Biology Bulletin Reviews

, Volume 8, Issue 6, pp 489–496 | Cite as

The Adaptation Role of Serine/Threonine Kinase Akt1 in Anabolism of Muscular Tissue

  • V. S. SukhorukovEmail author
  • T. I. BaranichEmail author
  • D. N. AtochinEmail author
  • V. V. GlinkinaEmail author


The article reviews the particular qualities of the key signal component of anabolic pathways (serine/threonine kinase Akt1) in the regulation of skeletal muscle functioning, both under normal conditions and in the dystrophic process, including Duchenne’s muscular dystrophy. The current data confirm the participation of the Akt1 signal pathway in the processes of skeletal muscle regeneration, as well as in the mechanism of angiogenesis amplification, which demonstrates the great therapeutic potential of Akt1 as a target for the treatment of a wide range of hereditary and acquired neuromuscular diseases.


Akt1 skeletal muscle hypertrophy dystrophy angiogenesis 



This study was supported by the Russian Science Foundation (grant no. 17-15-01111).


Сonflict of interests. The authors declare that they have no conflict of interest.

Statement on the welfare of animals. This article does not contain any studies involving animals performed by any of the authors.


  1. 1.
    Akasaki, Y., Ouchi, N., Izumiya, Y., et al., Glycolytic fast-twitch muscle fiber restoration counters adverse age-related changes in body composition and metabolism, Aging Cell, 2014, vol. 13, pp. 80–91.CrossRefGoogle Scholar
  2. 2.
    Altomare, D.A. and Testa, J.R., Perturbations of the Akt signaling pathway in human cancer, Oncogene, 2005, vol. 24, pp. 7455–7464.CrossRefGoogle Scholar
  3. 3.
    Amoasii, L., Hnia, K., Chicanne, G., et al., Myotubularin and PtdIns3P remodel the sarcoplasmic reticulum in muscle in vivo, J. Cell Sci., 2013, vol. 126, pp. 1806–1819.CrossRefGoogle Scholar
  4. 4.
    Araki, S., Izumiya, Y., Hanatani, S., et al., Akt1-mediated skeletal muscle growth attenuates cardiac dysfunction and remodeling after experimental myocardial infarction, Circ. Heart Fail, 2012, vol. 5, pp. 116–125.CrossRefGoogle Scholar
  5. 5.
    Atochin, D. and Huang, P., Protective role of Akt1-S1177 against stroke, in Adaptation Biology and Medicine: Current Trends, New Delhi: Narosa Press, 2017, pp. 167–172.Google Scholar
  6. 6.
    Bellacosa, A., Kumar, C.C., Di Cristofano, A., and Testa, J.R., Activation of Akt kinases in cancer: implications for therapeutic targeting, Adv. Cancer Res., 2005, vol. 94, pp. 29–86.CrossRefGoogle Scholar
  7. 7.
    Blaauw, B., The Effects of Akt Overexpression in Normal and Dystrophic Skeletal Muscle, Padova: Univ. Degli Stud. Padova, 2008.Google Scholar
  8. 8.
    Bodine, S.C., Latres, E., Baumhueter, S., et al., Identification of ubiquitin ligases required for skeletal muscle atrophy, Science, 2001, vol. 294, pp. 1704–1708.CrossRefGoogle Scholar
  9. 9.
    Boppart, M.D., Burkin, D.J., and Kaufman, S.J., Activation of Akt signaling promotes cell growth and survival in α7β1 integrin-mediated alleviation of muscular dystrophy, Biochim. Biophys. Acta, 2011, vol. 1812, no. 4, pp. 439–446.CrossRefGoogle Scholar
  10. 10.
    Brazil, D.P. and Hemmings, B.A., Ten years of protein kinase B signaling: a hard Akt to follow, Trends Biochem. Sci., 2001, vol. 26, pp. 657–664.CrossRefGoogle Scholar
  11. 11.
    Brazil, D.P., Park, J., and Hemmings, B.A., PKB binding proteins. Getting in on the Akt, Cell, 2002, vol. 111, pp. 293–303.CrossRefGoogle Scholar
  12. 12.
