Skip to main content
SpringerLink
Log in

mTOR Signaling Pathway and Protein Synthesis: From Training to Aging and Muscle Autophagy

  • Chapter
  • First Online:
Book cover Muscle Atrophy

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 1088))

Abstract

In muscle tissue there is a balance between the processes muscle synthesis and degradation. The mammalian target of rapamycin (mTOR) signaling pathway plays a critical role in regulating protein synthesis in order to maintain muscular protein turnover and trophism. Studies have shown that both down- and upregulation mechanisms are involved in this process in a manner dependent on stimulus and cellular conditions. Additionally, mTOR signaling has recently been implicated in several physiological conditions related to cell survival, such as self-digestion (autophagy), energy production, and the preservation of cellular metabolic balance over the lifespan. Here we briefly describe the mTOR structure and its regulatory protein synthesis pathway. Furthermore, the role of mTOR protein in autophagy, aging, and mitochondrial function in muscle tissue is presented.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 189.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 249.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Baroni BM, Rodrigues R, Franke RA, Geremia JM, Rassier DE, Vaz MA (2013) Time course of neuromuscular adaptations to knee extensor eccentric training. Int J Sports Med 34(10):904–911. https://doi.org/10.1055/s-0032-1333263

    Article  CAS  PubMed  Google Scholar 

  2. Kern H, Hofer C, Loefler S, Zampieri S, Gargiulo P, Baba A et al (2017) Atrophy, ultra-structural disorders, severe atrophy and degeneration of denervated human muscle in SCI and aging. Implications for their recovery by functional electrical stimulation, updated 2017. Neurol Res 39(7):660–666. https://doi.org/10.1080/01616412.2017.1314906

    Article  PubMed  Google Scholar 

  3. Suetta C (2017) Plasticity and function of human skeletal muscle in relation to disuse and rehabilitation: influence of ageing and surgery. Dan Med J 64(8):B5377

    Google Scholar 

  4. Lundell LS, Savikj M, Kostovski E, Iversen PO, Zierath JR, Krook A et al (2018) Protein translation, proteolysis and autophagy in human skeletal muscle atrophy after spinal cord injury. Acta Physiol (Oxf) 223:e13051. https://doi.org/10.1111/apha.13051

    Article  CAS  Google Scholar 

  5. Léger B, Cartoni R, Praz M, Lamon S, Dériaz O, Crettenand A et al (2006) Akt signalling through GSK-3beta, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy. J Physiol 576(Pt 3):923–933. https://doi.org/10.1113/jphysiol.2006.116715

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Bodine SC, Stitt TN, Gonzalez M, Kline WO, Stover GL, Bauerlein R et al (2001) Akt/mTOR pathway is a crucial regulator of skeletal muscle hypertrophy and can prevent muscle atrophy in vivo. Nat Cell Biol 3(11):1014–1019. https://doi.org/10.1038/ncb1101-1014

    Article  CAS  PubMed  Google Scholar 

  7. Dreyer HC, Glynn EL, Lujan HL, Fry CS, DiCarlo SE, Rasmussen BB (2008) Chronic paraplegia-induced muscle atrophy downregulates the mTOR/S6K1 signaling pathway. J Appl Physiol (1985) 104(1):27–33. https://doi.org/10.1152/japplphysiol.00736.2007

    Article  CAS  Google Scholar 

  8. Mizushima N, Levine B, Cuervo AM, Klionsky DJ (2008) Autophagy fights disease through cellular self-digestion. Nature 451(7182):1069–1075. https://doi.org/10.1038/nature06639

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Vézina C, Kudelski A, Sehgal SN (1975) Rapamycin (AY-22,989), a new antifungal antibiotic. I. Taxonomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 28(10):721–726

    Article  Google Scholar 

  10. Heitman J, Movva NR, Hall MN (1991) Targets for cell cycle arrest by the immunosuppressant rapamycin in yeast. Science 253(5022):905–909

    Article  CAS  Google Scholar 

  11. Kunz J, Henriquez R, Schneider U, Deuter-Reinhard M, Movva NR, Hall MN (1993) Target of rapamycin in yeast, TOR2, is an essential phosphatidylinositol kinase homolog required for G1 progression. Cell 73(3):585–596

