Skip to main content
SpringerLink
Log in

Autophagic Cellular Responses to Physical Exercise in Skeletal Muscle

  • Review Article
  • Published:
Sports Medicine Aims and scope Submit manuscript

Abstract

Autophagy is an evolutionarily conserved biological process that functions to recycle protein aggregate and malfunctioned organelles. The activation of autophagy can be stimulated by a number of ways including infection, caloric restriction, and physical exercise. In addition to cellular metabolism and cell survival/death machinery, autophagy plays an important role in the maintenance of cellular homeostasis in skeletal muscle especially during physical exercise in which energy demand can be extremely high. By degrading macromolecules and subcellular organelles through the fusion of autophagosomes and lysosomes, useful materials such as amino acids can be released and re-used to sustain normal metabolism in cells. Autophagy is suggested to be involved in glucose and lipid metabolism and is proposed to be a critical physiological process in the regulation of intracellular metabolism. The effects of physical exercise on autophagy have been investigated. Although physical exercise has been demonstrated to be an autophagic inducer, cellular autophagic responses to exercise in skeletal muscle appear to be varied in different exercise protocols and disease models. It is also not known whether the exercise-induced beneficial health consequences involve the favorable modulation of cellular autophagy. Furthermore, the cellular mechanisms of exercise-induced autophagy still remain largely unclear. In this review article, we discuss the general principle of autophagy, cellular signaling of autophagy, autophagic responses to acute and chronic aerobic exercise, and the potential cross-talks among autophagy, mitochondrial biogenesis, and ubiquitination. This article aims to stimulate further studies in exercise and autophagy.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1

Similar content being viewed by others

References

  1. Guller I, Russell AP. MicroRNAs in skeletal muscle: their role and regulation in development, disease and function. J Physiol. 2010;588(Pt 21):4075–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  2. Katz A. Modulation of glucose transport in skeletal muscle by reactive oxygen species. J Appl Physiol. 2007;102(4):1671–6.

    CAS  PubMed  Google Scholar 

  3. Delp MD, Colleran PN, Wilkerson MK, McCurdy MR, Muller-Delp J. Structural and functional remodeling of skeletal muscle microvasculature is induced by simulated microgravity. Am J Physiol Heart Circ Physiol. 2000;278(6):H1866–73.

    CAS  PubMed  Google Scholar 

  4. Poole K, Froggatt K. Loss of weight and loss of appetite in advanced cancer: a problem for the patient, the carer, or the health professional? Palliat Med. 2002;16(6):499–506.

    PubMed  Google Scholar 

  5. Tisdale MJ. Mechanisms of cancer cachexia. Physiol Rev. 2009;89(2):381–410.

    CAS  PubMed  Google Scholar 

  6. Doherty TJ. Invited review: aging and sarcopenia. J Appl Physiol. 2003;95(4):1717–27.

    CAS  PubMed  Google Scholar 

  7. Koopman R, van Loon LJ. Aging, exercise, and muscle protein metabolism. J Appl Physiol. 2009;106(6):2040–8.

    CAS  PubMed  Google Scholar 

  8. Gibala MJ, Little JP, Macdonald MJ, Hawley JA. Physiological adaptations to low-volume, high-intensity interval training in health and disease. J Physiol. 2012;590(Pt 5):1077–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Praet SF, van Loon LJ. Optimizing the therapeutic benefits of exercise in type 2 diabetes. J Appl Physiol. 2007;103(4):1113–20.

    PubMed  Google Scholar 

  10. Combaret L, Dardevet D, Rieu I, Pouch MN, Bechet D, Taillandier D, et al. A leucine-supplemented diet restores the defective postprandial inhibition of proteasome-dependent proteolysis in aged rat skeletal muscle. J Physiol. 2005;569(Pt 2):489–99.

    CAS  PubMed Central  PubMed  Google Scholar 

  11. Rubinsztein DC. The roles of intracellular protein-degradation pathways in neurodegeneration. Nature. 2006;443(7113):780–6.

    CAS  PubMed  Google Scholar 

  12. Mizushima N. Autophagy: process and function. Genes Dev. 2007;21(22):2861–73.

    CAS  PubMed  Google Scholar 

  13. Maiuri MC, Zalckvar E, Kimchi A, Kroemer G. Self-eating and self-killing: crosstalk between autophagy and apoptosis. Nat Rev Mol Cell Biol. 2007;8(9):741–52.

