journal article Open Access Aug 09, 2016

The role of mTOR signalling in the regulation of skeletal muscle mass in a rodent model of resistance exercise

View at Publisher Save 10.1038/srep31142
Abstract
Abstract
Resistance exercise (RE) activates signalling by the mammalian target of rapamycin (mTOR) and it has been suggested that rapamycin-sensitive mTOR signalling controls RE-induced changes in protein synthesis, ribosome biogenesis, autophagy and the expression of peroxisome proliferator gamma coactivator 1 alpha (PGC-1α). However, direct evidence to support the aforementioned relationships is lacking. Therefore, in this study, we investigated the role of rapamycin-sensitive mTOR in the RE-induced activation of muscle protein synthesis, ribosome biogenesis, PGC-1α expression and hypertrophy. The results indicated that the inhibition of rapamycin-sensitive mTOR could prevent the induction of ribosome biogenesis by RE, but it only partially inhibited the activation of muscle protein synthesis. Likewise, the inhibition of rapamycin-sensitive mTOR only partially blocked the hypertrophic effects of chronic RE. Furthermore, both acute and chronic RE promoted an increase in PGC-1α expression and these alterations were not affected by the inhibition of rapamycin-sensitive mTOR. Combined, the results from this study not only establish that rapamycin-sensitive mTOR plays an important role in the RE-induced activation of protein synthesis and the induction of hypertrophy, but they also demonstrate that additional (rapamycin-sensitive mTOR-independent) mechanisms contribute to these fundamentally important events.
Topics

No keywords indexed for this article. Browse by subject →

References
57
[1]
mTOR Signaling in Growth Control and Disease

Mathieu Laplante, David M. Sabatini

Cell 2012 10.1016/j.cell.2012.03.017
[2]
Sengupta, S., Peterson, T. R. & Sabatini, D. M. Regulation of the mTOR complex 1 pathway by nutrients, growth factors and stress. Mol Cell 40, 310–322 (2010). 10.1016/j.molcel.2010.09.026
[3]
Benjamin, D., Colombi, M., Moroni, C. & Hall, M. N. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat Rev Drug Discov 10, 868–880 (2011). 10.1038/nrd3531
[4]
mTORC1 Phosphorylation Sites Encode Their Sensitivity to Starvation and Rapamycin

Seong A. Kang, Michael E. Pacold, Christopher L. Cervantes et al.

Science 2013 10.1126/science.1236566
[5]
Zhou, H. & Huang, S. The complexes of mammalian target of rapamycin. Curr Protein Pept Sci 11, 409–424 (2010). 10.2174/138920310791824093
[6]
Patursky-Polischuk, I. et al. Reassessment of the role of TSC, mTORC1 and microRNAs in amino acids-meditated translational control of TOP mRNAs. PLoS One 9, e109410 (2014). 10.1371/journal.pone.0109410
[7]
Goodman, C. A. et al. The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth. J Physiol 589, 5485–5501 (2011). 10.1113/jphysiol.2011.218255
[8]
Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo

Sue C. Bodine, Trevor N. Stitt, Michael Gonzalez et al.

Nature Cell Biology 2001 10.1038/ncb1101-1014
[9]
Ogasawara, R., Sato, K., Higashida, K., Nakazato, K. & Fujita, S. Ursolic acid stimulates mTORC1 signaling after resistance exercise in rat skeletal muscle. American journal of physiology. Endocrinology and metabolism 305, E760–E765 (2013). 10.1152/ajpendo.00302.2013
[10]
Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle

Sarah B. Wilkinson, Stuart M. Phillips, Philip J. Atherton et al.

The Journal of Physiology 2008 10.1113/jphysiol.2008.153916
[11]
Dreyer, H. C. et al. Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol 576, 613–624 (2006). 10.1113/jphysiol.2006.113175
[12]
Ogasawara, R., Sato, K., Matsutani, K., Nakazato, K. & Fujita, S. The order of concurrent endurance and resistance exercise modifies mTOR signaling and protein synthesis in rat skeletal muscle. American journal of physiology. Endocrinology and metabolism 306, E1155–E1162 (2014). 10.1152/ajpendo.00647.2013
[13]
West, D. W. et al. Acute resistance exercise activates rapamycin-sensitive and -insensitive mechanisms that control translational activity and capacity in skeletal muscle. J Physiol 594, 453–468 (2016). 10.1113/jp271365
[14]
Cunningham, J. T. et al. mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450, 736–740 (2007). 10.1038/nature06322
[15]
Atherton, P. J. et al. Selective activation of AMPK-PGC-1alpha or PKB-TSC2-mTOR signaling can explain specific adaptive responses to endurance or resistance training-like electrical muscle stimulation. FASEB J 19, 786–788 (2005). 10.1096/fj.04-2179fje
[16]
Apro, W., Wang, L., Ponten, M., Blomstrand, E. & Sahlin, K. Resistance exercise induced mTORC1 signaling is not impaired by subsequent endurance exercise in human skeletal muscle. American journal of physiology. Endocrinology and metabolism 305, E22–E32 (2013). 10.1152/ajpendo.00091.2013
[17]
Hill, K. M., Stathis, C. G., Grinfeld, E., Hayes, A. & McAinch, A. J. Co-ingestion of carbohydrate and whey protein isolates enhance PGC-1alpha mRNA expression: a randomised, single blind, cross over study. J Int Soc Sports Nutr 10, 8 (2013). 10.1186/1550-2783-10-8
[18]
Wang, L., Mascher, H., Psilander, N., Blomstrand, E. & Sahlin, K. Resistance exercise enhances the molecular signaling of mitochondrial biogenesis induced by endurance exercise in human skeletal muscle. J Appl Physiol (1985) 111, 1335–1344 (2011). 10.1152/japplphysiol.00086.2011
[19]
Rommel, C. et al. Mediation of IGF-1-induced skeletal myotube hypertrophy by PI(3)K/Akt/mTOR and PI(3)K/Akt/GSK3 pathways. Nat Cell Biol 3, 1009–1013 (2001). 10.1038/ncb1101-1009
[20]
Morley, S. J., Coldwell, M. J. & Clemens, M. J. Initiation factor modifications in the preapoptotic phase. Cell Death Differ 12, 571–584 (2005). 10.1038/sj.cdd.4401591
[21]
Ferguson, G., Mothe-Satney, I. & Lawrence, J. C., Jr. Ser-64 and Ser-111 in PHAS-I are dispensable for insulin-stimulated dissociation from eIF4E. J Biol Chem 278, 47459–47465 (2003). 10.1074/jbc.m307949200
[22]
Mothe-Satney, I., Yang, D., Fadden, P., Haystead, T. A. & Lawrence, J. C., Jr. Multiple mechanisms control phosphorylation of PHAS-I in five (S/T)P sites that govern translational repression. Mol Cell Biol 20, 3558–3567 (2000). 10.1128/mcb.20.10.3558-3567.2000
[23]
Miyazaki, M., McCarthy, J. J., Fedele, M. J. & Esser, K. A. Early activation of mTORC1 signalling in response to mechanical overload is independent of phosphoinositide 3-kinase/Akt signalling. J Physiol 589, 1831–1846 (2011). 10.1113/jphysiol.2011.205658
[24]
You, J. S., Frey, J. W. & Hornberger, T. A. Mechanical stimulation induces mTOR signaling via an ERK-independent mechanism: implications for a direct activation of mTOR by phosphatidic acid. PLoS One 7, e47258 (2012). 10.1371/journal.pone.0047258
[25]
AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1

Joungmok Kim, Mondira Kundu, Benoit Viollet et al.

Nature Cell Biology 2011 10.1038/ncb2152
[26]
Garelick, M. G. et al. Chronic rapamycin treatment or lack of S6K1 does not reduce ribosome activity in vivo. Cell Cycle 12, 2493–2504 (2013). 10.4161/cc.25512
[27]
Lamming, D. W. et al. Rapamycin-induced insulin resistance is mediated by mTORC2 loss and uncoupled from longevity. Science 335, 1638–1643 (2012). 10.1126/science.1215135
[28]
Sarbassov, D. D. et al. Prolonged rapamycin treatment inhibits mTORC2 assembly and Akt/PKB. Mol Cell 22, 159–168 (2006). 10.1016/j.molcel.2006.03.029
[30]
Kang, C., Goodman, C. A., Hornberger, T. A. & Ji, L. L. PGC-1alpha overexpression by in vivo transfection attenuates mitochondrial deterioration of skeletal muscle caused by immobilization. FASEB J 29, 4092–4106 (2015). 10.1096/fj.14-266619
[31]
Sandri, M. et al. PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci USA 103, 16260–16265 (2006). 10.1073/pnas.0607795103
[32]
Chaillou, T., Kirby, T. J. & McCarthy, J. J. Ribosome biogenesis: emerging evidence for a central role in the regulation of skeletal muscle mass. J Cell Physiol 229, 1584–1594 (2014). 10.1002/jcp.24604
[33]
Iadevaia, V., Huo, Y., Zhang, Z., Foster, L. J. & Proud, C. G. Roles of the mammalian target of rapamycin, mTOR, in controlling ribosome biogenesis and protein synthesis. Biochem Soc Trans 40, 168–172 (2012). 10.1042/bst20110682
[34]
Hannan, K. M. et al. mTOR-dependent regulation of ribosomal gene transcription requires S6K1 and is mediated by phosphorylation of the carboxy-terminal activation domain of the nucleolar transcription factor UBF. Mol Cell Biol 23, 8862–8877 (2003). 10.1128/mcb.23.23.8862-8877.2003
[35]
Drummond, M. J. et al. Expression of growth-related genes in young and older human skeletal muscle following an acute stimulation of protein synthesis. J Appl Physiol (1985) 106, 1403–1411 (2009). 10.1152/japplphysiol.90842.2008
[36]
Figueiredo, V. C. et al. Impact of resistance exercise on ribosome biogenesis is acutely regulated by post-exercise recovery strategies. Physiol Rep 4, e12670 (2016). 10.14814/phy2.12670
[37]
Teleman, A. A., Hietakangas, V., Sayadian, A. C. & Cohen, S. M. Nutritional control of protein biosynthetic capacity by insulin via Myc in Drosophila. Cell Metab 7, 21–32 (2008). 10.1016/j.cmet.2007.11.010
[38]
Phillips, S. M., Tipton, K. D., Aarsland, A., Wolf, S. E. & Wolfe, R. R. Mixed muscle protein synthesis and breakdown after resistance exercise in humans. Am J Physiol 273, E99–107 (1997).
[39]
Fry, C. S. et al. Aging impairs contraction-induced human skeletal muscle mTORC1 signaling and protein synthesis. Skelet Muscle 1, 11 (2011). 10.1186/2044-5040-1-11
[40]
Brook, M. S. et al. Skeletal muscle hypertrophy adaptations predominate in the early stages of resistance exercise training, matching deuterium oxide-derived measures of muscle protein synthesis and mechanistic target of rapamycin complex 1 signaling. FASEB J 29, 4485–4496 (2015). 10.1096/fj.15-273755
[41]
Egan, B. & Zierath, J. R. Exercise metabolism and the molecular regulation of skeletal muscle adaptation. Cell Metab 17, 162–184 (2013). 10.1016/j.cmet.2012.12.012
[42]
Drummond, M. J. et al. Rapamycin administration in humans blocks the contraction-induced increase in skeletal muscle protein synthesis. J Physiol 587, 1535–1546 (2009). 10.1113/jphysiol.2008.163816
[43]
Kubica, N., Bolster, D. R., Farrell, P. A., Kimball, S. R. & Jefferson, L. S. Resistance exercise increases muscle protein synthesis and translation of eukaryotic initiation factor 2Bepsilon mRNA in a mammalian target of rapamycin-dependent manner. J Biol Chem 280, 7570–7580 (2005). 10.1074/jbc.m413732200
[44]
Krisan, A. D. et al. Resistance training enhances components of the insulin signaling cascade in normal and high-fat-fed rodent skeletal muscle. J Appl Physiol (1985) 96, 1691–1700 (2004). 10.1152/japplphysiol.01054.2003
[45]
Ogasawara, R. et al. mTOR signaling response to resistance exercise is altered by chronic resistance training and detraining in skeletal muscle. J Appl Physiol (1985) 114, 934–940 (2013). 10.1152/japplphysiol.01161.2012
[46]
Philp, A. et al. Rapamycin does not prevent increases in myofibrillar or mitochondrial protein synthesis following endurance exercise. J Physiol 593, 4275–4284 (2015). 10.1113/jp271219
[47]
Ramos, F. J. et al. Rapamycin reverses elevated mTORC1 signaling in lamin A/C-deficient mice, rescues cardiac and skeletal muscle function and extends survival. Sci Transl Med 4, 144ra103 (2012). 10.1126/scitranslmed.3003802
[48]
Mobley, C. B. et al. Comparative effects of whey protein versus L-leucine on skeletal muscle protein synthesis and markers of ribosome biogenesis following resistance exercise. Amino Acids 48, 733–750 (2016). 10.1007/s00726-015-2121-z
[49]
Figueiredo, V. C. et al. Ribosome biogenesis adaptation in resistance training-induced human skeletal muscle hypertrophy. American journal of physiology. Endocrinology and metabolism 309, E72–E83 (2015). 10.1152/ajpendo.00050.2015
[50]
Dang, C. V. M. Y. C., metabolism, cell growth and tumorigenesis. Cold Spring Harb Perspect Med 3, a014217 (2013). 10.1101/cshperspect.a014217

Showing 50 of 57 references