    Article  CAS  Google Scholar 

  12. Chiu MI, Katz H, Berlin V (1994) RAPT1, a mammalian homolog of yeast Tor, interacts with the FKBP12/rapamycin complex. Proc Natl Acad Sci U S A 91(26):12574–12578

    Article  CAS  Google Scholar 

  13. Hay N, Sonenberg N (2004) Upstream and downstream of mTOR. Genes Dev 18(16):1926–1945. https://doi.org/10.1101/gad.1212704

    Article  CAS  PubMed  Google Scholar 

  14. Peterson RT, Beal PA, Comb MJ, Schreiber SL (2000) FKBP12-rapamycin-associated protein (FRAP) autophosphorylates at serine 2481 under translationally repressive conditions. J Biol Chem 275(10):7416–7423

    Article  CAS  Google Scholar 

  15. Gingras AC, Raught B, Sonenberg N (2001) Regulation of translation initiation by FRAP/mTOR. Genes Dev 15(7):807–826. https://doi.org/10.1101/gad.887201

    Article  CAS  PubMed  Google Scholar 

  16. Perry J, Kleckner N (2003) The ATRs, ATMs, and TORs are giant HEAT repeat proteins. Cell 112(2):151–155

    Article  CAS  Google Scholar 

  17. Soliman GA, Acosta-Jaquez HA, Dunlop EA, Ekim B, Maj NE, Tee AR et al (2010) mTOR Ser-2481 autophosphorylation monitors mTORC-specific catalytic activity and clarifies rapamycin mechanism of action. J Biol Chem 285(11):7866–7879. https://doi.org/10.1074/jbc.M109.096222

    Article  CAS  PubMed  Google Scholar 

  18. Feldman ME, Apsel B, Uotila A, Loewith R, Knight ZA, Ruggero D et al (2009) Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol 7(2):e38. https://doi.org/10.1371/journal.pbio.1000038

    Article  CAS  PubMed  Google Scholar 

  19. Miyazaki M, Esser KA (2009) Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals. J Appl Physiol (1985) 106(4):1367–1373. https://doi.org/10.1152/japplphysiol.91355.2008

    Article  CAS  Google Scholar 

  20. Jordan NJ, Dutkowski CM, Barrow D, Mottram HJ, Hutcheson IR, Nicholson RI et al (2014) Impact of dual mTORC1/2 mTOR kinase inhibitor AZD8055 on acquired endocrine resistance in breast cancer in vitro. Breast Cancer Res 16(1):R12. https://doi.org/10.1186/bcr3604

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Sandri M (2008) Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda) 23:160–170. https://doi.org/10.1152/physiol.00041.2007

    Article  CAS  Google Scholar 

  22. Smerdon SJ (2014) A year in structural signaling: mTOR–the PIKK of the bunch? Sci Signal 7(315):pe6. https://doi.org/10.1126/scisignal.2005174

    Article  CAS  PubMed  Google Scholar 

  23. Anjum R, Blenis J (2008) The RSK family of kinases: emerging roles in cellular signalling. Nat Rev Mol Cell Biol 9(10):747–758. https://doi.org/10.1038/nrm2509

    Article  CAS  PubMed  Google Scholar 

  24. Latres E, Amini AR, Amini AA, Griffiths J, Martin FJ, Wei Y et al (2005) Insulin-like growth factor-1 (IGF-1) inversely regulates atrophy-induced genes via the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway. J Biol Chem 280(4):2737–2744. https://doi.org/10.1074/jbc.M407517200

    Article  CAS  PubMed  Google Scholar 

  25. Reid MB (2005) Response of the ubiquitin-proteasome pathway to changes in muscle activity. Am J Physiol Regul Integr Comp Physiol 288(6):R1423–R1431. https://doi.org/10.1152/ajpregu.00545.2004

    Article  CAS  PubMed  Google Scholar 

  26. Pallafacchina G, Calabria E, Serrano AL, Kalhovde JM, Schiaffino S (2002) A protein kinase B-dependent and rapamycin-sensitive pathway controls skeletal muscle growth but not fiber type specification. Proc Natl Acad Sci U S A 99(14):9213–9218. https://doi.org/10.1073/pnas.142166599

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Laplante M, Sabatini DM (2012) mTOR Signaling. Cold Spring Harb Perspect Biol 4(2):a011593. https://doi.org/10.1101/cshperspect.a011593

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Krieg J, Hofsteenge J, Thomas G (1988) Identification of the 40 S ribosomal protein S6 phosphorylation sites induced by cycloheximide. J Biol Chem 263(23):11473–11477

    CAS  PubMed  Google Scholar 

  29. Jefferies HB, Fumagalli S, Dennis PB, Reinhard C, Pearson RB, Thomas G (1997) Rapamycin suppresses 5’TOP mRNA translation through inhibition of p70s6k. EMBO J 16(12):3693–3704. https://doi.org/10.1093/emboj/16.12.3693

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kawasome H, Papst P, Webb S, Keller GM, Johnson GL, Gelfand EW et al (1998) Targeted disruption of p70(s6k) defines its role in protein synthesis and rapamycin sensitivity. Proc Natl Acad Sci U S A 95(9):5033–5038

    Article  CAS  Google Scholar 

  31. Hershey JWB, Merrick WC (2000) Pathway and mechanism of initiation of protein synthesis. In: Sonenberg N, Hershey JWB, Mathews MB (eds) Translational control of gene expression. Cold Spring Harbor Laboratory Press, New York, pp 33–88

    Google Scholar 

  32. Wang X, Regufe da Mota S, Liu R, Moore CE, Xie J, Lanucara F et al (2014) Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling. Mol Cell Biol 34(22):4088–4103. https://doi.org/10.1128/MCB.01035-14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Ma XM, Blenis J (2009) Molecular mechanisms of mTOR-mediated translational control. Nat Rev Mol Cell Biol 10(5):307–318. https://doi.org/10.1038/nrm2672

    Article  CAS  PubMed  Google Scholar 

  34. Marcotrigiano J, Gingras AC, Sonenberg N, Burley SK (1999) Cap-dependent translation initiation in eukaryotes is regulated by a molecular mimic of eIF4G. Mol Cell 3(6):707–716

    Article  CAS  Google Scholar 

  35. Rommel C, Bodine SC, Clarke BA, Rossman R, Nunez L, Stitt TN et al (2001) 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(11):1009–1013. https://doi.org/10.1038/ncb1101-1009

    Article  CAS  PubMed  Google Scholar 

  36. Goodman CA, Frey JW, Mabrey DM, Jacobs BL, Lincoln HC, You JS et al (2011) The role of skeletal muscle mTOR in the regulation of mechanical load-induced growth. J Physiol 589(Pt 22):5485–5501. https://doi.org/10.1113/jphysiol.2011.218255

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Dreyer HC, Fujita S, Cadenas JG, Chinkes DL, Volpi E, Rasmussen BB (2006) Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol 576(Pt 2):613–624. https://doi.org/10.1113/jphysiol.2006.113175

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wilkinson SB, Phillips SM, Atherton PJ, Patel R, Yarasheski KE, Tarnopolsky MA et al (2008) Differential effects of resistance and endurance exercise in the fed state on signalling molecule phosphorylation and protein synthesis in human muscle. J Physiol 586(15):3701–3717. https://doi.org/10.1113/jphysiol.2008.153916

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ohanna M, Sobering AK, Lapointe T, Lorenzo L, Praud C, Petroulakis E et al (2005) Atrophy of S6K1(-/-) skeletal muscle cells reveals distinct mTOR effectors for cell cycle and size control. Nat Cell Biol 7(3):286–294. https://doi.org/10.1038/ncb1231

    Article  CAS  PubMed  Google Scholar 

  40. Ogasawara R, Fujita S, Hornberger TA, Kitaoka Y, Makanae Y, Nakazato K et al (2016) The role of mTOR signalling in the regulation of skeletal muscle mass in a rodent model of resistance exercise. Sci Rep 6:31142. https://doi.org/10.1038/srep31142

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Vavvas D, Apazidis A, Saha AK, Gamble J, Patel A, Kemp BE et al (1997) Contraction-induced changes in acetyl-CoA carboxylase and 5’-AMP-activated kinase in skeletal muscle. J Biol Chem 272(20):13255–13261

    Article  CAS  Google Scholar 

  42. Musi N, Hayashi T, Fujii N, Hirshman MF, Witters LA, Goodyear LJ (2001) AMP-activated protein kinase activity and glucose uptake in rat skeletal muscle. Am J Physiol Endocrinol Metab 280(5):E677–E684. https://doi.org/10.1152/ajpendo.2001.280.5.E677

    Article  CAS  PubMed  Google Scholar 

  43. Ogasawara R, Sato K, Matsutani K, Nakazato K, Fujita S (2014) The order of concurrent endurance and resistance exercise modifies mTOR signaling and protein synthesis in rat skeletal muscle. Am J Physiol Endocrinol Metab 306(10):E1155–E1162. https://doi.org/10.1152/ajpendo.00647.2013

    Article  CAS  PubMed  Google Scholar 

  44. West DW, Baehr LM, Marcotte GR, Chason CM, Tolento L, Gomes AV et al (2016) Acute resistance exercise activates rapamycin-sensitive and -insensitive mechanisms that control translational activity and capacity in skeletal muscle. J Physiol 594(2):453–468. https://doi.org/10.1113/JP271365

    Article  CAS  PubMed  Google Scholar 

  45. Pardo OE, Seckl MJ (2013) S6K2: the neglected S6 kinase family member. Front Oncol 3:191. https://doi.org/10.3389/fonc.2013.00191

    Article  PubMed  PubMed Central  Google Scholar 

  46. Pende M, Um SH, Mieulet V, Sticker M, Goss VL, Mestan J et al (2004) S6K1(-/-)/S6K2(-/-) mice exhibit perinatal lethality and rapamycin-sensitive 5′-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway. Mol Cell Biol 24(8):3112–3124

    Article  CAS  Google Scholar 

  47. Valovka T, Verdier F, Cramer R, Zhyvoloup A, Fenton T, Rebholz H et al (2003) Protein kinase C phosphorylates ribosomal protein S6 kinase betaII and regulates its subcellular localization. Mol Cell Biol 23(3):852–863

    Article  CAS  Google Scholar 

  48. Sanchez AM, Bernardi H, Py G, Candau RB (2014) Autophagy is essential to support skeletal muscle plasticity in response to endurance exercise. Am J Physiol Regul Integr Comp Physiol 307(8):R956–R969. https://doi.org/10.1152/ajpregu.00187.2014

    Article  CAS  PubMed  Google Scholar 

  49. Kennedy BK, Lamming DW (2016) The mechanistic target of rapamycin: the grand conducTOR of metabolism and aging. Cell Metab 23(6):990–1003. https://doi.org/10.1016/j.cmet.2016.05.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Weichhart T (2018) mTOR as regulator of lifespan, aging, and cellular senescence: a mini-review. Gerontology 64(2):127–134. https://doi.org/10.1159/000484629

    Article  CAS  PubMed  Google Scholar 

  51. Dasuri K, Zhang L, Keller JN (2013) Oxidative stress, neurodegeneration, and the balance of protein degradation and protein synthesis. Free Radic Biol Med 62:170–185. https://doi.org/10.1016/j.freeradbiomed.2012.09.016

    Article  CAS  PubMed  Google Scholar 

  52. Perluigi M, Di Domenico F, Butterfield DA (2015) mTOR signaling in aging and neurodegeneration: at the crossroad between metabolism dysfunction and impairment of autophagy. Neurobiol Dis 84:39–49. https://doi.org/10.1016/j.nbd.2015.03.014

    Article  CAS  PubMed  Google Scholar 

  53. Castets P, Rüegg MA (2013) MTORC1 determines autophagy through ULK1 regulation in skeletal muscle. Autophagy 9(9):1435–1437. https://doi.org/10.4161/auto.25722

    Article  CAS  PubMed  Google Scholar 

  54. Pagano AF, Py G, Bernardi H, Candau RB, Sanchez AM (2014) Autophagy and protein turnover signaling in slow-twitch muscle during exercise. Med Sci Sports Exerc 46(7):1314–1325. https://doi.org/10.1249/MSS.0000000000000237

    Article  CAS  PubMed  Google Scholar 

  55. Møller AB, Vendelbo MH, Christensen B, Clasen BF, Bak AM, Jørgensen JO et al (2015) Physical exercise increases autophagic signaling through ULK1 in human skeletal muscle. J Appl Physiol (1985) 118(8):971–979. https://doi.org/10.1152/japplphysiol.01116.2014

    Article  CAS  Google Scholar 

  56. Fritzen AM, Madsen AB, Kleinert M, Treebak JT, Lundsgaard AM, Jensen TE et al (2016) Regulation of autophagy in human skeletal muscle: effects of exercise, exercise training and insulin stimulation. J Physiol 594(3):745–761. https://doi.org/10.1113/JP271405

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Tan VP, Miyamoto S (2016) Nutrient-sensing mTORC1: integration of metabolic and autophagic signals. J Mol Cell Cardiol 95:31–41. https://doi.org/10.1016/j.yjmcc.2016.01.005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Cunningham JT, Rodgers JT, Arlow DH, Vazquez F, Mootha VK, Puigserver P (2007) mTOR controls mitochondrial oxidative function through a YY1-PGC-1alpha transcriptional complex. Nature 450(7170):736–740. https://doi.org/10.1038/nature06322

    Article  CAS  PubMed  Google Scholar 

  59. Scarpulla RC (2011) Metabolic control of mitochondrial biogenesis through the PGC-1 family regulatory network. Biochim Biophys Acta 1813(7):1269–1278. https://doi.org/10.1016/j.bbamcr.2010.09.019

    Article  CAS  PubMed  Google Scholar 

  60. Schieke SM, Finkel T (2007) TOR and aging: less is more. Cell Metab 5(4):233–235. https://doi.org/10.1016/j.cmet.2007.03.005

    Article  CAS  PubMed  Google Scholar 

  61. Schieke SM, Phillips D, McCoy JP, Aponte AM, Shen RF, Balaban RS et al (2006) The mammalian target of rapamycin (mTOR) pathway regulates mitochondrial oxygen consumption and oxidative capacity. J Biol Chem 281(37):27643–27652. https://doi.org/10.1074/jbc.M603536200

    Article  CAS  PubMed  Google Scholar 

  62. Finley LW, Haigis MC (2009) The coordination of nuclear and mitochondrial communication during aging and calorie restriction. Ageing Res Rev 8(3):173–188. https://doi.org/10.1016/j.arr.2009.03.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Sack MN, Finkel T (2012) Mitochondrial metabolism, sirtuins, and aging. Cold Spring Harb Perspect Biol 4(12):a013102. https://doi.org/10.1101/cshperspect.a013102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Johnson ML, Robinson MM, Nair KS (2013) Skeletal muscle aging and the mitochondrion. Trends Endocrinol Metab 24(5):247–256. https://doi.org/10.1016/j.tem.2012.12.003

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Russell AP, Foletta VC, Snow RJ, Wadley GD (2014) Skeletal muscle mitochondria: a major player in exercise, health and disease. Biochim Biophys Acta 1840(4):1276–1284. https://doi.org/10.1016/j.bbagen.2013.11.016

    Article  CAS  PubMed  Google Scholar 

  66. Carter HN, Chen CC, Hood DA (2015) Mitochondria, muscle health, and exercise with advancing age. Physiology (Bethesda) 30(3):208–223. https://doi.org/10.1152/physiol.00039.2014

    Article  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Programa de Pós-Graduação em Fisioterapia (PPGFt), Departamento de Fisioterapia, Centro de Ciências da Saúde e do Esporte (CEFID), Universidade do Estado de Santa Catarina (UDESC), Florianópolis, Santa Catarina, Brazil

    Jocemar Ilha, Caroline Cunha do Espírito-Santo & Gabriel Ribeiro de Freitas

  2. Laboratório Neurobiologia da Dor e Inflamação (LANDI), Departamento de Ciências Fisiológicas, Universidade Federal de Santa Catarina (UFSC), Florianópolis, Santa Catarina, Brazil

    Caroline Cunha do Espírito-Santo

Authors
  1. Jocemar Ilha
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Caroline Cunha do Espírito-Santo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gabriel Ribeiro de Freitas
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jocemar Ilha .

Editor information

Editors and Affiliations

  1. Cardiac Regeneration and Ageing Lab, Institute of Cardiovascular Sciences, School of Life Science, Shanghai University, Shanghai, China

    Junjie Xiao

Rights and permissions

Reprints and permissions

Copyright information

© 2018 Springer Nature Singapore Pte Ltd.

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Ilha, J., do Espírito-Santo, C.C., de Freitas, G.R. (2018). mTOR Signaling Pathway and Protein Synthesis: From Training to Aging and Muscle Autophagy. In: Xiao, J. (eds) Muscle Atrophy. Advances in Experimental Medicine and Biology, vol 1088. Springer, Singapore. https://doi.org/10.1007/978-981-13-1435-3_7

Download citation

Publish with us

Policies and ethics

Search

Navigation