Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Regulation of muscle growth and regeneration by the immune system

Nature Reviews Immunology volume 17, pages 165–178 (2017)Cite this article

Subjects

Key Points

  • Changes in the stages of myogenesis during muscle regeneration following injury coincide with changes in the phenotype and activation state of leukocytes that invade the damaged, regenerating tissue.

  • Macrophages dominate the inflammatory infiltrate in regenerating muscle, and they are biased towards an M1 phenotype during the early, proliferative stages of muscle regeneration and towards an M2 phenotype during the differentiation and growth phase of regeneration.

  • Signalling initiated by tumour necrosis factor (TNF), interferon-γ (IFNγ), interleukin-10 (IL-10) and insulin-like growth factor 1 (IGF1) has key roles in controlling the normal inflammatory response and myogenic response to muscle damage that is required to achieve muscle regeneration.

  • Disruptions of normal regulatory interactions between myeloid cells and muscle with regulatory T (Treg) cells, CD8+ T cells and fibro-adipogenic progenitor (FAP) cells can prevent successful muscle regeneration following acute injury.

  • Chronic muscle disease and muscle ageing disrupt the normal function of myeloid cells, FAP cells and Treg cells, which can lead to impaired muscle regeneration and increased muscle fibrosis.

  • Manipulations of myeloid cell phenotypes can improve muscle regeneration and growth following muscle trauma.

Abstract

Diseases of muscle that are caused by pathological interactions between muscle and the immune system are devastating, but rare. However, muscle injuries that involve trauma and regeneration are fairly common, and inflammation is a clear feature of the regenerative process. Investigations of the inflammatory response to muscle injury have now revealed that the apparently nonspecific inflammatory response to trauma is actually a complex and coordinated interaction between muscle and the immune system that determines the success or failure of tissue regeneration.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Myogenic precursor cells proceed through a tightly regulated sequence of myogenic-regulatory gene expression during muscle regeneration.
Figure 2: Myogenesis during muscle regeneration is temporally linked with a transition from the initial inflammatory response to a type 2 immune response.
Figure 3: Pro-inflammatory cytokines link inflammation with muscle regeneration.
Figure 4: Interactions between myeloid cells, lymphoid cells, fibro-adipogenic progenitor cells and myogenic precursor cells determine the course of muscle growth and regeneration.
Figure 5: Dysregulation of the immune response to muscle injury increases muscle damage and fibrosis.

Similar content being viewed by others

References

  1. World Health Organization in Global Status Report on Road Safety 2015 340 (World Health Organization, 2015).

  2. Herridge, M. S. et al. One year outcomes in survivors of the acute respiratory distress syndrome. N. Engl. J. Med. 348, 683–693 (2003).

    Article  PubMed  Google Scholar 

  3. Chargé, S. B. & Rudnicki, M. A. Cellular and molecular regulation of muscle regeneration. Physiol. Rev. 84, 209–238 (2004).

    Article  PubMed  Google Scholar 

  4. Sambasivan, R. et al. PAX7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138, 3647–3656 (2011).

    Article  CAS  PubMed  Google Scholar 

  5. Lepper, C., Partridge, T. A. & Fan, C. M. An absolute requirement for PAX7-positive satellite cells in acute injury-induced skeletal muscle regeneration. Development 138, 3639–3646 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  6. Murphy, M. M., Lawson, J. A., Mathew, S. J., Hutcheson, D. A. & Kardon, G. Satellite cells, connective tissue fibroblasts and their interactions are crucial for muscle regeneration. Development 138, 3625–3637 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Megeney, L. A., Kablar, B., Garrett, K., Anderson, J. E. & Rudnicki, M. A. MYOD is required for myogenic stem cell function in adult skeletal muscle. Genes Dev. 10, 1173–1183 (1996).

    Article  CAS  PubMed  Google Scholar 

  8. George, R. M. et al. Numb-deficient satellite cells have regeneration and proliferation defects. Proc. Natl Acad. Sci. USA 110, 18549–18554 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Martinez, C. O. et al. Regulation of skeletal muscle regeneration by CCR2-activating chemokines is directly related to macrophage recruitment. Am. J. Physiol. Regul. Integr. Comp. Physiol. 299, R832–R842 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Villalta, S. A. et al. Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci. Transl Med. 6, 258ra142 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  11. Wang, Y., Wehling-Henricks, M., Samengo, G. & Tidball, J. G. Increases of M2a macrophages and fibrosis in aging muscle are influenced by bone marrow aging and negatively regulated by muscle-derived nitric oxide. Aging Cell 14, 678–688 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Honda, H., Kimura, H. & Rostami, A. Demonstration and phenotypic characterization of resident macrophages in rat skeletal muscle. Immunology 70, 272–277 (1990).

