Investigating the Role of mTORC1 in the Androgen‐Mediated Regulation of Skeletal Muscle Growth

Androgens play an important role in regulating skeletal muscle growth largely through changes in muscle protein balance (synthesis + breakdown). Despite this, the underlying molecular mechanism(s) by which androgens alter protein balance and subsequent muscle growth are poorly defined. Previous research has implicated signaling through the mechanistic target of rapamycin complex 1 (mTORC1) in the androgen‐mediated regulation of protein balance as phosphorylation of mTORC1 substrates that control both protein synthesis and protein breakdown have been shown to be altered by androgen depletion/treatment. However, the role of mTORC1 in the androgen‐mediated regulation of muscle growth in vivo has yet to be defined. To define this role, 10‐week old male mice were randomized into four groups of equal body weight, subjected to a sham or castration surgery, then allowed to recover for 7 weeks to induce muscle atrophy in the castrated groups. Following the recovery, sham and castrated mice were implanted with either a control pellet or a pellet designed to release rapamycin at a rate of ~3 mg/kg of body weight/day over a period of 60 days. One‐week post implantation, a group of castrated mice implanted with either control pellets or rapamycin pellets began receiving weekly, intramuscular injections of nandrolone decanoate (ND) to induce muscle regrowth. All other sham and castrated mice received vehicle only. Mice were treated with vehicle or ND for 6 weeks (42 days). The tibialis anterior (TA) was harvested for analysis. The efficacy of the rapamycin pellets to inhibit mTORC1 was confirmed by the inability of insulin to increase phosphorylation of mTORC1 substrates [i.e. 70 kDa ribosomal protein S6 kinase 1 (Thr389), eIF4E binding protein 1 (Ser65), and uncoordinated like kinase 1(Ser757)] in mice receiving rapamycin even though induction of Akt (Thr308) phosphorylation was unaffected. Castration reduced TA wet weight and muscle fiber cross sectional area (CSA), but these values were restored to sham levels with ND administration, even in the presence of rapamycin. Further, the protein content of the TA was also decreased by castration, and ND administration restored this value to sham levels even in the presence of rapamycin. These changes in protein content were not due to changes in the translational capacity of the muscle as RNA content was similar across treatments. In all, these data indicate that androgens alter protein balance and muscle regrowth in an mTORC1‐independent manner. Support or Funding Information Start‐up funds from the University of Central Florida This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .