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.
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.
Subscribe to Journal
Get full journal access for 1 year
only $22.08 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
World Health Organization in Global Status Report on Road Safety 2015 340 (World Health Organization, 2015).
Herridge, M. S. et al. One year outcomes in survivors of the acute respiratory distress syndrome. N. Engl. J. Med. 348, 683–693 (2003).
Chargé, S. B. & Rudnicki, M. A. Cellular and molecular regulation of muscle regeneration. Physiol. Rev. 84, 209–238 (2004).
Sambasivan, R. et al. PAX7-expressing satellite cells are indispensable for adult skeletal muscle regeneration. Development 138, 3647–3656 (2011).
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).
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).
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).
George, R. M. et al. Numb-deficient satellite cells have regeneration and proliferation defects. Proc. Natl Acad. Sci. USA 110, 18549–18554 (2013).
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).
Villalta, S. A. et al. Regulatory T cells suppress muscle inflammation and injury in muscular dystrophy. Sci. Transl Med. 6, 258ra142 (2014).
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).
Honda, H., Kimura, H. & Rostami, A. Demonstration and phenotypic characterization of resident macrophages in rat skeletal muscle. Immunology 70, 272–277 (1990).
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).
Krippendorf, B. B. & Riley, D. A. Distinguishing unloading- versus reloading-induced changes in rat soleus muscle. Muscle Nerve 16, 99–108 (1993).
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).
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).
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).
Warren, G. L. et al. Chemokine receptor CCR2 involvement in skeletal muscle regeneration. FASEB J. 19, 413–415 (2005).
Shireman, P. K. et al. MCP-1 deficiency causes altered inflammation with impaired skeletal muscle regeneration. J. Leukoc. Biol. 81, 775–785 (2007).
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).
Sun, D. et al. Bone marrow-derived cell regulation of skeletal muscle regeneration. FASEB J. 23, 382–395 (2009).
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).
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).
Warren, G. L. et al. Physiological role of tumor necrosis factor-α in traumatic muscle injury. FASEB J. 16, 1630–1632 (2002).
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).
Wang, H. et al. Altered macrophage phenotype transition impairs skeletal muscle regeneration. Am. J. Pathol. 184, 1167–1184 (2014).
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).
Locati, M., Mantovani, A. & Sica, A. Macrophage activation and polarization as an adaptive component of innate immunity. Adv. Immunol. 120, 163–184 (2013).
Mills, C. D. Anatomy of a discovery: M1 and M2 macrophages. Front. Immunol. 6, 212 (2015).
Martinez, F. O. & Gordon, S. The M1 and M2 paradigm of macrophage activation: time for reassessment. F1000Prime Rep. 6, 13 (2014).
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.
Heredia, J. E. et al. Type 2 innate signals stimulate fibro/adipogenic progenitors to facilitate muscle regeneration. Cell 153, 376–388 (2013).
Boehm, U., Klamp, T., Groot, M. & Howard, J. C. Cellular responses to interferon-γ. Annu. Rev. Immunol. 15, 749–795 (1997).
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).
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).
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).
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.
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).
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.
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).
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).
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).
Chen, S. E. et al. Role of TNFα signaling in regeneration of cardiotoxin-injured muscle. Am. J. Physiol. Cell Physiol. 289, C1179–C1187 (2005).
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.
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).
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).
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).
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).
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).
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.
Seenundun, S. et al. UTX mediates demethylation of H3K27me3 at muscle-specific genes during myogenesis. EMBO J. 29, 1401–1411 (2010).
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).
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).
Rigamonti, E. et al. Requirement of inducible nitric oxide synthase for skeletal muscle regeneration after acute damage. J. Immunol. 190, 1767–1777 (2013).
Mantovani, A. et al. The chemokine system in diverse forms of macrophage activation and polarization. Trends Immunol. 25, 677–686 (2004).
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).
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).
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).
O'Neill, L. A. & Hardie, D. G. Metabolism of inflammation limited by AMPK and pseudo-starvation. Nature 493, 346–355 (2013).
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).
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).
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.
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).
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).
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).
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).
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).
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).
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).
Bae, H. B. et al. AMP-activated protein kinase enhances the phagocytic ability of macrophages and neutrophils. FASEB J. 25, 4358–4368 (2011).
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.
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).
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).
Sulahian, T. H. et al. Human monocytes express CD163, which is upregulated by IL-10 and identical to p155. Cytokine 12, 1312–1321 (2000).
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).
Kristiansen, M. et al. Identification of the haemoglobin scavenger receptor. Nature 409, 198–201 (2001).
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).
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).
Akahori, H. et al. CD163 interacts with TWEAK to regulate tissue regeneration after ischaemic injury. Nat. Commun. 6, 7792 (2015).
Bover, L. C. et al. A previously unrecognized protein-protein interaction between TWEAK and CD163: potential biological implications. J. Immunol. 178, 8183–8194 (2007).
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).
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).
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).
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.
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).
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).
Joe, A. W. et al. Muscle injury activates resident fibro/adipogenic progenitors that facilitate myogenesis. Nat. Cell Biol. 12, 153–163 (2010).
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).
Uezumi, A. et al. Fibrosis and adipogenesis originate from a common mesenchymal progenitor in skeletal muscle. J. Cell Sci. 124, 3654–3664 (2011).
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).
Holmes, A. et al. CTGF and SMADs, maintenance of scleroderma phenotype is independent of SMAD signaling. J. Biol. Chem. 276, 10594–10601 (2001).
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).
Witte, M. B. & Barbul, A. Arginine physiology and its implication for wound healing. Wound Repair Regen. 11, 419–423 (2003).
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).
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).
Wehling-Henricks, M. et al. Arginine metabolism by macrophages promotes cardiac and muscle fibrosis in mdx muscular dystrophy. PLoS ONE 5, e10763 (2010).
Conboy, I. M. & Rando, T. A. Aging, stem cells and tissue regeneration: lessons from muscle. Cell Cycle 4, 407–410 (2005).
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).
Williams, J. W. et al. Transcription factor IRF4 drives dendritic cells to promote TH2 differentiation. Nat. Commun. 4, 2990 (2013).
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).
Flurkey, K., Currer, J. M. & Harrison, D. E. in The Mouse in Biomedical Research 2nd edn (ed. Fox, J. G. ) 637–672 (Elsevier, 2007).
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).
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).
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).
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).
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).
Beachley, V. A. et al. Tissue matrix arrays for high-throughput screening and systems analysis of cell function. Nat. Methods 12, 1197–1204 (2015).
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).
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).
Schultz, E. A quantitative study of the satellite cell population in postnatal mouse lumbrical muscle. Anat. Rec. 180, 589–595 (1974).
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).
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).
Tierney, M. T. et al. STAT3 signaling controls satellite cell expansion and skeletal muscle repair. Nat. Med. 20, 1182–1186 (2014).
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).
Segawa, M. et al. Suppression of macrophage functions impairs skeletal muscle regeneration with severe fibrosis. Exp. Cell Res. 314, 3232–3244 (2008).
Zhang, L. et al. Chemokine CXCL16 regulates neutrophil and macrophage infiltration into injured muscle, promoting muscle regeneration. Am. J. Pathol. 175, 2518–2527 (2009).
Hardy, D. et al. Comparative study of injury models for studying muscle regeneration in mice. PLoS ONE 11, e0147198 (2016).
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).
Gutiérrez, J. M. & Lomonte, B. Phospholipase A2 myotoxins from Bothrops snake venoms. Curr. Org. Chem. 8, 1677–1690 (2004).
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).
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).
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).
Hasty, P. et al. Muscle deficiency and neonatal death in mice with a targeted mutation in the myogenin gene. Nature 364, 501–506 (1993).
Nabeshima, Y. et al. Myogenin gene disruption results in perinatal lethality because of severe muscle defect. Nature 364, 532–535 (1993).
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).
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).
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).
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).
Suelves, M. et al. Plasmin activity is required for myogenesis in vitro and skeletal muscle regeneration in vivo. Blood 99, 2835–2844 (2002).
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).
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).
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.
The author declares no competing financial interests.
- 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.
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.
About this article
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
Bridging molecules are secreted from the skeletal muscle and potentially regulate muscle differentiation
Biochemical and Biophysical Research Communications (2020)
International Journal of Molecular Sciences (2020)
Frontiers in Physiology (2020)
Myotoxicity induced by Cerastes cerastes venom: Beneficial effect of heparin in skeletal muscle tissue regeneration
Acta Tropica (2020)
Bio-inspired multiple composite film with anisotropic surface wettability and adhesion for tissue repair
Chemical Engineering Journal (2020)