1 act to blunt the anabolic response to feeding in the soleus muscle of a cast-immobilized mouse hindlimb.

We recently reported results showing that cast immobilization of a rat hindlimb rapidly leads to development of anabolic resistance as demonstrated by failure of oral leucine administration to activate the mechanistic target of rapamycin complex 1 (mTORC1) and stimulate protein synthesis in the soleus muscle. The goal of this study was to assess the possible contribution of several mTORC1 regulatory proteins to the development of anabolic resistance. To accomplish this, 14-week-old male C57BL/6 mice (n = 21) were subjected to unilateral cast immobilization of the hindlimb for either 1 or 3 days, and the immobilized limb was compared to its contralateral control. The mass of the soleus muscle was decreased in the immobilized compared to the non-immobilized limb within 72-h in association with diminished protein synthesis. In agreement with our previous report, a 24-h casting period was sufficient to induce anabolic resistance, as demonstrated by blunted re-feeding-induced activation of mTORC1. Moreover, resistance of mTORC1 activation was associated not only with upregulated expression of REDD1, but also with altered expression of other mTORC1 regulatory proteins, that is, Sestrin1 and DEP domain-containing mTOR interacting protein (DEPTOR). In addition, re-feeding-induced phosphorylation of DEPTOR was significantly impaired in the immobilized compared to the non-immobilized limb. This work builds upon previous discoveries by our laboratory to elucidate the blunted mTORC1 response to stimuli during disuse of skeletal muscle induced by cast immobilization while highlighting new potential therapeutic targets for future countermeasures against muscle atrophy.