    CAS  PubMed  Google Scholar 

  14. Kuma A, Hatano M, Matsui M, Yamamoto A, Nakaya H, Yoshimori T, et al. The role of autophagy during the early neonatal starvation period. Nature. 2004;432(7020):1032–6.

    CAS  PubMed  Google Scholar 

  15. Hara T, Nakamura K, Matsui M, Yamamoto A, Nakahara Y, Suzuki-Migishima R, et al. Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature. 2006;441(7095):885–9.

    CAS  PubMed  Google Scholar 

  16. Komatsu M, Waguri S, Ueno T, Iwata J, Murata S, Tanida I, et al. Impairment of starvation-induced and constitutive autophagy in Atg7-deficient mice. J Cell Biol. 2005;169(3):425–34.

    CAS  PubMed Central  PubMed  Google Scholar 

  17. Elfrink HL, Zwart R, Baas F, Scheper W. Inhibition of endoplasmic reticulum associated degradation reduces endoplasmic reticulum stress and alters lysosomal morphology and distribution. Mol Cells. 2013;35:291–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Caccamo A, Magri A, Medina DX, Wisely EV, Lopez-Aranda MF, Silva AJ, et al. mTOR regulates tau phosphorylation and degradation: implications for Alzheimer’s disease and other tauopathies. Aging Cell. 2013;12:370–80.

    CAS  PubMed  Google Scholar 

  19. Xiong N, Xiong J, Jia M, Liu L, Zhang X, Chen Z, et al. The role of autophagy in Parkinson’s disease: rotenone-based modeling. Behav Brain Funct. 2013;9(1):13.

    CAS  PubMed Central  PubMed  Google Scholar 

  20. Weihl CC. Monitoring autophagy in the treatment of protein aggregate diseases: steps toward identifying autophagic biomarkers. Neurotherapeutics. 2013;10:383–90.

    CAS  PubMed  Google Scholar 

  21. Guo L, Xie B, Mao Z. Autophagy in premature senescent cells is activated via AMPK pathway. Int J Mol Sci. 2012;13(3):3563–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  22. Grumati P, Coletto L, Sabatelli P, Cescon M, Angelin A, Bertaggia E, et al. Autophagy is defective in collagen VI muscular dystrophies, and its reactivation rescues myofiber degeneration. Nat Med. 2010;16(11):1313–20.

    CAS  PubMed  Google Scholar 

  23. Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol. 2011;13(2):132–41.

    CAS  PubMed Central  PubMed  Google Scholar 

  24. Ching JK, Elizabeth SV, Ju JS, Lusk C, Pittman SK, Weihl CC. mTOR dysfunction contributes to vacuolar pathology and weakness in valosin-containing protein associated inclusion body myopathy. Hum Mol Genet. 2013;22(6):1167–79.

    CAS  PubMed Central  PubMed  Google Scholar 

  25. He C, Bassik MC, Moresi V, Sun K, Wei Y, Zou Z, et al. Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis. Nature. 2012;481(7382):511–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Ogura Y, Iemitsu M, Naito H, Kakigi R, Kakehashi C, Maeda S, et al. Single bout of running exercise changes LC3-II expression in rat cardiac muscle. Biochem Biophys Res Commun. 2011;414(4):756–60.

    CAS  PubMed  Google Scholar 

  27. Wohlgemuth SE, Seo AY, Marzetti E, Lees HA, Leeuwenburgh C. Skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise. Exp Gerontol. 2010;45(2):138–48.

    CAS  PubMed Central  PubMed  Google Scholar 

  28. Lum JJ, Bauer DE, Kong M, Harris MH, Li C, Lindsten T, et al. Growth factor regulation of autophagy and cell survival in the absence of apoptosis. Cell. 2005;120(2):237–48.

    CAS  PubMed  Google Scholar 

  29. Yorimitsu T, Klionsky DJ. Autophagy: molecular machinery for self-eating. Cell Death Differ. 2005;12(Suppl 2):1542–52.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Burman C, Ktistakis NT. Autophagosome formation in mammalian cells. Semin Immunopathol. 2010;32(4):397–413.

    CAS  PubMed  Google Scholar 

  31. Xie Z, Klionsky DJ. Autophagosome formation: core machinery and adaptations. Nat Cell Biol. 2007;9(10):1102–9.

    CAS  PubMed  Google Scholar 

  32. Tooze SA, Yoshimori T. The origin of the autophagosomal membrane. Nat Cell Biol. 2010;12(9):831–5.

    CAS  PubMed  Google Scholar 

  33. Hayashi-Nishino M, Fujita N, Noda T, Yamaguchi A, Yoshimori T, Yamamoto A. A subdomain of the endoplasmic reticulum forms a cradle for autophagosome formation. Nat Cell Biol. 2009;11(12):1433–7.

