Acute resistance exercise activates rapamycin‐sensitive and ‐insensitive mechanisms that control translational activity and capacity in skeletal muscle

Abstract

Key pointsr Ribosome biogenesis is the primary determinant of translational capacity, but its regulation in skeletal muscle following acute resistance exercise is poorly understood.r Resistance exercise increases muscle protein synthesis acutely, and muscle mass with training, but the role of translational capacity in these processes is unclear.r Here, we show that acute resistance exercise activated pathways controlling translational activity and capacity through both rapamycin-sensitive and -insensitive mechanisms.r Transcription factor c-Myc and its downstream targets, which are known to regulate ribosome biogenesis in other cell types, were upregulated after resistance exercise in a rapamycin-independent manner and may play a role in determining translational capacity in skeletal muscle.r Local inhibition of myostatin was also not affected by rapamycin and may contribute to the rapamycin-independent effects of resistance exercise.Abstract This study aimed to determine (1) the effect of acute resistance exercise on mechanisms of ribosome biogenesis, and (2) the impact of mammalian target of rapamycin on ribosome biogenesis, and muscle protein synthesis (MPS) and degradation. Female F344BN rats underwent unilateral electrical stimulation of the sciatic nerve to mimic resistance exercise in the tibialis anterior (TA) muscle. TA muscles were collected at intervals over the 36 h of exercise recovery (REx); separate groups of animals were administered rapamycin pre-exercise (REx+Rapamycin). Resistance exercise led to a prolonged (6-36 h) elevation (30-50%) of MPS that was fully blocked by rapamycin at 6 h but only partially at 18 h. REx also altered pathways that regulate protein homeostasis and mRNA translation in a manner that was both rapamycin-sensitive (proteasome activity; phosphorylation of S6K1 and rpS6) and rapamycin-insensitive (phosphorylation of eEF2, ERK1/2 and UBF; gene expression of the myostatin target Mighty as well as c-Myc and its targets involved in ribosome biogenesis). The role of c-Myc was tested in vitro using the inhibitor 10058-F4, which, over time, decreased basal RNA and MPS in a dose-dependent manner (correlation of RNA and MPS, r 2 = 0.98), even though it had no effect on the acute stimulation of protein synthesis. In conclusion, acute resistance exercise stimulated rapamycin-sensitive and -insensitive mechanisms that regulate translation activity and capacity.

Ribosome biogenesis may augment resistance training-induced myofiber hypertrophy and is required for myotube growth in vitro

“…The present findings indicate translational capacity is central to the myotube hypertrophic response. In support of our findings, West et al (48) have recently shown that inhibiting c-Myc in C 2 C 12 myotubes significantly blunts ribosome biogenesis and protein synthesis (but not acute protein synthesis following an anabolic stimulus), demonstrating that c-Myc regulates muscle ribosome biogenesis, and that the process of ribosome biogenesis is crucial for maintaining myotube protein synthesis. To complement our current findings, future studies should examine the effects of the Pol I inhibitor CX-5461 during a more physiologically relevant scenario, such as overload-induced hypertrophy, and whether blocking Pol I differentially affects hypertrophic responses in young and aged muscle.…”

“…This elevation in c-Myc protein content in the Mod and Xtr responder clusters following RT is a novel finding that leads us to suggest c-Myc-driven increases in ribosome biogenesis may facilitate RT-induced myofiber hypertrophy. It is important to note that recent evidence suggests that the resistance exerciseinduced upregulation of c-Myc (and several other regulators of ribosome biogenesis) is not entirely dependent on mTOR signaling (48). Thus, we cannot be sure whether increased c-Myc protein levels in the Mod and Xtr clusters following RT were due to heightened mTOR signaling in these subjects.…”

Progressive resistance‐loaded voluntary wheel running increases hypertrophy and differentially affects muscle protein synthesis, ribosome biogenesis, and proteolytic markers in rat muscle

“…Recent research has reported that an acute bout of resistance exercise in rodents West et al, 2016) and humans (Stec et al, 2015) increases ribosome content or 45S pre-rRNA (which is a precursor to 28S, 18S and 5.8S rRNA (Chaillou et al, 2014 (Kirby et al, 2015) similarly reported that 14 days of synergist ablation in 5-mo-old mice, which elicited a 71% increase in plantaris mass, induced a twofold increase in ribosome content and increased the mRNA expression of numerous ribosomal proteins. In humans, Stec et al (Stec et al, 2016) reported that 4 weeks of lower body resistance training increased vastus lateralis mixed-fibre total RNA levels in "extreme responders"…”

“…Acute resistance exercise bouts increase MPS in humans and rodents (Kubica, Bolster, Farrell, Kimball, & Jefferson, 2005;Phillips, Tipton, Aarsland, Wolf, & Wolfe, 1997). Likewise, acute resistance exercise bouts in rodents West et al, 2016) and humans (Stec, Mayhew, & Bamman, 2015) have also been reported to increase markers of ribosome biogenesis. With regard to alterations in markers of ribosome biogenesis with chronic overload, recent studies have reported that 14 days of synergist ablation in mice induced a twofold increase in ribosome content as well as robust increases in the mRNA expression of other markers of ribosome biogenesis (Kirby et al, 2015;von Walden, Casagrande, Ostlund Farrants, & Nader, 2012).…”

Regulation of muscle protein metabolism by nutrition and exercise

“…Acute resistance exercise induces mTORC1 activation and ribosome biogenesis by mechanical stimuli 11,12) contraction-induced growth factors 13,14) , and metabolic stress 15) , and subsequently augments muscle protein synthesis by accelerating translation. Acute resistance exercise also increases muscle protein breakdown.…”