    Brodbeck, D., Cron, P., and Hemmings, B.A., A human protein kinase B[gamma] with regulatory phosphorylation sites in the activation loop and in the C-terminal hydrophobic domain, J. Biol. Chem., 1999, vol. 274, pp. 9133–9136.CrossRefGoogle Scholar
  13. 13.
    Brookes, P.S., Yoon, Y., Robotham, J.L., et al., Calcium, ATP, and ROS: a mitochondrial love-hate triangle, Am. J. Physiol. Cell Physiol., 2004, vol. 287, pp. 817–833.CrossRefGoogle Scholar
  14. 14.
    Brugarolas, J., Lei, K., Hurley, R.L., et al., Regulation of mTOR function in response to hypoxia by REDD1 and the TSC1/TSC2 tumor suppressor complex, Genes Dev., 2004, vol. 18, pp. 2893–2904.CrossRefGoogle Scholar
  15. 15.
    Brunet, A., Bonni, A., Zigmond, M.J., et al., Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor, Cell, 1999, vol. 96, pp. 857–868.CrossRefGoogle Scholar
  16. 16.
    Burkin, D.J., Wallace, G.Q., Nichol, K.J., et al., Enhanced expression of the α7β1 integrin reduces muscular dystrophy and restores viability in dystrophic mice, J. Cell Biol., 2001, vol. 152, pp. 1207–1218.CrossRefGoogle Scholar
  17. 17.
    Capetanaki, Y., Bloch, R.J., Kouloumenta, A., et al., Muscle intermediate filaments and their links to membranes and membranous organelles, Exp. Cell Res., 2007, vol. 313, pp. 2063–2076.CrossRefGoogle Scholar
  18. 18.
    Cheung, M. and Testa, J.R., Diverse mechanisms of Akt pathway activation in human malignancy, Curr. Cancer Drug Targ., 2013, vol. 13, pp. 234–244.CrossRefGoogle Scholar
  19. 19.
    Clarke, B.A., Drujan, D., Willis, M.S., et al., The E3 ligase MuRF1 degrades myosin heavy chain protein in dexamethasone-treated skeletal muscle, Cell Metab., 2007, vol. 6, pp. 376–385.CrossRefGoogle Scholar
  20. 20.
    Cohen, S., Brault, J.J., Gygi, S.P., et al., During muscle atrophy, thick, but not thin, filament components are degraded by MuRF1-dependent ubiquitylation, J. Cell Biol., 2009, vol. 185, pp. 1083–1095.CrossRefGoogle Scholar
  21. 21.
    Csibi, A., Cornille, K., Leibovitch, M.P., et al., The translation regulatory subunit eIF3f controls the kinase-dependent mTOR signaling required for muscle differentiation and hypertrophy in mouse, PLoS One, 2010, vol. 5, no. 2, p. 8994.CrossRefGoogle Scholar
  22. 22.
    Deconinck, N., Tinsley, J., De Backer, F., et al., Expression of truncated utrophin leads to major functional improvements in dystrophin-deficient muscles of mice, Nat. Med., 1997, vol. 3, pp. 1216–1221.CrossRefGoogle Scholar
  23. 23.
    Dogra, C., Changotra, H., Wergedal, J.E., and Kumar, A., Regulation of phosphatidylinositol 3-kinase (PI3K)/Akt and nuclear factor-kappa B signaling pathways in dystrophin-deficient skeletal muscle in response to mechanical stretch, J. Cell Physiol., 2006, vol. 208, pp. 575–585.CrossRefGoogle Scholar
  24. 24.
    Dubowitz, V., Sewry, C.A., and Oldfors, A., Muscle Biopsy: A Practical Approach, Amsterdam: Elsevier, 2013.Google Scholar
  25. 25.
    Durbeej, M. and Campbell, K.P., Muscular dystrophies involving the dystrophin-glycoprotein complex: an overview of current mouse models, Curr. Opin. Genet. Dev., 2002, vol. 12, pp. 349–361.CrossRefGoogle Scholar
  26. 26.
    Ebihara, S., Guibinga, G.H., Gilbert, R., et al., Differential effects of dystrophin and utrophin gene transfer in immunocompetent muscular dystrophy (mdx) mice, Physiol. Genomics, 2000, vol. 3, pp. 133–144.CrossRefGoogle Scholar
  27. 27.
    Egerman, M.A. and Glass, D.J., Signaling pathways controlling skeletal muscle mass, Crit. Rev. Biochem. Mol. Biol., 2014, vol. 49, pp. 59–68.CrossRefGoogle Scholar
  28. 28.