    PubMed  PubMed Central  CAS  Google Scholar 

  13. Brigette, M. et al. Muscle resident macrophages control the immune cell reaction in a mouse model of notexin-induced myoinjury. Arthritis Rheum. 62, 268–279 (2010).

    Article  CAS  Google Scholar 

  14. Krippendorf, B. B. & Riley, D. A. Distinguishing unloading- versus reloading-induced changes in rat soleus muscle. Muscle Nerve 16, 99–108 (1993).

    Article  CAS  PubMed  Google Scholar 

  15. Belcastro, A. N., Arthur, G. D., Albisser, T. A. & Raj, D. A. Heart, liver, and skeletal muscle myeloperoxidase activity during exercise. J. Appl. Physiol. 80, 1331–1335 (1996).

    Article  CAS  PubMed  Google Scholar 

  16. Fielding, R. A. et al. Acute phase response in exercise. III. Neutrophil and IL-1β accumulation in skeletal muscle. Am. J. Physiol. Regul. Integr. Comp. Physiol. 265, R166–R172 (1993).

    Article  CAS  Google Scholar 

  17. Lu, H., Huang, D., Ransohoff, R. M. & Zhou, L. Acute skeletal muscle injury: CCL2 expression by both monocytes and injured muscle is required for repair. FASEB J. 25, 3344–3355 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Warren, G. L. et al. Chemokine receptor CCR2 involvement in skeletal muscle regeneration. FASEB J. 19, 413–415 (2005).

    Article  CAS  PubMed  Google Scholar 

  19. Shireman, P. K. et al. MCP-1 deficiency causes altered inflammation with impaired skeletal muscle regeneration. J. Leukoc. Biol. 81, 775–785 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Contreras-Shannon, V. et al. Fat accumulation with altered inflammation and regeneration in skeletal muscle of CCR2−/− mice following ischemic injury. Am. J. Physiol. Cell Physiol. 292, C953–C967 (2007).

    Article  CAS  PubMed  Google Scholar 

  21. Sun, D. et al. Bone marrow-derived cell regulation of skeletal muscle regeneration. FASEB J. 23, 382–395 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  22. Zhang, J. et al. CD8 T cells are involved in skeletal muscle regeneration through facilitating MCP-1 secretion and GR1high macrophage infiltration. J. Immunol. 193, 5149–5160 (2014).

    Article  CAS  PubMed  Google Scholar 

  23. Collins, R. A. & Grounds, M. D. The role of tumor necrosis factor-α (TNFα) in skeletal muscle regeneration. Studies in TNFα−/− and TNFα−/−/LTα−/− mice. J. Histochem. Cytochem. 49, 989–1001 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Warren, G. L. et al. Physiological role of tumor necrosis factor-α in traumatic muscle injury. FASEB J. 16, 1630–1632 (2002).

    Article  CAS  PubMed  Google Scholar 

  25. Cheng, M., Nguyen, M. H., Fantuzzi, G. & Koh, T. J. Endogenous interferon-γ is required for efficient skeletal muscle regeneration. Am. J. Physiol. Cell Physiol. 294, C1183–C1191 (2008).

    Article  CAS  PubMed  Google Scholar 

  26. Wang, H. et al. Altered macrophage phenotype transition impairs skeletal muscle regeneration. Am. J. Pathol. 184, 1167–1184 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  27. Mills, C. D., Kincaid, K., Alt, J. M., Heilman, M. J. & Hill, A. M. M-1/M-2 macrophages and the TH1/TH2 paradigm. J. Immunol. 164, 6166–6173 (2000).

    Article  CAS  PubMed  Google Scholar 

  28. Locati, M., Mantovani, A. & Sica, A. Macrophage activation and polarization as an adaptive component of innate immunity. Adv. Immunol. 120, 163–184 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Mills, C. D. Anatomy of a discovery: M1 and M2 macrophages. Front. Immunol. 6, 212 (2015).