    CAS  PubMed  Google Scholar 

  34. van der Vaart A, Reggiori F. The Golgi complex as a source for yeast autophagosomal membranes. Autophagy. 2010;6(6):800–1.

    PubMed  Google Scholar 

  35. Hailey DW, Rambold AS, Satpute-Krishnan P, Mitra K, Sougrat R, Kim PK, et al. Mitochondria supply membranes for autophagosome biogenesis during starvation. Cell. 2010;141(4):656–67.

    CAS  PubMed Central  PubMed  Google Scholar 

  36. Ravikumar B, Moreau K, Jahreiss L, Puri C, Rubinsztein DC. Plasma membrane contributes to the formation of pre-autophagosomal structures. Nat Cell Biol. 2010;12(8):747–57.

    CAS  PubMed Central  PubMed  Google Scholar 

  37. Patschan S, Chen J, Polotskaia A, Mendelev N, Cheng J, Patschan D, et al. Lipid mediators of autophagy in stress-induced premature senescence of endothelial cells. Am J Physiol Heart Circ Physiol. 2008;294(3):H1119–29.

    CAS  PubMed  Google Scholar 

  38. Chan EY. mTORC1 phosphorylates the ULK1–mAtg13–FIP200 autophagy regulatory complex. Sci Signal. 2009;2(84):pe51.

    PubMed  Google Scholar 

  39. Ganley IG, du Lam H, Wang J, Ding X, Chen S, Jiang X. ULK1.ATG13.FIP200 complex mediates mTOR signaling and is essential for autophagy. J Biol Chem. 2009;284(18):12297–305.

    CAS  PubMed Central  PubMed  Google Scholar 

  40. Matsunaga K, Saitoh T, Tabata K, Omori H, Satoh T, Kurotori N, et al. Two Beclin 1-binding proteins, Atg14L and Rubicon, reciprocally regulate autophagy at different stages. Nat Cell Biol. 2009;11(4):385–96.

    CAS  PubMed  Google Scholar 

  41. Zhong Y, Wang QJ, Li X, Yan Y, Backer JM, Chait BT, et al. Distinct regulation of autophagic activity by Atg14L and Rubicon associated with Beclin 1–phosphatidylinositol-3-kinase complex. Nat Cell Biol. 2009;11(4):468–76.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. He C, Levine B. The Beclin 1 interactome. Curr Opin Cell Biol. 2010;22(2):140–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Pattingre S, Bauvy C, Carpentier S, Levade T, Levine B, Codogno P. Role of JNK1-dependent Bcl-2 phosphorylation in ceramide-induced macroautophagy. J Biol Chem. 2009;284(5):2719–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  44. Wei Y, Pattingre S, Sinha S, Bassik M, Levine B. JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Mol Cell. 2008;30(6):678–88.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Zalckvar E, Berissi H, Mizrachy L, Idelchuk Y, Koren I, Eisenstein M, et al. DAP-kinase-mediated phosphorylation on the BH3 domain of beclin 1 promotes dissociation of beclin 1 from Bcl-XL and induction of autophagy. EMBO Rep. 2009;10(3):285–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Kang R, Zeh HJ, Lotze MT, Tang D. The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ. 2011;18(4):571–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Kirisako T, Ichimura Y, Okada H, Kabeya Y, Mizushima N, Yoshimori T, et al. The reversible modification regulates the membrane-binding state of Apg8/Aut7 essential for autophagy and the cytoplasm to vacuole targeting pathway. J Cell Biol. 2000;151(2):263–76.

    CAS  PubMed Central  PubMed  Google Scholar 

  48. Kabeya Y, Mizushima N, Ueno T, Yamamoto A, Kirisako T, Noda T, et al. LC3, a mammalian homologue of yeast Apg8p, is localized in autophagosome membranes after processing. EMBO J. 2000;19(21):5720–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Humphries WHt, Szymanski CJ, Payne CK. Endo-lysosomal vesicles positive for Rab7 and LAMP1 are terminal vesicles for the transport of dextran. PLoS ONE. 2011;6(10):e26626.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Beertsen W, Willenborg M, Everts V, Zirogianni A, Podschun R, Schroder B, et al. Impaired phagosomal maturation in neutrophils leads to periodontitis in lysosomal-associated membrane protein-2 knockout mice. J Immunol. 2008;180(1):475–82.