    Ervasti, J.M., Structure and function of the dystrophinglycoprotein complex, in Molecular Mechanisms of Muscular Dystrophies, Winder, S.J., Ed., Boca Raton: CRC Press, 2006, pp. 1–13.Google Scholar
  29. 29.
    Ervasti, J.M., Ohlendieck, K., Kahl, S.D., et al., Deficiency of a glycoprotein component of the dystrophin complex in dystrophic muscle, Nature, 1990, vol. 345, pp. 315–319.CrossRefGoogle Scholar
  30. 30.
    Fanzani, A., Conraads, V.M., Penna, F., and Martinet, W., Molecular and cellular mechanisms of skeletal muscle atrophy: an update, J. Cachexia Sarcopenia Muscle, 2012, vol. 3, pp. 163–179.CrossRefGoogle Scholar
  31. 31.
    Fayard, E., Tintignac, L.A., Baudry, A., and Hemmings, B.A., Protein kinase B/Akt at a glance, J. Cell Sci., 2005, vol. 118, pp. 5675–5678.CrossRefGoogle Scholar
  32. 32.
    Gomes, M.D., Lecker, S.H., Jagoe, R.T., et al., Atrogin-1, a musclespecific F-box protein highly expressed during muscle atrophy, Proc. Natl. Acad. Sci. U.S.A., 2001, vol. 98, pp. 14440–14445.CrossRefGoogle Scholar
  33. 33.
    Gort, E.H., Groot, A.J., Derks van de Ven, T.L., et al., Hypoxia-inducible factor-1α expression requires PI 3-kinase activity and correlates with Akt1 phosphorylation in invasive breast carcinomas, Oncogene, 2006, vol. 25, pp. 6123–6127.CrossRefGoogle Scholar
  34. 34.
    Gunaratnam, L., Morley, M., Franovic, A., et al., Hypoxia inducible factor activates the transforming growth factor-alpha/epidermal growth factor receptor growth stimulatory pathway in VHL(–/–) renal cell carcinoma cells, J. Biol. Chem., 2003, vol. 278, pp. 44966–44974.CrossRefGoogle Scholar
  35. 35.
    Hanatani, S., Izumiya, Y., Araki, S., et al., Akt1-mediated fast/glycolytic skeletal muscle growth attenuates renal damage in experimental kidney disease, J. Am. Soc. Nephrol., 2014, vol. 25, pp. 2800–2811.CrossRefGoogle Scholar
  36. 36.
    Hers, I., Vincent, E.E., and Tavare, J.M., Akt signalling in health and disease, Cell. Signaling, 2011, vol. 23, pp. 1515–1527.CrossRefGoogle Scholar
  37. 37.
    Heydemann, A. and McNally, E.M., Consequences of disrupting the dystrophin-sarcoglycan complex in cardiac and skeletal myopathy, Trends Cardiovasc. Med., 2007, vol. 17, pp. 55–59.CrossRefGoogle Scholar
  38. 38.
    Hnia, K., Tronchere, H., Tomczak, K.K., et al., Myotubularin controls desmin intermediate filament architecture and mitochondrial dynamics in human and mouse skeletal muscle, J. Clin. Invest., 2011, vol. 121, pp. 70–85.CrossRefGoogle Scholar
  39. 39.
    Hodges, B.L., Hayashi, Y.K., Nonaka, I., et al., Altered expression of the α7β1 integrin in human and murine muscular dystrophies, J. Cell Sci., 1997, vol. 110, pp. 2873–2881.Google Scholar
  40. 40.
    Hoffman, E.P., Brown, R.H., and Kunkel, L.M., Dystrophin: the protein product of the Duchenne muscular dystrophy locus, Cell, 1987, vol. 51, pp. 919–928.CrossRefGoogle Scholar
  41. 41.
    Hollander, M.C., Maier, C.R., Hobbs, E.A., et al., Akt1 deletion prevents lung tumorigenesis by mutant K-ras, Oncogene, 2011, vol. 30, pp. 1812–1821.CrossRefGoogle Scholar
  42. 42.
    Izumiya, Y., Hopkins, T., Morris, C., et al., Fast/glycolytic muscle fiber growth reduces fat mass and improves metabolic parameters in obese mice, Cell Metab., 2008, vol. 7, pp. 159–172.CrossRefGoogle Scholar
  43. 43.
    Krag, T.O., Bogdanovich, S., Jensen, C.J., et al., Heregulin ameliorates the dystrophic phenotype in mdx mice, Proc. Natl. Acad. Sci. U.S.A., 2004, vol. 101, pp. 13856–13860.CrossRefGoogle Scholar
  44. 44.
    Lai, K.M., Gonzalez, M., Poueymirou, W.T., et al., Conditional activation of Akt in adult skeletal muscle induces rapid hypertrophy, Mol. Cell Biol., 2004, vol. 24, pp. 9295–9304.CrossRefGoogle Scholar
  45. 45.
    Langenbach, K.J. and Rando, T.A., Inhibition of dystroglycan binding to laminin disrupts the PI3K/Akt pathway and survival signaling in muscle cells, Muscle Nerve, 2002, vol. 26, pp. 644–653.CrossRefGoogle Scholar
  46. 46.
    Le Cras, T.D., Korfhagen, T.R., Davidson, C., et al., Inhibition of PI3K by PX-866 prevents transforming growth factoralpha-induced pulmonary fibrosis, Am. J. Pathol., 2010, vol. 176, pp. 679–686.CrossRefGoogle Scholar
  47. 47.
    Mammucari, C., Milan, G., Romanello, V., et al., FoxO3 controls autophagy in skeletal muscle in vivo, Cell Metab., 2007, vol. 6, pp. 458–471.CrossRefGoogle Scholar
  48. 48.
    Michael, A., Haq, S., Chen, X., et al., Glycogen synthase kinase-3β regulates growth, calcium homeostasis, and diastolic function in the heart, J. Biol. Chem., 2004, vol. 279, pp. 21383–21393.CrossRefGoogle Scholar
  49. 49.
    Nguyen, H.H., Jayasinha, V., Xia, B., et al., Overexpression of the cytotoxic T cell GalNAc transferase in skeletal muscle inhibits muscular dystrophy in mdx mice, Proc. Natl. Acad. Sci. U.S.A., 2002, vol. 99, pp. 5616–5621.CrossRefGoogle Scholar
  50. 50.
    Ohlendieck, K. and Campbell, K.P., Dystrophin: the protein product of the Duchenne muscular dystrophy locus, J. Cell Biol., 1991, vol. 115, pp. 1685–1694.CrossRefGoogle Scholar
  51. 51.
    Pallafacchina, G., Calabria, E., Serrano, A.L., et al., 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., 2002, vol. 99, pp. 9213–9218.CrossRefGoogle Scholar
  52. 52.
    Persad, S., Attwell, S., Gray, V., et al., Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase, J. Biol. Chem., 2001, vol. 276, pp. 27462–27469.CrossRefGoogle Scholar
  53. 53.
    Peter, A.K. and Crosbie, R.H., Hypertrophic response of Duchenne and limb-girdle muscular dystrophies is associated with activation of Akt pathway, Exp. Cell Res., 2006, vol. 312, pp. 2580–2591.CrossRefGoogle Scholar
  54. 54.
    Pistollato, F., Rampazzo, E., Abbadi, S., et al., Molecular mechanisms of HIF-1α modulation induced by oxygen tension and BMP2 in glioblastoma derived cells, PLoS One, 2009, vol. 4, p. e6206.CrossRefGoogle Scholar
  55. 55.
    Pong, T., Scherrer-Crosbie, M., Atochin, D.N., et al., Phosphomimetic modulation of eNOS improves myocardial reperfusion and mimics cardiac postconditioning in mice, PLoS One, 2014, vol. 9, no. 1, p. e85946.CrossRefGoogle Scholar
  56. 56.
    Rodgers, J.T., King, K.Y., Brett, J.O., et al., mTORC1 controls the adaptive transition of quiescent stem cells from G0 to G (Alert), Nature, 2014, vol. 510, pp. 393–396.CrossRefGoogle Scholar
  57. 57.
    Ruegg, M.A. and Glass, D.J., Molecular mechanisms and treatment options for muscle wasting diseases, Ann. Rev. Pharmacol. Toxicol., 2011, vol. 51, pp. 373–395.CrossRefGoogle Scholar
  58. 58.
    Sandri, M., Sandri, C., Gilbert, A., et al., FoxO transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy, Cell, 2004, vol. 117, pp. 399–412.CrossRefGoogle Scholar
  59. 59.
    Schiaffino, S., Dyar, K.A., Ciciliot, S., et al., Mechanisms regulating skeletal muscle growth and atrophy, FEBS J., 2013, vol. 280, pp. 4294–4314.CrossRefGoogle Scholar
  60. 60.
    Squire, S., Raymackers, J.M., Vandebrouck, C., et al., Prevention of pathology in mdx mice by expression of utrophin: analysis using an inducible transgenic expression system, Hum. Mol. Genet., 2002, vol. 11, pp. 3333–3344.CrossRefGoogle Scholar
  61. 61.
    Stitt, T.N., Drujan, D., Clarke, B.A., et al., The IGF-1/PI3K/Akt pathway prevents expression of muscle atrophy-induced ubiquitin ligases by inhibiting FoxO transcription factors, Mol. Cell, 2004, vol. 14, pp. 395–403.CrossRefGoogle Scholar
  62. 62.
    Stupka, N., Plant, D.R., Schertzer, J.D., et al., Activated calcineurin ameliorates contraction-induced injury to skeletal muscles of mdx dystrophic mice, J. Physiol., 2006, vol. 575, pp. 645–656.CrossRefGoogle Scholar
  63. 63.
    Takahashi, A., Kureishi, Y., Yang, J., et al., Myogenic Akt signaling regulates blood vessel recruitment during myofiber growth, Mol. Cell Biol., 2002, vol. 22, pp. 4803–4814.CrossRefGoogle Scholar
  64. 64.
    Takano, K., Watanabe-Takano, H., Suetsugu, S., et al., Nebulin and N-WASP cooperate to cause IGF-1-induced sarcomeric actin filament formation, Science, 2010, vol. 330, pp. 1536–1540.CrossRefGoogle Scholar
  65. 65.
    Tinsley, J.M., Potter, A.C., Phelps, S.R., et al., Amelioration of the dystrophic phenotype of mdx mice using a truncated utrophin transgene, Nature, 1996, vol. 384, pp. 349–353.CrossRefGoogle Scholar
  66. 66.
    Tinsley, J., Deconinck, N., Risher, R., et al., Expression of full-length utrophin prevents muscular dystrophy in mdx mice, Nat. Med., 1998, vol. 4, pp. 1441–1444.CrossRefGoogle Scholar
  67. 67.
    Tintignac, L.A., Lagirand, J., Batonnet, S., et al., Degradation of MyoD mediated by the SCF (MAFbx) ubiquitin ligase, J. Biol. Chem., 2005, vol. 280, no. 4, pp. 2847–2856.CrossRefGoogle Scholar
  68. 68.
    Troussard, A.A., Mawji, N.M., Ong, C., et al., Conditional knock-out of integrin-linked kinase (ILK) demonstrates an essential role in PKB/Akt activation, J. Biol. Chem., 2003, vol. 278, pp. 22374–22378.CrossRefGoogle Scholar
  69. 69.
    Whitmore, C. and Morgan, J., What do mouse models of muscular dystrophy tell us about the DAPC and its components? Int. J. Exp. Pathol., 2014, vol. 95, no. 6, pp. 365–377.CrossRefGoogle Scholar
  70. 70.
    Wilson, E.M. and Rotwein, P., Selective control of skeletal muscle differentiation by Akt1, J. Biol. Chem., 2007, vol. 282, pp. 5106–5110.CrossRefGoogle Scholar
  71. 71.
    Woolstenhulme, M.T., Conlee, R.K., Drummond, M.J., et al., Temporal response of desmin and dystrophin proteins to progressive resistance exercise in human skeletal muscle, J. Appl. Physiol., 2006, vol. 100, pp. 1876–1882.CrossRefGoogle Scholar
  72. 72.
    Wu, C.L., Satomi, Y., and Walsh, K., RNA-seq and metabolomic analyses of Akt1-mediated muscle growth reveals regulation of regenerative pathways and changes in the muscle secretome, BMC Genomics, 2017, vol. 18, no. 1, p. 181.CrossRefGoogle Scholar
  73. 73.
    Yoshida, M. and Ozawa, E., Glycoprotein complex anchoring dystrophin to sarcolemma, J. Biochem., 1990, vol. 108, pp. 748–752.CrossRefGoogle Scholar
  74. 74.
    Zhang, P., Liang, X., Shan, T., et al., mTOR is necessary for proper satellite cell activity and skeletal muscle regeneration, Biochem. Biophys. Res. Commun., 2015, vol. 463, pp. 102–108.CrossRefGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2018

Authors and Affiliations

  1. 1.Center of Personalized Medicine, Sechenov First Moscow State Medical UniversityMoscowRussia
  2. 2.Pirogov Russian National Research Medical UniversityMoscowRussia
  3. 3.Russian-Speaking Academic Science Association (RASA) Center, National Research Tomsk Polytechnic UniversityTomskRussia
  4. 4.Cardiovascular Research Center, Cardiology Department, Massachusetts General Hospital, Harvard Medical SchoolCharlestownUnited States

Personalised recommendations