    PubMed  PubMed Central  Google Scholar 

  30. Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  31. Lemos, D. R. et al. Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors. Nat. Med. 21, 786–794 (2015). This investigation delineates how dysregulated interactions between macrophages and FAP cells in chronic injury can contribute to muscle fibrosis.

    Article  CAS  PubMed  Google Scholar 

  32. Heredia, J. E. et al. Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell 153, 376–388 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Boehm, U., Klamp, T., Groot, M. & Howard, J. C. Cellular responses to interferon-γ. Annu. Rev. Immunol. 15, 749–795 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Lehtonen, A., Matikainen, S. & Julkunen, I. Interferons up-regulate STAT1, STAT2, and IRF family transcription factor gene expression in human peripheral blood mononuclear cells and macrophages. J. Immunol. 159, 794–803 (1997).

    CAS  PubMed  Google Scholar 

  35. Villalta, S. A., Deng, B., Rinaldi, C., Wehling-Henricks, M. & Tidball, J. G. IFNγ promotes muscle damage in the mdx mouse model of Duchenne muscular dystrophy by suppressing M2 macrophage activation and inhibiting muscle cell proliferation. J. Immunol. 187, 5419–5428 (2011).

    Article  PubMed  CAS  Google Scholar 

  36. Varga, T. et al. Highly dynamic transcriptional signature of distinct macrophage subsets during sterile inflammation, resolution, and tissue repair. J. Immunol. 196, 4771–4782 (2016).

    Article  CAS  PubMed  Google Scholar 

  37. Mounier, R. et al. AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell Metab. 18, 251–264 (2013). This study shows that AMPKα activity has a functionally important role in regulating macrophage phenotype and muscle regeneration following acute injury.

    Article  PubMed  CAS  Google Scholar 

  38. Londhe, P. & Davie, J. K. γ-interferon modulates myogenesis through the major histocompatibility complex class II transactivator, CIITA. Mol. Cell. Biol. 31, 2854–2866 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  39. Londhe, P. & Davie, J. K. Interferon-γ resets muscle cell fate by stimulating the sequential recruitment of JARID2 and PRC2 to promoters to repress myogenesis. Sci. Signal. 6, ra107 (2013). This study clarifies the mechanisms through which IFNγ can exert epigenetic controls on muscle differentiation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  40. Morris, A. C., Beresford, G. W., Mooney, M. R. & Boss, J. M. Kinetics of a γ-interferon response: expression and assembly of CIITA promoter IV and inhibition by methylation. Mol. Cell. Biol. 22, 4781–4791 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  41. Mitchell, C. A., McGeachie, J. K. & Grounds, M. D. Cellular differences in the regeneration of murine skeletal muscle: a quantitative histological study in SJL/J and BALB/c mice. Cell Tissue Res. 269, 159–166 (1992).

    Article  CAS  PubMed  Google Scholar 

  42. Deng, B., Wehling-Henricks, M., Villalta, S. A., Wang, Y. & Tidball, J. G. IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J. Immunol. 189, 3669–3680 (2012).

    Article  PubMed  CAS  Google Scholar 

  43. Chen, S. E. et al. Role of TNFα signaling in regeneration of cardiotoxin-injured muscle. Am. J. Physiol. Cell Physiol. 289, C1179–C1187 (2005).

    Article  PubMed  CAS  Google Scholar 

  44. Palacios, D. et al. TNF/p38α/Polycomb signaling to PAX7 locus in satellite cells links inflammation to the epigenetic control of muscle regeneration. Cell Stem Cell 7, 455–469 (2010). This investigation clarifies the mechanisms through which TNF-mediated signalling could influence PAX7 expression and thereby affect myogenesis.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  45. Juan, A. H. et al. Polycomb EZH2 controls self-renewal and safeguards the transcriptional identity of skeletal muscle stem cells. Genes Dev. 25, 789–794 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Woodhouse, S., Pugazhendhi, D., Brien, P. & Pell, J. M. EZH2 maintains a key phase of muscle satellite cell expansion but does not regulate terminal differentiation. J. Cell Sci. 126, 565–579 (2013).