    CAS  PubMed  Google Scholar 

  51. Agulhon C, Rostaing P, Ravassard P, Sagne C, Triller A, Giros B. Lysosomal amino acid transporter LYAAT-1 in the rat central nervous system: an in situ hybridization and immunohistochemical study. J Comp Neurol. 2003;462(1):71–89.

    CAS  PubMed  Google Scholar 

  52. Sagne C, Agulhon C, Ravassard P, Darmon M, Hamon M, El Mestikawy S, et al. Identification and characterization of a lysosomal transporter for small neutral amino acids. Proc Natl Acad Sci USA. 2001;98(13):7206–11.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Lee HJ, Cho ED, Lee KW, Kim JH, Cho SG, Lee SJ. Autophagic failure promotes the exocytosis and intercellular transfer of alpha-synuclein. Exp Mol Med. 2013;45:e22.

    PubMed Central  PubMed  Google Scholar 

  54. Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell. 2004;117(3):399–412.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab. 2007;6(6):472–83.

    CAS  PubMed  Google Scholar 

  56. Sanchez AM, Csibi A, Raibon A, Cornille K, Gay S, Bernardi H, et al. AMPK promotes skeletal muscle autophagy through activation of forkhead FoxO3a and interaction with Ulk1. J Cell Biochem. 2012;113(2):695–710.

    CAS  PubMed  Google Scholar 

  57. Bertaggia E, Coletto L, Sandri M. Posttranslational modifications control FoxO3 activity during denervation. Am J Physiol Cell Physiol. 2012;302(3):C587–96.

    CAS  PubMed  Google Scholar 

  58. Nakashima K, Yakabe Y. AMPK activation stimulates myofibrillar protein degradation and expression of atrophy-related ubiquitin ligases by increasing FOXO transcription factors in C2C12 myotubes. Biosci Biotechnol Biochem. 2007;71(7):1650–6.

    CAS  PubMed  Google Scholar 

  59. Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab. 2007;6(6):458–71.

    CAS  PubMed  Google Scholar 

  60. Lee IH, Finkel T. Regulation of autophagy by the p300 acetyltransferase. J Biol Chem. 2009;284(10):6322–8.

    CAS  PubMed  Google Scholar 

  61. Goodman CA, Mayhew DL, Hornberger TA. Recent progress toward understanding the molecular mechanisms that regulate skeletal muscle mass. Cell Signal. 2011;23(12):1896–906.

    CAS  PubMed Central  PubMed  Google Scholar 

  62. Gomes AV, Waddell DS, Siu R, Stein M, Dewey S, Furlow JD, et al. Upregulation of proteasome activity in muscle RING finger 1-null mice following denervation. FASEB J. 2012;26(7):2986–99.

    CAS  PubMed Central  PubMed  Google Scholar 

  63. Mammucari C, Schiaffino S, Sandri M. Downstream of Akt: FoxO3 and mTOR in the regulation of autophagy in skeletal muscle. Autophagy. 2008;4(4):524–6.

    CAS  PubMed  Google Scholar 

  64. Jamart C, Benoit N, Raymackers JM, Kim HJ, Kim CK, Francaux M. Autophagy-related and autophagy-regulatory genes are induced in human muscle after ultraendurance exercise. Eur J Appl Physiol. 2012;112(8):3173–7.

    CAS  PubMed  Google Scholar 

  65. Romanello V, Guadagnin E, Gomes L, Roder I, Sandri C, Petersen Y, et al. Mitochondrial fission and remodelling contributes to muscle atrophy. EMBO J. 2010;29(10):1774–85.

    CAS  PubMed Central  PubMed  Google Scholar 

  66. Raben N, Hill V, Shea L, Takikita S, Baum R, Mizushima N, et al. Suppression of autophagy in skeletal muscle uncovers the accumulation of ubiquitinated proteins and their potential role in muscle damage in Pompe disease. Hum Mol Genet. 2008;17(24):3897–908.

    CAS  PubMed Central  PubMed  Google Scholar 

  67. Masiero E, Agatea L, Mammucari C, Blaauw B, Loro E, Komatsu M, et al. Autophagy is required to maintain muscle mass. Cell Metab. 2009;10(6):507–15.

