Implications for myofibrillar protein translation due to high-intensity muscle contraction via a rapamycin-insensitive mechanism

Muscle protein metabolism is thought to regulate muscle mass. High-intensity muscle contraction (HiMC) increases muscle protein synthesis (MPS), resulting in muscle hypertrophy. Inhibiting the mechanistic target of rapamycin complex 1 (mTORC1) using rapamycin leads to partially inhibited mTORC1 activation, along with increased MPS, and muscle hypertrophy after HiMC. Therefore, we hypothesized that rapamycin-sensitive mTORC1 regulates myofibrillar protein translation, and the purpose of this study was to investigate this possibility. The right gastrocnemius muscle of male Sprague Dawley rats was contracted isometrically via percutaneous electrical stimulation, and the left gastrocnemius muscle served as control. Vehicle or rapamycin was intraperitoneally injected 1 h before HiMC. Gastrocnemius muscles were collected at 6 h after a bout of HiMC and 48 h after chronic muscle contractions for 4 wk (3 HiMC per week). Rapamycin completely inhibited HiMC-induced activation of 70 kDa ribosomal protein S6 kinase, which is a rapamycin-sensitive mTORC1 substrate. However, rapamycin completely inhibited HiMC-induced dissociation of eukaryotic translation initiation factor 4E (eIF4E):eukaryotic translation initiation factor 4E (eIF4E)-binding protein (4E-BP1) and the interaction of eIF4E:eIF4G, despite the HiMC-induced phosphorylation of 4E-BP1 (Thr37/46, Thr70, and Ser65) being unaffected by rapamycin. Importantly, HiMC-induced myofibrillar protein synthesis was not influenced by rapamycin. Changes in myosin and actin levels relative to muscle mass induced by chronic muscle contraction remained constant even under rapamycin administration. These results indicated that rapamycin-sensitive mTORC1 signaling is not fully responsible for contraction-induced increases in myofibrillar protein synthesis.<b>NEW & NOTEWORTHY</b> Muscle contraction activates mTOR signaling, resulting in increased protein synthesis and muscle hypertrophy. Rapamycin-sensitive mTORC1 is important for cap-dependent translation, but the effects of suppressing mTORC1 function using rapamycin on myofibrillar protein synthesis caused by contraction remains unclear. We observed that the eIF4F complex is a translation initiator induced by contraction dependently on rapamycin-sensitive mTORC1. Myofibrillar protein translation increased by muscle contraction was insensitive to rapamycin.