    Article  CAS  PubMed  Google Scholar 

  47. Wilson-Rawls, J., Molkentin, J. D., Black, B. L. & Olson, E. N. Activated notch inhibits myogenic activity of the MADS-Box transcription factor myocyte enhancer factor 2C. Mol. Cell. Biol. 19, 2853–2862 (1999).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  48. Conboy, I. M. & Rando, T. A. The regulation of NOTCH signaling controls satellite cell activation and cell fate determination in postnatal myogenesis. Dev. Cell 3, 397–409 (2002).

    Article  CAS  PubMed  Google Scholar 

  49. Acharyya, S. et al. TNF inhibits NOTCH1 in skeletal muscle cells by EZH2 and DNA methylation mediated repression: implications in Duchenne muscular dystrophy. PLoS ONE 5, e12479 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  50. Faralli, H. et al. UTX demethylase activity is required for satellite cell-mediated muscle regeneration. J. Clin. Invest. 126, 1555–1565 (2016). This study shows a functionally important role for UTX in regulating the expression of myogenic genes in regenerating muscle in vivo.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Seenundun, S. et al. UTX mediates demethylation of H3K27me3 at muscle-specific genes during myogenesis. EMBO J. 29, 1401–1411 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. St. Pierre, B. A. & Tidball, J. G. Differential response of macrophage subpopulations to soleus muscle reloading after rat hindlimb suspension. J. Appl. Physiol. 77, 290–297 (1994).

    Article  CAS  PubMed  Google Scholar 

  53. Villalta, S. A. et al. Interleukin-10 reduces the pathology of mdx muscular dystrophy by deactivating M1 macrophages and modulating macrophage phenotype. Hum. Mol. Genet. 20, 790–805 (2011).

    Article  CAS  PubMed  Google Scholar 

  54. Rigamonti, E. et al. Requirement of inducible nitric oxide synthase for skeletal muscle regeneration after acute damage. J. Immunol. 190, 1767–1777 (2013).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).

    Article  PubMed  CAS  Google Scholar 

  56. Tidball, J. G. & Wehling-Henricks, M. Macrophages promote muscle membrane repair and muscle fibre growth and regeneration during modified muscle loading in mice in vivo. J. Physiol. 578, 327–336 (2007).

    Article  CAS  PubMed  Google Scholar 

  57. Arnold, L. et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J. Exp. Med. 204, 1057–1069 (2007).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Hardie, D. G., Scott, J. W., Pan, D. A. & Hudson, E. R. Management of cellular energy by the AMP-activated protein kinase system. FEBS Lett. 546, 113–120 (2003).

    Article  CAS  PubMed  Google Scholar 

  59. O'Neill, L. A. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).

    Article  CAS  PubMed  Google Scholar 

  60. Zhu, Y. P., Brown, J. R., Sag, D., Zhang, L. & Suttles, J. Adenosine 5′-monophosphate-activated protein kinase regulates IL-10-mediated anti-inflammatory signaling pathways in macrophages. J. Immunol. 194, 584–594 (2015).

    Article  CAS  PubMed  Google Scholar 

  61. Sag, D., Carling, D., Stout, R. D. & Suttles, J. Adenosine 5′-monophosphate-activated protein kinase promotes macrophage polarization to an anti-inflammatory functional phenotype. J. Immunol. 181, 8633–8641 (2008).

    Article  PubMed  CAS  Google Scholar 

  62. Tonkin, J. et al. Monocyte/macrophage-derived IGF1 orchestrates murine skeletal muscle regeneration and modulates autocrine polarization. Mol. Ther. 23, 1189–1200 (2015). This investigation shows that macrophage-derived IGF1 could mediate both myogenesis and macrophage phenotype transitions in injured muscle in vivo.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  63. Tollefsen, S. E., Sadow, J. L. & Rotwein, P. Coordinate expression of insulin-like growth factor II and its receptor during muscle differentiation. Proc. Natl Acad. Sci. USA 86, 1543–1547 (1989).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Barton-Davis, E. R., Shoturma, D. I. & Sweeney, H. L. Contribution of satellite cells to IGF1 induced hypertrophy of skeletal muscle. Acta Physiol. Scand. 167, 301–305 (1999).

    Article  CAS  PubMed  Google Scholar 

  65. Musarò, A., McCullagh, K. J., Naya, F. J., Olson, E. N. & Rosenthal, N. IGF1 induces skeletal myocyte hypertrophy through calcineurin in association with GATA-2 and NF-ATc1. Nature 400, 581–585 (1999).

    Article  PubMed  Google Scholar 

  66. Summan, M. et al. Macrophages and skeletal muscle regeneration: a clodronate-containing liposome depletion study. Am. J. Physiol. Regul. Integr. Comp. Physiol. 290, R1488–R1495 (2006).

    Article  CAS  PubMed  Google Scholar 

  67. Zhao, W., Lu, H., Wang, X., Ransohoff, R. M. & Zhou, L. CX3CR1 deficiency delays acute skeletal muscle injury repair by impairing macrophage functions. FASEB J. 30, 380–393 (2016).

    Article  CAS  PubMed  Google Scholar 

  68. Fadok, V. A. et al. Macrophages that have ingested apoptotic cells in vitro inhibit proinflammatory cytokine production through autocrine/paracrine mechanisms involving TGFβ, PGE2, and PAF. J. Clin. Invest. 101, 890–898 (1998).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  69. Fadok, V. A., Bratton, D. L., Guthrie, L. & Henson, P. M. Differential effects of apoptotic versus lysed cells on macrophage production of cytokines: role of proteases. J. Immunol. 166, 6847–6854 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Bae, H. B. et al. AMP-activated protein kinase enhances the phagocytic ability of macrophages and neutrophils. FASEB J. 25, 4358–4368 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  71. Weavers, H., Evans, I. R., Martin, P. & Wood, W. Corpse engulfment generates a molecular memory that primes the macrophage inflammatory response. Cell 165, 1658–1671 (2016). This investigation shows that phagocytosis of apoptotic bodies by macrophages during Drosophila melanogaster development influences macrophage responsiveness to subsequent acute injuries.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  72. Schaer, D. J. et al. Molecular cloning and characterization of the mouse CD163 homologue, a highly glucocorticoid-inducible member of the scavenger receptor cysteine-rich family. Immunogenetics 53, 170–177 (2001).

    Article  CAS  PubMed  Google Scholar 

  73. Buechler, C. et al. Regulation of scavenger receptor CD163 expression in human monocytes and macrophages by pro- and antiinflammatory stimuli. J. Leukoc. Biol. 67, 97–103 (2000).

    Article  CAS  PubMed  Google Scholar 

  74. Sulahian, T. H. et al. Human monocytes express CD163, which is upregulated by IL-10 and identical to p155. Cytokine 12, 1312–1321 (2000).

    Article  CAS  PubMed  Google Scholar 

  75. Schaer, D. J., Boretti, F. S., Schoedon, G. & Schaffner, A. Induction of the CD163-dependent haemoglobin uptake by macrophages as a novel anti-inflammatory action of glucocorticoids. Br. J. Haematol. 119, 239–243 (2002).

    Article  CAS  PubMed  Google Scholar 

  76. Kristiansen, M. et al. Identification of the haemoglobin scavenger receptor. Nature 409, 198–201 (2001).

    Article  CAS  PubMed  Google Scholar 

  77. Moestrup, S. K. & Moller, H. J. CD163: a regulated hemoglobin scavenger receptor with a role in the anti-inflammatory response. Ann. Med. 36, 347–354 (2004).

    Article  CAS  PubMed  Google Scholar 

  78. Philippidis, P. et al. Hemoglobin scavenger receptor CD163 mediates interleukin-10 release and heme oxygenase-1 synthesis: antiinflammatory monocyte-macrophage responses in vitro, in resolving skin blisters in vivo, and after cardiopulmonary bypass surgery. Circ. Res. 94, 119–126 (2004).

    Article  CAS  PubMed  Google Scholar 

  79. Akahori, H. et al. CD163 interacts with TWEAK to regulate tissue regeneration after ischaemic injury. Nat. Commun. 6, 7792 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Bover, L. C. et al. A previously unrecognized protein-protein interaction between TWEAK and CD163: potential biological implications. J. Immunol. 178, 8183–8194 (2007).

    Article  CAS  PubMed  Google Scholar 

  81. Girgenrath, M. et al. TWEAK, via its receptor FN14, is a novel regulator of mesenchymal progenitor cells and skeletal muscle regeneration. EMBO J. 25, 5826–5839 (2006).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Mittal, A. et al. Genetic ablation of TWEAK augments regeneration and post-injury growth of skeletal muscle in mice. Am. J. Pathol. 177, 1732–1742 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  83. McLennan, I. S. Degenerating and regenerating skeletal muscles contain several subpopulations of macrophages with distinct spatial and temporal distributions. J. Anat. 188, 17–28 (1996).