    CAS  PubMed  Google Scholar 

  68. Jamart C, Francaux M, Millet GY, Deldicque L, Frere D, Feasson L. Modulation of autophagy and ubiquitin–proteasome pathways during ultra-endurance running. J Appl Physiol. 2012;112(9):1529–37.

    CAS  PubMed  Google Scholar 

  69. Sandri M. Autophagy in skeletal muscle. FEBS Lett. 2010;584(7):1411–6.

    CAS  PubMed  Google Scholar 

  70. Grumati P, Coletto L, Schiavinato A, Castagnaro S, Bertaggia E, Sandri M, et al. Physical exercise stimulates autophagy in normal skeletal muscles but is detrimental for collagen VI-deficient muscles. Autophagy. 2011;7(12):1415–23.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Cabrera S, Marino G, Fernandez AF, Lopez-Otin C. Autophagy, proteases and the sense of balance. Autophagy. 2010;6(7):961–3.

    PubMed  Google Scholar 

  72. Bechet D, Tassa A, Combaret L, Taillandier D, Attaix D. Regulation of skeletal muscle proteolysis by amino acids. J Ren Nutr. 2005;15(1):18–22.

    PubMed  Google Scholar 

  73. Mazure NM, Pouyssegur J. Atypical BH3-domains of BNIP3 and BNIP3L lead to autophagy in hypoxia. Autophagy. 2009;5(6):868–9.

    PubMed  Google Scholar 

  74. Guo Y, Xiao P, Lei S, Deng F, Xiao GG, Liu Y, et al. How is mRNA expression predictive for protein expression? A correlation study on human circulating monocytes. Acta Biochim Biophys Sin (Shanghai). 2008;40(5):426–36.

    CAS  Google Scholar 

  75. Vogel C, Marcotte EM. Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev Genet. 2012;13(4):227–32.

    CAS  PubMed Central  PubMed  Google Scholar 

  76. Hardie DG. AMP-activated protein kinase: a cellular energy sensor with a key role in metabolic disorders and in cancer. Biochem Soc Trans. 2011;39(1):1–13.

    CAS  PubMed  Google Scholar 

  77. Kim KH, Jeong YT, Oh H, Kim SH, Cho JM, Kim YN, et al. Autophagy deficiency leads to protection from obesity and insulin resistance by inducing Fgf21 as a mitokine. Nat Med. 2013;19(1):83–92.

    CAS  PubMed  Google Scholar 

  78. Davey RA, MacLean HE. Current and future approaches using genetically modified mice in endocrine research. Am J Physiol Endocrinol Metab. 2006;291(3):E429–38.

    CAS  PubMed  Google Scholar 

  79. Kim YA, Kim YS, Song W. Autophagic response to a single bout of moderate exercise in murine skeletal muscle. J Physiol Biochem. 2012;68(2):229–35.

    CAS  PubMed  Google Scholar 

  80. Corton JM, Gillespie JG, Hardie DG. Role of the AMP-activated protein kinase in the cellular stress response. Curr Biol. 1994;4(4):315–24.

    CAS  PubMed  Google Scholar 

  81. Hardie DG, Salt IP, Davies SP. Analysis of the role of the AMP-activated protein kinase in the response to cellular stress. Methods Mol Biol. 2000;99:63–74.

    CAS  PubMed  Google Scholar 

  82. Derave W, Ai H, Ihlemann J, Witters LA, Kristiansen S, Richter EA, et al. Dissociation of AMP-activated protein kinase activation and glucose transport in contracting slow-twitch muscle. Diabetes. 2000;49(8):1281–7.

    CAS  PubMed  Google Scholar 

  83. Wojtaszewski JF, Jorgensen SB, Hellsten Y, Hardie DG, Richter EA. Glycogen-dependent effects of 5-aminoimidazole-4-carboxamide (AICA)-riboside on AMP-activated protein kinase and glycogen synthase activities in rat skeletal muscle. Diabetes. 2002;51(2):284–92.

    CAS  PubMed  Google Scholar 

  84. Smuder AJ, Kavazis AN, Min K, Powers SK. Exercise protects against doxorubicin-induced markers of autophagy signaling in skeletal muscle. J Appl Physiol. 2011;111(4):1190–8.

    CAS  PubMed  Google Scholar 

  85. Yamamoto Y, Hoshino Y, Ito T, Nariai T, Mohri T, Obana M, et al. Atrogin-1 ubiquitin ligase is upregulated by doxorubicin via p38-MAP kinase in cardiac myocytes. Cardiovasc Res. 2008;79(1):89–96.

    CAS  PubMed  Google Scholar 

  86. Leeuwenburgh C, Fiebig R, Chandwaney R, Ji LL. Aging and exercise training in skeletal muscle: responses of glutathione and antioxidant enzyme systems. Am J Physiol. 1994;267(2 Pt 2):R439–45.

    CAS  PubMed  Google Scholar 

  87. Feng Z, Bai L, Yan J, Li Y, Shen W, Wang Y, et al. Mitochondrial dynamic remodeling in strenuous exercise-induced muscle and mitochondrial dysfunction: regulatory effects of hydroxytyrosol. Free Radic Biol Med. 2011;50(10):1437–46.

    CAS  PubMed  Google Scholar 

  88. LaMonte MJ, Barlow CE, Jurca R, Kampert JB, Church TS, Blair SN. Cardiorespiratory fitness is inversely associated with the incidence of metabolic syndrome: a prospective study of men and women. Circulation. 2005;112(4):505–12.

    PubMed  Google Scholar 

  89. Wohlgemuth SE, Lees HA, Marzetti E, Manini TM, Aranda JM, Daniels MJ, et al. An exploratory analysis of the effects of a weight loss plus exercise program on cellular quality control mechanisms in older overweight women. Rejuvenation Res. 2011;14(3):315–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Matsakas A, Macharia R, Otto A, Elashry MI, Mouisel E, Romanello V, et al. Exercise training attenuates the hypermuscular phenotype and restores skeletal muscle function in the myostatin null mouse. Exp Physiol. 2012;97(1):125–40.

    CAS  PubMed  Google Scholar 

  91. Lee Y, Kim JH, Hong Y, Lee SR, Chang KT. Prophylactic effects of swimming exercise on autophagy-induced muscle atrophy in diabetic rats. Lab Anim Res. 2012;28(3):171–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  92. Lira VA, Okutsu M, Zhang M, Greene NP, Laker RC, Breen DS, et al. Autophagy is required for exercise training-induced skeletal muscle adaptation and improvement of physical performance. FASEB J. 2013;27:4184–93.

    CAS  PubMed  Google Scholar 

  93. Kim YA, Kim YS, Oh SL, et al. Autophagic response to exercise training in skeletal muscle with age. J Physiol Biochem. Epub 2013 Mar 8.

  94. Miyazaki H, Oh-ishi S, Ookawara T, Kizaki T, Toshinai K, Ha S, et al. Strenuous endurance training in humans reduces oxidative stress following exhausting exercise. Eur J Appl Physiol. 2001;84(1–2):1–6.

    CAS  PubMed  Google Scholar 

  95. Peters PG, Alessio HM, Hagerman AE, Ashton T, Nagy S, Wiley RL. Short-term isometric exercise reduces systolic blood pressure in hypertensive adults: possible role of reactive oxygen species. Int J Cardiol. 2006;110(2):199–205.

    PubMed  Google Scholar 

  96. Powers SK, Duarte J, Kavazis AN, Talbert EE. Reactive oxygen species are signalling molecules for skeletal muscle adaptation. Exp Physiol. 2010;95(1):1–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Scherz-Shouval R, Shvets E, Fass E, Shorer H, Gil L, Elazar Z. Reactive oxygen species are essential for autophagy and specifically regulate the activity of Atg4. EMBO J. 2007;26(7):1749–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. O’Leary MF, Hood DA. Denervation-induced oxidative stress and autophagy signaling in muscle. Autophagy. 2009;5(2):230–1.

    PubMed  Google Scholar 

  99. Chu CT, Zhu J, Dagda R. Beclin 1-independent pathway of damage-induced mitophagy and autophagic stress: implications for neurodegeneration and cell death. Autophagy. 2007;3(6):663–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  100. Wenz T, Rossi SG, Rotundo RL, Spiegelman BM, Moraes CT. Increased muscle PGC-1alpha expression protects from sarcopenia and metabolic disease during aging. Proc Natl Acad Sci USA. 2009;106(48):20405–10.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Baar K, Wende AR, Jones TE, Marison M, Nolte LA, Chen M, et al. Adaptations of skeletal muscle to exercise: rapid increase in the transcriptional coactivator PGC-1. FASEB J. 2002;16(14):1879–86.

    CAS  PubMed  Google Scholar 

  102. Calvo JA, Daniels TG, Wang X, Paul A, Lin J, Spiegelman BM, et al. Muscle-specific expression of PPARgamma coactivator-1alpha improves exercise performance and increases peak oxygen uptake. J Appl Physiol (1985). 2008;104(5):1304–12.