    PubMed  PubMed Central  Google Scholar 

  84. Burzyn, D. et al. A special population of regulatory T cells potentiates muscle repair. Cell 155, 1282–1295 (2013). This study shows that T reg cells can influence muscle regeneration and modulate macrophage phenotype following acute injury, and indicates that a muscle-specific T reg cell population is mainly responsible for these effects.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Castiglioni, A. et al. FOXP3+ T cells recruited to sites of sterile skeletal muscle injury regulate the fate of satellite cells and guide effective tissue regeneration. PLoS ONE 10, e0128094 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Uezumi, A., Fukada, S., Yamamoto, N., Takeda, S. & Tsuchida, K. Mesenchymal progenitors distinct from satellite cells contribute to ectopic fat cell formation in skeletal muscle. Nat. Cell Biol. 12, 143–152 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Joe, A. W. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153–163 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  88. Fiore, D. et al. Pharmacological blockage of fibro/adipogenic progenitor expansion and suppression of regenerative fibrogenesis is associated with impaired skeletal muscle regeneration. Stem Cell Res. 17, 161–169 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Uezumi, A. et al. Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J. Cell Sci. 124, 3654–3664 (2011).

    Article  CAS  PubMed  Google Scholar 

  90. Verrecchia, F., Chu, M. L. & Mauviel, A. Identification of novel TGFβ /SMAD gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J. Biol. Chem. 276, 17058–17062 (2001).

    Article  CAS  PubMed  Google Scholar 

  91. Holmes, A. et al. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J. Biol. Chem. 276, 10594–10601 (2001).

    Article  CAS  PubMed  Google Scholar 

  92. Curran, J. N., Winter, D. C. & Bouchier-Hayes, D. Biological fate and clinical implications of arginine metabolism in tissue healing. Wound Repair Regen. 14, 376–386 (2006).

    Article  PubMed  Google Scholar 

  93. Witte, M. B. & Barbul, A. Arginine physiology and its implication for wound healing. Wound Repair Regen. 11, 419–423 (2003).

    PubMed  Google Scholar 

  94. Petrof, B. J., Shrager, J. B., Stedman, H. H., Kelly, A. M. & Sweeney, H. L. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc. Natl Acad. Sci. USA 90, 3710–3714 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Wehling, M., Spencer, M. J. & Tidball, J. G. A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice. J. Cell Biol. 155, 123–131 (2001).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Wehling-Henricks, M. et al. Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy. PLoS ONE 5, e10763 (2010).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Conboy, I. M. & Rando, T. A. Aging, stem cells and tissue regeneration: lessons from muscle. Cell Cycle 4, 407–410 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Kuswanto, W. et al. Poor repair of skeletal muscle in aging mice reflects a defect in local, interleukin-33-dependent accumulation of regulatory T cells. Immunity 44, 355–367 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Williams, J. W. et al. Transcription factor IRF4 drives dendritic cells to promote TH2 differentiation. Nat. Commun. 4, 2990 (2013).

    Article  PubMed  CAS  Google Scholar 

  100. Sato, S., Yanagawa, Y., Hiraide, S. & Iizuka, K. Cyclic AMP signaling enhances lipopolysaccharide sensitivity and interleukin-33 production in RAW264.7 macrophages. Microbiol. Immunol. 60, 382–389 (2016).

    Article  CAS  PubMed  Google Scholar 

  101. Flurkey, K., Currer, J. M. & Harrison, D. E. in The Mouse in Biomedical Research 2nd edn (ed. Fox, J. G. ) 637–672 (Elsevier, 2007).

  102. Rybalko, V., Hsieh, P. L., Merscham-Banda, M., Suggs, L. J. & Farrar, R. P. The development of macrophage-mediated cell therapy to improve skeletal muscle function after injury. PLoS ONE 10, e0145550 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  103. Lesault, P. F. et al. Macrophages improve survival, proliferation and migration of engrafted myogenic precursor cells into MDX skeletal muscle. PLoS ONE 7, e46698 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Badylak, S. F., Valentin, J. E., Ravindra, A. K., McCabe, G. P. & Stewart-Akers, A. M. Macrophage phenotype as a determinant of biologic scaffold remodeling. Tissue Eng. Part A 14, 1835–1842 (2008).

    Article  CAS  PubMed  Google Scholar 

  105. Brown, B. N., Valentin, J. E., Stewart-Akers, A. M., McCabe, G. P. & Badylak, S. F. Macrophage phenotype and remodeling outcomes in response to biologic scaffolds with and without a cellular component. Biomaterials 30, 1482–1491 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  106. Fishman, J. M. et al. Immunomodulatory effect of a decellularized skeletal muscle scaffold in a discordant xenotransplantation model. Proc. Natl Acad. Sci. USA 110, 14360–14365 (2013).

    Article  PubMed  PubMed Central  Google Scholar 

  107. Beachley, V. A. et al. Tissue matrix arrays for high-throughput screening and systems analysis of cell function. Nat. Methods 12, 1197–1204 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  108. Perdiguero, E. et al. p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair. J. Cell Biol. 195, 307–322 (2011).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  109. Allbrook, D. B., Han, M. F. & Hellmuth, A. E. Population of muscle satellite cells in relation to age and mitotic activity. Pathology 3, 223–243 (1971).

    Article  CAS  PubMed  Google Scholar 

  110. Schultz, E. A quantitative study of the satellite cell population in postnatal mouse lumbrical muscle. Anat. Rec. 180, 589–595 (1974).

    Article  CAS  PubMed  Google Scholar 

  111. Clarke, M. S. & Feeback, D. L. Mechanical load induces sarcoplasmic wounding and FGF release in differentiated human skeletal muscle cultures. FASEB J. 10, 502–509 (1996).

    Article  CAS  PubMed  Google Scholar 

  112. Fry, C. S. et al. Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nat. Med. 21, 76–80 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Tierney, M. T. et al. STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat. Med. 20, 1182–1186 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  114. Lieber, R. L., Thornell, L. E. & Fridén, J. Muscle cytoskeletal disruption occurs within the first 15 min of cyclic eccentric contraction. J. Appl. Physiol. 80, 278–284 (1996).

    Article  CAS  PubMed  Google Scholar 

  115. Segawa, M. et al. Suppression of macrophage functions impairs skeletal muscle regeneration with severe fibrosis. Exp. Cell Res. 314, 3232–3244 (2008).

    Article  CAS  PubMed  Google Scholar 

  116. Zhang, L. et al. Chemokine CXCL16 regulates neutrophil and macrophage infiltration into injured muscle, promoting muscle regeneration. Am. J. Pathol. 175, 2518–2527 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  117. Hardy, D. et al. Comparative study of injury models for studying muscle regeneration in mice. PLoS ONE 11, e0147198 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  118. Teixeira, C. F., Landucci, E. C., Antunes, E., Chacur, M. & Cury, Y. Inflammatory effects of snake venom myotoxic phospholipases A2. Toxicon 42, 947–962 (2003).

    Article  CAS  PubMed  Google Scholar 

  119. Gutiérrez, J. M. & Lomonte, B. Phospholipase A2 myotoxins from Bothrops snake venoms. Curr. Org. Chem. 8, 1677–1690 (2004).

    Article  Google Scholar 

  120. Zuliani, J. P., Fernandes, C. M., Zamuner, S. R., Gutiérrez, J. M. & Teixeira, C. F. Inflammatory events induced by Lys-49 and Asp-49 phospholipases A2 isolated from Bothrops asper snake venom: role of catalytic activity. Toxicon 45, 335–346 (2005).

    Article  CAS  PubMed  Google Scholar 

  121. Zuliani, J. P. et al. Activation of cellular functions in macrophages by venom secretory Asp-49 and Lys-49 phospholipases A2 . Toxicon 46, 523–532 (2005).

    Article  CAS  PubMed  Google Scholar 

  122. Gasanov, S. E., Dagda, R. K. & Rael, E. D. Snake venom cytotoxins, phospholipase A2s, and Zn2+-dependent metalloproteinases: mechanisms of action and pharmacological relevance. J. Clin. Toxicol. 4, 1000181 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  123. Hasty, P. et al. Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Nature 364, 501–506 (1993).