    CAS  Google Scholar 

  103. Gibala MJ, McGee SL, Garnham AP, Howlett KF, Snow RJ, Hargreaves M. Brief intense interval exercise activates AMPK and p38 MAPK signaling and increases the expression of PGC-1alpha in human skeletal muscle. J Appl Physiol. 2009;106(3):929–34.

    CAS  PubMed  Google Scholar 

  104. Pilegaard H, Saltin B, Neufer PD. Exercise induces transient transcriptional activation of the PGC-1alpha gene in human skeletal muscle. J Physiol. 2003;546(Pt 3):851–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Safdar A, Little JP, Stokl AJ, Hettinga BP, Akhtar M, Tarnopolsky MA. Exercise increases mitochondrial PGC-1alpha content and promotes nuclear-mitochondrial cross-talk to coordinate mitochondrial biogenesis. J Biol Chem. 2011;286(12):10605–17.

    CAS  PubMed Central  PubMed  Google Scholar 

  106. Man WD, Natanek SA, Riddoch-Contreras J, Lewis A, Marsh GS, Kemp PR, et al. Quadriceps myostatin expression in COPD. Eur Respir J. 2010;36(3):686–8.

    PubMed Central  PubMed  Google Scholar 

  107. Lenk K, Erbs S, Hollriegel R, Beck E, Linke A, Gielen S, et al. Exercise training leads to a reduction of elevated myostatin levels in patients with chronic heart failure. Eur J Prev Cardiol. 2011;19(3):404–11.

    PubMed  Google Scholar 

  108. Baumann AP, Ibebunjo C, Grasser WA, Paralkar VM. Myostatin expression in age and denervation-induced skeletal muscle atrophy. J Musculoskelet Neuronal Interact. 2003;3(1):8–16.

    CAS  PubMed  Google Scholar 

  109. Penna F, Costamagna D, Pin F, Camperi A, Fanzani A, Chiarpotto EM, et al. Autophagic degradation contributes to muscle wasting in cancer cachexia. Am J Pathol. 2013;182(4):1367–78.

    CAS  PubMed  Google Scholar 

  110. Paddon-Jones D, Sheffield-Moore M, Cree MG, Hewlings SJ, Aarsland A, Wolfe RR, et al. Atrophy and impaired muscle protein synthesis during prolonged inactivity and stress. J Clin Endocrinol Metab. 2006;91(12):4836–41.

    CAS  PubMed  Google Scholar 

  111. Lee JY, Hopkinson NS, Kemp PR. Myostatin induces autophagy in skeletal muscle in vitro. Biochem Biophys Res Commun. 2011;415(4):632–6.

    CAS  PubMed  Google Scholar 

  112. Amthor H, Macharia R, Navarrete R, Schuelke M, Brown SC, Otto A, et al. Lack of myostatin results in excessive muscle growth but impaired force generation. Proc Natl Acad Sci USA. 2007;104(6):1835–40.

    CAS  PubMed Central  PubMed  Google Scholar 

  113. Lecker SH, Solomon V, Price SR, Kwon YT, Mitch WE, Goldberg AL. Ubiquitin conjugation by the N-end rule pathway and mRNAs for its components increase in muscles of diabetic rats. J Clin Invest. 1999;104(10):1411–20.

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Spangenburg EE, Le Roith D, Ward CW, Bodine SC. A functional insulin-like growth factor receptor is not necessary for load-induced skeletal muscle hypertrophy. J Physiol. 2008;586(1):283–91.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Ravikumar B, Sarkar S, Davies JE, Futter M, Garcia-Arencibia M, Green-Thompson ZW, et al. Regulation of mammalian autophagy in physiology and pathophysiology. Physiol Rev. 2010;90(4):1383–435.

    CAS  PubMed  Google Scholar 

  116. Sakamoto K, Aschenbach WG, Hirshman MF, Goodyear LJ. Akt signaling in skeletal muscle: regulation by exercise and passive stretch. Am J Physiol Endocrinol Metab. 2003;285(5):E1081–8.

    CAS  PubMed  Google Scholar 

  117. Deldicque L, Atherton P, Patel R, Theisen D, Nielens H, Rennie MJ, et al. Decrease in Akt/PKB signalling in human skeletal muscle by resistance exercise. Eur J Appl Physiol. 2008;104(1):57–65.

    CAS  PubMed  Google Scholar 

  118. Atherton PJ, Smith K. Muscle protein synthesis in response to nutrition and exercise. J Physiol. 2012;590(Pt 5):1049–57.

    CAS  PubMed Central  PubMed  Google Scholar 

  119. Wadley GD, Lee-Young RS, Canny BJ, Wasuntarawat C, Chen ZP, Hargreaves M, et al. Effect of exercise intensity and hypoxia on skeletal muscle AMPK signaling and substrate metabolism in humans. Am J Physiol Endocrinol Metab. 2006;290(4):E694–702.

    CAS  PubMed  Google Scholar 

  120. Friedrichsen M, Mortensen B, Pehmoller C, Birk JB, Wojtaszewski JF. Exercise-induced AMPK activity in skeletal muscle: role in glucose uptake and insulin sensitivity. Mol Cell Endocrinol. 2013;366(2):204–14.

    CAS  PubMed  Google Scholar 

  121. Hardie DG, Hawley SA. AMP-activated protein kinase: the energy charge hypothesis revisited. Bioessays. 2001;23(12):1112–9.

    CAS  PubMed  Google Scholar 

  122. Jung CH, Ro SH, Cao J, Otto NM, Kim DH. mTOR regulation of autophagy. FEBS Lett. 2010;584(7):1287–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Ren JM, Semenkovich CF, Gulve EA, Gao J, Holloszy JO. Exercise induces rapid increases in GLUT4 expression, glucose transport capacity, and insulin-stimulated glycogen storage in muscle. J Biol Chem. 1994;269(20):14396–401.

    CAS  PubMed  Google Scholar 

  124. Douen AG, Ramlal T, Rastogi S, Bilan PJ, Cartee GD, Vranic M, et al. Exercise induces recruitment of the “insulin-responsive glucose transporter”: evidence for distinct intracellular insulin- and exercise-recruitable transporter pools in skeletal muscle. J Biol Chem. 1990;265(23):13427–30.

    CAS  PubMed  Google Scholar 

  125. Russo GL, Russo M, Ungaro P. AMP-activated protein kinase: a target for old drugs against diabetes and cancer. Biochem Pharmacol. 2013;86:339–50.

    CAS  PubMed  Google Scholar 

  126. Musi N, Hirshman MF, Nygren J, Svanfeldt M, Bavenholm P, Rooyackers O, et al. Metformin increases AMP-activated protein kinase activity in skeletal muscle of subjects with type 2 diabetes. Diabetes. 2002;51(7):2074–81.

    CAS  PubMed  Google Scholar 

  127. Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, et al. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001;108(8):1167–74.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Dreyer HC, Fujita S, Cadenas JG, Chinkes DL, Volpi E, Rasmussen BB. Resistance exercise increases AMPK activity and reduces 4E-BP1 phosphorylation and protein synthesis in human skeletal muscle. J Physiol. 2006;576(Pt 2):613–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  129. Musi N, Fujii N, Hirshman MF, Ekberg I, Froberg S, Ljungqvist O, et al. AMP-activated protein kinase (AMPK) is activated in muscle of subjects with type 2 diabetes during exercise. Diabetes. 2001;50(5):921–7.

    CAS  PubMed  Google Scholar 

  130. Cui M, Yu H, Wang J, Gao J, Li J. Chronic caloric restriction and exercise improve metabolic conditions of dietary-induced obese mice in autophagy correlated manner without involving AMPK. J Diabetes Res. 2013;2013:852754.

    PubMed Central  PubMed  Google Scholar 

  131. Mizushima N, Yoshimori T, Levine B. Methods in mammalian autophagy research. Cell. 2010;140(3):313–26.

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgments

During the written process of the present article, the research work of PM Siu was supported by the General Research Fund (PolyU 5632/10M) from the Hong Kong Research Grants Council, Hong Kong Jockey Club Charities Trust, and the Hong Kong Polytechnic University Research Fund. The authors have no potential conflicts of interest that are directly relevant to the content of this review.

Author information

Authors and Affiliations

  1. Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong, China

    Bjorn T. Tam & Parco M. Siu

Authors
  1. Bjorn T. Tam
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Parco M. Siu
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Parco M. Siu.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tam, B.T., Siu, P.M. Autophagic Cellular Responses to Physical Exercise in Skeletal Muscle. Sports Med 44, 625–640 (2014). https://doi.org/10.1007/s40279-013-0140-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40279-013-0140-z

Keywords

Search

Navigation