    Article  CAS  PubMed  Google Scholar 

  124. Nabeshima, Y. et al. Myogenin gene disruption results in perinatal lethality because of severe muscle defect. Nature 364, 532–535 (1993).

    Article  CAS  PubMed  Google Scholar 

  125. Warren, G. L. et al. Role of CC chemokines in skeletal muscle functional restoration after injury. Am. J. Physiol. Cell Physiol. 286, C1031–C1036 (2004).

    Article  CAS  PubMed  Google Scholar 

  126. Hu, X. & Ivashkiv, L. B. Cross-regulation of signaling pathways by interferon-γ: implications for immune responses and autoimmune diseases. Immunity 31, 539–550 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  127. Giordano, C. et al. Toll-like receptor 4 ablation in mdx mice reveals innate immunity as a therapeutic target in Duchenne muscular dystrophy. Hum. Mol. Genet. 24, 2147–2162 (2015).

    Article  CAS  PubMed  Google Scholar 

  128. Henriques-Pons, A. et al. Role of Toll-like receptors in the pathogenesis of dystrophin-deficient skeletal and heart muscle. Hum. Mol. Genet. 23, 2604–2617 (2014).

    Article  CAS  PubMed  Google Scholar 

  129. Suelves, M. et al. Plasmin activity is required for myogenesis in vitro and skeletal muscle regeneration in vivo. Blood 99, 2835–2844 (2002).

    Article  CAS  PubMed  Google Scholar 

  130. Nguyen, H. X., Lusis, A. J. & Tidball, J. G. Null mutation of myeloperoxidase in mice prevents mechanical activation of neutrophil lysis of muscle cell membranes in vitro and in vivo. J. Physiol. 565, 403–413 (2005).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  131. Wehling-Henricks, M. et al. Major basic protein-1 promotes fibrosis of dystrophic muscle and attenuates the cellular immune response in muscular dystrophy. Hum. Mol. Genet. 17, 2280–2292 (2008).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

Download references

Acknowledgements

The author is supported by National Institutes of Health grants 1RO1AR066036, 1RO1AG041147, 1RO1AR062579 and 1R21AR066817. The author apologizes to scientists whose work was not included in this Review because of limitations on the length of the Review.

Author information

Authors and Affiliations

  1. Molecular, Cellular and Integrative Physiology Program, University of California, Los Angeles, 90095–1606, California, USA

    James G. Tidball

Authors
  1. James G. Tidball
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James G. Tidball.

Ethics declarations

Competing interests

The author declares no competing financial interests.

PowerPoint slides

Glossary

Satellite cells

A population of muscle stem cells that are committed to the myogenic lineage and normally reside in a quiescent state at the surface of fully differentiated muscle fibres. They can be activated by muscle injury, leading them to proliferate and then either return to quiescence, fuse with existing muscle fibres or continue to differentiate to form new muscle fibres.

Myotubes

During muscle development and regeneration, postmitotic, mononucleated muscle cells fuse with neighbouring postmitotic muscle cells to form long, cylindrical, multinucleated myotubes. Eventually myotubes can grow to include hundreds of muscle nuclei, and they then undergo terminal differentiation to become mature muscle fibres.

mdx mice

Mutant mice that lack dystrophin, the deficient gene product in Duchenne muscular dystrophy (DMD), which is a progressive, lethal, muscle-wasting disease in humans. Both mdx dystrophy and DMD involve an early, acute onset of muscle damage and inflammation. However, subsequent DMD pathology is more severe than mdx pathology, in which there is an extensive period of remission following initial onset.

Macrophage memory

Cells of the innate immune system, including macrophages, can show changes in their response to immune challenges according to the conditions under which they differentiated or were previously activated. This 'trained' immunity or memory reflects epigenetic changes that influence signalling or metabolic pathways.

Fibro-adipogenic progenitor cells

(FAP cells). A population of muscle-resident mesenchymal cells that are lineage-negative, lack expression of integrin α7 and express CD34 and stem cell antigen 1, and that have the ability to differentiate into fibroblasts or adipocytes. Following acute injury, FAP cells can release factors that increase muscle cell differentiation and that promote repair.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tidball, J. Regulation of muscle growth and regeneration by the immune system. Nat Rev Immunol 17, 165–178 (2017). https://doi.org/10.1038/nri.2016.150

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nri.2016.150

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing