Skip to main content

The Inflammatory Response to Skeletal Muscle Injury

Illuminating Complexities

Abstract

Injury of skeletal muscle, and especially mechanically induced damage such as contusion injury, frequently occurs in contact sports, as well as in accidental contact sports, such as hockey and squash. The large variations with regard to injury severity and affected muscle group, as well as nonspecificity of reported symptoms, complicate research aimed at finding suitable treatments. Therefore, in order to increase the chances of finding a successful treatment, it is important to understand the underlying mechanisms inherent to this type of skeletal muscle injury and the cellular processes involved in muscle healing following a contusion injury.

Arguably the most important of these processes is inflammation since it is a consistent and lasting response. The inflammatory response is dependent on two factors, namely the extent of actual physical damage and the degree of muscle vascularization at the time of injury. However, long-term antiinflammatory treatment is not necessarily effective in promoting healing, as indicated by various studies on NSAID treatment. Because of the factors named earlier, human studies on the inflammatory response to contusion injury are limited, but several experimental animal models have been designed to study muscle damage and regeneration.

The early recovery phase is characterized by the overlapping processes of inflammation and occurrence of secondary damage. Although neutrophil infiltration has been named as a contributor to the latter, no clear evidence exists to support this claim. Macrophages, although forming part of the inflammatory response, have been shown to have a role in recovery, rather than in exacerbating secondary damage. Several probable roles for this cell type in the second phase of recovery, involving resolution processes, have been identified and include the following: (i) phagocytosis to remove cellular debris; (ii) switching from a pro- to anti-inflammatory phenotype in regenerating muscle; (iii) preventing muscle cells from undergoing apoptosis; (iv) releasing factors to promote muscle precursor cell activation and growth; and (v) secretion of cytokines and growth factors to facilitate vascular and muscle fibre repair. These many different roles suggest that a single treatment with one specific target cell population (e.g. neutrophils, macrophages or satellite cells) may not be equally effective in all phases of the post-injury response.

To find the optimal targeted, but time-course-dependent, treatments requires substantial further investigations. However, the techniques currently used to induce mechanical injury vary considerably in terms of invasiveness, tools used to induce injury, muscle group selected for injury and contractile status of the muscle, all of which have an influence on the immune and/or cytokine responses. This makes interpretation of the complex responses more difficult. After our review of the literature, we propose that a standardized non-invasive contusion injury is the ideal model for investigations into the immune responses to mechanical skeletal muscle injury. Despite its suitability as a model, the currently available literature with respect to the inflammatory response to injury using contusion models is largely inadequate.

Therefore, it may be premature to investigate highly targeted therapies, which may ultimately prove more effective in decreasing athlete recovery time than current therapies that are either not phase-specific, or not administered in a phase-specific fashion.

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

Fig. 1
Fig. 2
Table I
Table II
Fig. 3

References

  1. 1.

    Crisco JJ, Jokl P, Heinen GT, et al. A muscle contusion injury model. Am J Sports Med 1994; 22: 702–10

    PubMed  CAS  Article  Google Scholar 

  2. 2.

    Garrett Jr WE. Muscle strain injuries: clinical and basic aspects. Med Sci Sports Exerc 1990 Aug; 22 (4): 436–43

    PubMed  Google Scholar 

  3. 3.

    University of Maryland Medical Centre. Men’s health: sports injuries [online]. Available from URL: http://www.umm.edu/men/sports.htm [Accessed 2008 Sept 19]

  4. 4.

    Kearns SR, Daly AF, Sheehan K, et al. Oral vitamin C reduces the injury to skeletal muscle caused by compartmentsyndrome. J Bone Joint Surg Br 2004 Aug; 86 (6): 906–11

    PubMed  CAS  Article  Google Scholar 

  5. 5.

    Beiner JM, Jokl P, Cholewicki J, et al. The effect of anabolic steroids and corticosteroids on healing of musclecontusion injury. Am J Sports Med 1999 Jan-Feb; 27 (1)

    Google Scholar 

  6. 6.

    Diaz JA, Fischer DA, Rettig AC, et al. Severe quadriceps muscle contusions in athletes: a report of three cases. Am J Sports Med 2003 Mar-Apr; 31 (2): 289–93

    PubMed  Google Scholar 

  7. 7.

    Gissane C, Jennings DC, Cumine AJ, et al. Differences in the incidence of injury between rugby league forwardsand backs. Aust J Sci Med Sport 1997 Dec; 29 (4): 91–4

    PubMed  CAS  Google Scholar 

  8. 8.

    Yard EE, Comstock RD. Injuries sustained by rugby players presenting to United States emergency departments,1978 through 2004. J Athl Train 2006 Jul-Sep; 41 (3): 325–31

    PubMed  Google Scholar 

  9. 9.

    Arnason A, Gudmundsson A, Dahl HA, et al. Soccer injuries in Iceland. Scand J Med Sci Sports 1996 Feb; 6 (1): 40–5

    PubMed  CAS  Article  Google Scholar 

  10. 10.

    Jarret GJ, Orwin JF, Dick RW. Injuries in collegiate wrestling. Am J Sports Med 1998 Sep-Oct; 26 (5): 674–80

    PubMed  CAS  Google Scholar 

  11. 11.

    Watson AW. Sports injuries in the game of hurling: a one year prospective study. Am J Sports Med 1996 May-Jun;24 (3): 323–8

    PubMed  CAS  Article  Google Scholar 

  12. 12.

    Cummings Jr RS, Shurland AT, Prodoehl JA, et al. Injuries in the sport of luge: epidemiology and analysis. Am JSports Med 1997 Jul-Aug; 25 (4): 508–13

    Article  Google Scholar 

  13. 13.

    Egermann M, Brocai D, Lill CA, et al. Analysis of injuries in long-distance triathletes. Int J Sports Med 2003 May;24 (4): 271–6

    PubMed  CAS  Article  Google Scholar 

  14. 14.

    Thorsson O, Lilja B, Nilsson P, et al. Immediate external compression in the management of an acute muscle injury. Scand J Med Sci Sports 1997 Jun; 7 (3): 182–90

    PubMed  CAS  Article  Google Scholar 

  15. 15.

    Jarvinen TA, Jarvinen TL, Kaariainen M, et al. Muscle injuries: biology and treatment. Am J Sports Med 2005 May; 33 (5): 745–64

    PubMed  Article  Google Scholar 

  16. 16.

    Beiner JM, Jokl P. Muscle contusion injuries: current treatment options. J Am Acad Orthop Surg 2001 Jul-Aug; 9 (4): 227–37

    PubMed  CAS  Google Scholar 

  17. 17.

    Pedersen BK, Ostrowski K, Rohde T, et al. The cytokine response to strenuous exercise. Can J Physiol Pharmacol 1998 May; 76 (5): 505–11

    PubMed  CAS  Article  Google Scholar 

  18. 18.

    Tidball JG. Inflammatory processes in muscle injury and repair. Am J Physiol Regul Integr Comp Physiol 2005 Feb; 288 (2): 345–53

    Article  Google Scholar 

  19. 19.

    Merrick MA. Secondary injury aftermusculoskeletal trauma: a review and update. J Athl Train 2002 Apr; 37 (2): 209–17

    PubMed  Google Scholar 

  20. 20.

    Bunn JR, Canning J, Burke G, et al. Production of consistent crush lesions in murine quadriceps muscle: abiomechanical, histomorphological and immuno histochemical study. J Orthop Res 2004 Nov; 22 (6): 1336–44

    PubMed  Article  Google Scholar 

  21. 21.

    Gallucci S, Provenzano C, Mazzarelli P, et al. Myoblasts produce IL-6 in response to inflammatory stimuli. Int Immunol 1998 Mar; 10 (3): 267–73

    PubMed  CAS  Article  Google Scholar 

  22. 22.

    Ostrowski K, Rohde T, Asp S, et al. Pro and antiinflammatory cytokine balance in strenuous exercise in humans. J Physiol 1999; 515 (Pt 1): 287–91

    PubMed  CAS  Article  Google Scholar 

  23. 23.

    Smith LL, Anwar A, Fragen M, et al. Cytokines and cell adhesion molecules associated with high-intensity eccentricexercise. Eur J Appl Physiol 2000 May; 82 (1-2): 61–7

    PubMed  CAS  Article  Google Scholar 

  24. 24.

    Li Y, Cummins J, Huard J. Muscle injury and repair. Curr Opin Orthop 2001; 12: 409–15

    Article  Google Scholar 

  25. 25.

    Shephard RJ, Shek PN. Immune responses to inflammation and trauma: a physical training model. Can J Physiol Pharmacol 1998 May; 76 (5): 469–72

    PubMed  CAS  Article  Google Scholar 

  26. 26.

    Tidball JG. Inflammatory cell response to acute muscle injury. Med Sci Sports Exerc 1995 Jul; 27 (7): 1022–32

    PubMed  CAS  Article  Google Scholar 

  27. 27.

    Predel HG, Koll R, Pabst H, et al. Diclofenac patch for topical treatment of acute impact injuries: a randomised,double blind, placebo controlled, multicentre study. Br J Sports Med 2004 Jun; 38 (3): 318–23

    PubMed  CAS  Article  Google Scholar 

  28. 28.

    Martin P, Leibovich SJ. Inflammatory cells during wound repair: the good, the bad and the ugly. Trends Cell Biol 2005 Nov; 15 (11): 599–607

    PubMed  CAS  Article  Google Scholar 

  29. 29.

    Stramer BM, Mori R, Martin P. The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during woundrepair. J Invest Dermatol 2007 May; 127 (5): 1009–17

    PubMed  CAS  Article  Google Scholar 

  30. 30.

    Foster W, Li Y, Usas A, et al. Gamma interferon as an antifibrosis agent in skeletal muscle. J Orthop Res 2003 Sep; 21 (5): 798–804

    PubMed  CAS  Article  Google Scholar 

  31. 31.

    Fukushima K, Badlani N, Usas A, et al. The use of an antifibrosis agent to improve muscle recovery after laceration. Am J Sports Med 2001 Jul-Aug; 29 (4): 394–402

    PubMed  CAS  Google Scholar 

  32. 32.

    Greco A, McNamara MT, Escher RM, et al. Spin-echo and STIR MR imaging of sports-related muscle injuriesat 1.5 T. J Comput Assist Tomogr 1991 Nov-Dec; 15 (6): 994–9

    PubMed  CAS  Article  Google Scholar 

  33. 33.

    Kujala UM, Orava S, Jarvinen M. Hamstring injuries: current trends in treatment and prevention. Sports Med 1997 Jun; 23 (6): 397–404

    PubMed  CAS  Article  Google Scholar 

  34. 34.

    Leibovich SJ, Ross R. The role of the macrophage in wound repair: a study with hydrocortisone and antimacrophageserum. Am J Pathol 1975 Jan; 78 (1): 71–100

    PubMed  CAS  Google Scholar 

  35. 35.

    Tidball JG, Wehling-Henricks M. Macrophages promote muscle membrane repair and muscle fibre growth andregeneration during modified muscle loading in mice invivo. J Physiol 2007 Jan 1; 578 (Pt 1): 327–36

    PubMed  CAS  Google Scholar 

  36. 36.

    Reid SA, Speedy DB, Thompson JM, et al. Study of hematological and biochemical parameters in runners completing a standard marathon. Clin J Sport Med 2004 Nov; 14 (6): 344–53

    PubMed  Article  Google Scholar 

  37. 37.

    Wharam PC, Speedy DB, Noakes TD, et al. NSAID use increases the risk of developing hyponatremia during an Ironman triathlon. Med Sci Sports Exerc 2006 Apr; 38 (4): 618–22

    PubMed  CAS  Article  Google Scholar 

  38. 38.

    Meyers MC, Brown BR, Bloom JA. Fast pitch softball injuries. Sports Med 2001; 31 (1): 61–73

    PubMed  CAS  Article  Google Scholar 

  39. 39.

    Taioli E. Use of permitted drugs in Italian professional soccer players. Br J Sports Med 2007 Jul; 41 (7): 439–41

    PubMed  Article  Google Scholar 

  40. 40.

    Shen W, Li Y, Tang Y, et al. NS-398, a cyclooxygenase- 2-specific inhibitor, delays skeletal muscle healing by decreasing regeneration and promoting fibrosis. Am J Pathol 2005 Oct; 167 (4): 1105–17

    PubMed  CAS  Article  Google Scholar 

  41. 41.

    Shen W, Prisk V, Li Y, et al. Inhibited skeletal muscle healing in cyclooxygenase-2 gene-deficient mice: the role of PGE2 and PGF2 alpha. J Appl Physiol 2006 Oct; 101 (4): 1215–21

    PubMed  CAS  Article  Google Scholar 

  42. 42.

    Bondesen BA, Mills ST, Kegley KM, et al. The COX-2 pathway is essential during early stages of skeletal muscleregeneration. Am J Physiol Cell Physiol 2004 Aug; 287 (2): 475–83

    Article  Google Scholar 

  43. 43.

    Almekinders LC. Anti-inflammatory treatment of muscular injuries in sport: an update of recent studies. Sports Med 1999 Dec; 28 (6): 383–8

    PubMed  CAS  Article  Google Scholar 

  44. 44.

    Cheung EV, Tidball JG. Administration of the non-steroidal anti-inflammatory drug ibuprofen increases macrophageconcentrations but reduces necrosis during modified muscle use. Inflamm Res 2003 Apr; 52 (4): 170–6

    PubMed  CAS  Article  Google Scholar 

  45. 45.

    D’Andrea A, Caso P, Salerno G, et al. Left ventricular early myocardial dysfunction after chronic misuse ofanabolic androgenic steroids: a Doppler myocardial andstrain imaging analysis. Br J Sports Med 2007 Mar; 41 (3): 149–55

    PubMed  Article  Google Scholar 

  46. 46.

    Hurme T, Kalimo H. Activation of myogeni+c precursor cells after muscle injury. Med Sci Sports Exerc 1992 Feb;24 (2): 197–205

    PubMed  CAS  Google Scholar 

  47. 47.

    Hurme T, Kalimo H, Lehto M, et al. Healing of skeletal muscle injury: an ultrastructural and immunohistochemical study. Med Sci Sports Exerc 1991 Jul; 23 (7): 801–10

    PubMed  CAS  Google Scholar 

  48. 48.

    Sherwood L. Body defenses. In: Adams P, editor. Human physiology: from cells to systems. 6th ed. Belmont (CA): Thomson Brooks/Cole, 2007: 410–3

    Google Scholar 

  49. 49.

    Wang WZ, Fang XH, Stepheson LL, et al. Acute microvascular action of vascular endothelial growth factor inskeletal muscle ischemia/reperfusion injury. PlastReconstr Surg 2005 Apr 15; 115 (5): 1355–65

    PubMed  CAS  Article  Google Scholar 

  50. 50.

    Frantz S, Vincent KA, Feron O, et al. Innate immunity and angiogenesis. Circ Res 2005 Jan 7; 96 (1): 15–26

    PubMed  CAS  Article  Google Scholar 

  51. 51.

    Monaco C, Andreakos E, Kiriakidis S, et al. T-cell-mediated signalling in immune, inflammatory and angiogenicprocesses: the cascade of events leading to inflammatorydiseases. Curr Drug Targets Inflamm Allergy 2004 Mar;3 (1): 35–42

    PubMed  CAS  Article  Google Scholar 

  52. 52.

    Christov C, Chretien F, Khalil RA, et al. Muscle satellite cells and endothelial cells: close neighbors and privilegedpartners. Mol Biol Cell 2007; 18 (4): 1397–409

    PubMed  CAS  Article  Google Scholar 

  53. 53.

    Ouchi N, Shibata R, Walsh K. AMP-activated protein kinase signaling stimulates VEGF expression and angiogenesisin skeletal muscle. Circ Res 2005 Apr 29; 96 (8): 838–46

    PubMed  CAS  Article  Google Scholar 

  54. 54.

    Menger MD, Vollmar B. Adhesion molecules as determinants of disease: from molecular biology to surgical research. Br J Surg 1996 May; 83 (5): 588–601

    PubMed  CAS  Article  Google Scholar 

  55. 55.

    Dunzendorfer S, Kaneider N, Rabensteiner A, et al. Cell surface heparan sulfate proteoglycan-mediated regulationof human neutrophil migration by the serpin antithrombinIII. Blood 2001 Feb 15; 97 (4): 1079–85

    PubMed  CAS  Article  Google Scholar 

  56. 56.

    van der Voort R, Keehnen RM, Beuling EA, et al. Regulation of cytokine signaling by B cell antigen receptorand CD40-controlled expression of heparan sulfate proteoglycans.J Exp Med 2000 Oct 16; 192 (8): 1115–24

    PubMed  Article  Google Scholar 

  57. 57.

    Djanani A, Mosheimer B, Kaneider NC, et al. Heparan sulfate proteoglycan-dependent neutrophil chemotaxistoward PR-39 cathelicidin. J Inflamm (Lond) 2006; 3: 14

    Article  CAS  Google Scholar 

  58. 58.

    Gotte M. Syndecans in inflammation. Faseb J 2003 Apr; 17 (6): 575–91

    PubMed  CAS  Article  Google Scholar 

  59. 59.

    Saadi S, Wrenshall LE, Platt JL. Regional manifestations and control of the immune system. Faseb J 2002 Jun;16 (8): 849–56

    PubMed  CAS  Article  Google Scholar 

  60. 60.

    Luo BH, Carman CV, Springer TA. Structural basis of integrin regulation and signaling. Annu Rev Immunol 2007; 25: 619–47

    PubMed  CAS  Article  Google Scholar 

  61. 61.

    Berlin C, Bargatze RF, Campbell JJ, et al. Alpha 4 integrins mediate lymphocyte attachment and rolling under physiologicflow. Cell 1995 Feb 10; 80 (3): 413–22

    PubMed  CAS  Article  Google Scholar 

  62. 62.

    Elices MJ, Osborn L, Takada Y, et al. VCAM-1 on activated endothelium interacts with the leukocyte integrinVLA-4 at a site distinct from the VLA-4/fibronectinbinding site. Cell 1990 Feb 23; 60 (4): 577–84

    PubMed  CAS  Article  Google Scholar 

  63. 63.

    Hemler ME. VLA proteins in the integrin family: structures, functions, and their role on leukocytes. Annu Rev Immunol 1990; 8: 365–400

    PubMed  CAS  Article  Google Scholar 

  64. 64.

    Arnaout MA. Structure and function of the leukocyte adhesion molecules CD11/CD18. Blood 1990 Mar 1; 75 (5): 1037–50

    PubMed  CAS  Google Scholar 

  65. 65.

    Kinashi T. Integrin regulation of lymphocyte trafficking: lessons from structural and signaling studies. Adv Immunol 2007; 93: 185–227

    PubMed  CAS  Article  Google Scholar 

  66. 66.

    Gao JX, Issekutz AC. Mac-1 (CD11b/CD18) is the predominant beta 2 (CD18) integrin mediating human neutrophilmigration through synovial and dermal fibroblastbarriers. Immunology 1996 Jul; 88 (3): 463–70

    PubMed  CAS  Article  Google Scholar 

  67. 67.

    Sonnet C, Lafuste P, Arnold L, et al. Human macrophages rescue myoblasts and myotubes from apoptosis througha set of adhesion molecular systems. J Cell Sci 2006 Jun15; 119 (Pt 12): 2497–507

    PubMed  CAS  Article  Google Scholar 

  68. 68.

    Roberts CK, Won D, Pruthi S, et al. Effect of a diet and exercise intervention on oxidative stress, inflammationand monocyte adhesion in diabetic men. Diabetes ResClin Pract 2006 Sep; 73 (3): 249–59

    PubMed  CAS  Article  Google Scholar 

  69. 69.

    Petridou A, Chatzinikolaou A, Fatouros I, et al. Resistance exercise does not affect the serum concentrations of celladhesion molecules. Br J Sports Med 2007 Feb; 41 (2): 76–9

    PubMed  Article  Google Scholar 

  70. 70.

    Marder SR, Chenoweth DE, Goldstein IM, et al. Chemotactic responses of human peripheral blood monocytes tothe complement-derived peptides C5a and C5a des Arg. J Immunol 1985 May; 134 (5): 3325–31

    PubMed  CAS  Google Scholar 

  71. 71.

    Tiidus PM. Radical species in inflammation and overtraining. Can J Physiol Pharmacol 1998 May; 76 (5): 533–8

    PubMed  CAS  Article  Google Scholar 

  72. 72.

    Rosenberg HF, Gallin JI. Neutrophil-specific granule deficiency includes eosinophils. Blood 1993 Jul 1; 82 ( 1): 268–73

    PubMed  CAS  Google Scholar 

  73. 73.

    Cannon JG, St Pierre BA. Cytokines in exertion-induced skeletal muscle injury. Mol Cell Biochem 1998 Feb; 179 (1-2): 159–67

    PubMed  CAS  Article  Google Scholar 

  74. 74.

    Evans WJ, Cannon JG. The metabolic effects of exerciseinduced muscle damage. Exerc Sport Sci Rev 1991; 19: 99–125

    PubMed  CAS  Article  Google Scholar 

  75. 75.

    Jolly SR, Kane WJ, Hook BG, et al. Reduction of myocardial infarct size by neutrophil depletion: effect of durationof occlusion. Am Heart J 1986 Oct; 112 (4): 682–90

    PubMed  CAS  Article  Google Scholar 

  76. 76.

    Kyriakides C, Austen Jr W, Wang Y, et al. Skeletal muscle reperfusion injury is mediated by neutrophils and thecomplement membrane attack complex. Am J Physiol 1999 Dec; 277 (6 Pt 1): 1263–8

    Google Scholar 

  77. 77.

    Toumi H, F’Guyer S, Best TM. The role of neutrophils in injury and repair following muscle stretch. J Anat 2006 Apr; 208 (4): 459–70

    PubMed  CAS  Article  Google Scholar 

  78. 78.

    Honda H, Kimura H, Rostami A. Demonstration and phenotypic characterization of resident macrophagesin rat skeletal muscle. Immunology 1990 Jun; 70 (2): 272–7

    PubMed  CAS  Google Scholar 

  79. 79.

    McLennan IS. Resident macrophages (ED2- and ED3- positive) do not phagocytose degenerating rat skeletalmuscle fibres. Cell Tissue Res 1993 Apr; 272 (1): 193–6

    PubMed  CAS  Article  Google Scholar 

  80. 80.

    Farges MC, Balcerzak D, Fisher BD, et al. Increased muscle proteolysis after local trauma mainly reflects macrophage-associated lysosomal proteolysis. Am J Physiol Endocrinol Metab 2002 Feb; 282 (2): 326–35

    Google Scholar 

  81. 81.

    Arnold L, Henry A, Poron F, et al. Inflammatory monocytes recruited after skeletal muscle injury switch intoantiinflammatory macrophages to support myogenesis. J Exp Med 2007 May 14; 204 (5): 1057–69

    PubMed  CAS  Article  Google Scholar 

  82. 82.

    Summan M, Warren GL, Mercer RR, et al. Macrophages and skeletal muscle regeneration: a clodronate-containingliposome depletion study. Am J Physiol Regul IntegrComp Physiol 2006 Jun; 290 (6): 1488–95

    Article  CAS  Google Scholar 

  83. 83.

    Damoiseaux JG, Dopp EA, Calame W, et al. Rat macrophage lysosomal membrane antigen recognized by monoclonalantibody ED1. Immunology 1994 Sep; 83 (1): 140–7

    PubMed  CAS  Google Scholar 

  84. 84.

    Dijkstra CD, Dopp EA, Joling P, et al. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinctmacrophage subpopulations in the rat recognized bymonoclonal antibodies ED1, ED2 and ED3. Immunology 1985 Mar; 54 (3): 589–99

    PubMed  CAS  Google Scholar 

  85. 85.

    Cohen RE, Talarico G, Noble B. Phenotypic characterization of mononuclear inflammatory cells in salivary glands of bio-breeding rats. Arch Oral Biol 1997 Sep; 42 (9): 649–55

    PubMed  CAS  Article  Google Scholar 

  86. 86.

    Gordon S. Alternative activation of macrophages. Nat Rev Immunol 2003 Jan; 3 (1): 23–35

    PubMed  CAS  Article  Google Scholar 

  87. 87.

    Gordon S, Taylor PR. Monocyte and macrophage heterogeneity. Nat Rev Immunol 2005 Dec; 5 (12): 953–64

    PubMed  CAS  Article  Google Scholar 

  88. 88.

    Rushton JL, Davies I, Horan MA, et al. Production of consistent crush lesions of murine skeletal muscle in vivousing an electromechanical device. J Anat 1997 Apr; 190 (Pt 3): 417–22

    PubMed  Article  Google Scholar 

  89. 89.

    Chazaud B, Sonnet C, Lafuste P, et al. Satellite cells attract monocytes and use macrophages as a support to escapeapoptosis and enhance muscle growth. J Cell Biol 2003 Dec 8; 163 (5): 1133–43

    PubMed  CAS  Article  Google Scholar 

  90. 90.

    Gierer P, Mittlmeier T, Bordel R, et al. Selective cyclooxygenase- 2 inhibition reverses microcirculatory and inflammatory sequelae of closed soft-tissue trauma in ananimal model. J Bone Joint Surg Am 2005 Jan; 87 (1): 153–60

    PubMed  Article  Google Scholar 

  91. 91.

    Kostin S, Pool L, Elsasser A, et al. Myocytes die by multiple mechanisms in failing human hearts. Circ Res 2003 Apr 18; 92 (7): 715–24

    CAS  Article  Google Scholar 

  92. 92.

    Yasuhara S, Perez ME, Kanakubo E, et al. Skeletal muscle apoptosis after burns is associated with activation ofproapoptotic signals. Am J Physiol Endocrinol Metab 2000 Nov; 279 (5): 1114–21

    Google Scholar 

  93. 93.

    Schaser KD, Disch AC, Stover JF, et al. Prolonged superficial local cryotherapy attenuates microcirculatory impairment,regional inflammation, and muscle necrosisafter closed soft tissue injury in rats. Am J Sports Med 2007 Jan; 35 (1): 93–102

    PubMed  Article  Google Scholar 

  94. 94.

    Fujimoto-Ouchi K, Tamura S, Mori K, et al. Establishment and characterization of cachexia-inducing and noninducing clones of murine colon 26 carcinoma. Int J Cancer 1995; 61 (4): 522–8

    PubMed  CAS  Article  Google Scholar 

  95. 95.

    Karayiannakis AJ, Zbar A, Polychronidis A, et al. Serum and drainage fluid vascular endothelial growth factorlevels in early surgical wounds. Eur Surg Res 2003 Nov-Dec; 35 (6): 492–6

    PubMed  CAS  Article  Google Scholar 

  96. 96.

    Becker C, Lacchini S, Muotri AR, et al. Skeletal muscle cells expressing VEGF induce capillary formation andreduce cardiac injury in rats. Int J Cardiol 2006 Nov 18;113 (3): 348–54

    PubMed  Article  Google Scholar 

  97. 97.

    Ochoa O, Sun D, Reyes-Reyna SM, et al. Delayed angiogenesis and VEGF production in CCR2/mice duringimpaired skeletal muscle regeneration. Am J PhysiolRegul Integr Comp Physiol 2007 Aug; 293 (2): 651–61

    Article  CAS  Google Scholar 

  98. 98.

    Schmeisser A, Strasser RH. Phenotypic overlap between hematopoietic cells with suggested angioblastic potentialand vascular endothelial cells. J Hematother Stem Cell Res 2002 Feb; 11 (1): 69–79

    PubMed  CAS  Article  Google Scholar 

  99. 99.

    Moldovan L, Moldovan NI. Role of monocytes and macrophages in angiogenesis. EXS 2005; 94: 127–46

    PubMed  Google Scholar 

  100. 100.

    Sunderkotter C, Steinbrink K, Goebeler M, et al. Macrophages and angiogenesis. J Leukoc Biol 1994 Mar; 55 (3): 410–22

    PubMed  CAS  Google Scholar 

  101. 101.

    Massimino ML, Rapizzi E, Cantini M, et al. ED2þ macrophages increase selectively myoblast proliferation inmuscle cultures. Biochem Biophys Res Commun 1997 Jun 27; 235 (3): 754–9

    PubMed  CAS  Article  Google Scholar 

  102. 102.

    Ferre PJ, Liaubet L, Concordet D, et al. Longitudinal analysis of gene expression in porcine skeletal muscleafter post-injection local injury. Pharm Res 2007 Aug; 24 (8): 1480–9

    PubMed  CAS  Article  Google Scholar 

  103. 103.

    Warren GL, Summan M, Gao X, et al. Mechanisms of skeletal muscle injury and repair revealed by gene expression studies in mouse models. J Physiol 2007 Jul 15;582 (Pt 2): 825–41

    PubMed  CAS  Article  Google Scholar 

  104. 104.

    Mealy K, van Lanschot JJ, Robinson BG, et al. Are the catabolic effects of tumor necrosis factor mediated byglucocorticoids? Arch Surg 1990 Jan; 125 (1): 42–7

    PubMed  CAS  Article  Google Scholar 

  105. 105.

    Panzer S, Madden M, Matsuki K. Interaction of IL-1 beta, IL-6 and tumour necrosis factor-alpha (TNF-alpha) inhuman T cells activated by murine antigens. Clin ExpImmunol 1993 Sep; 93 (3): 471–8

    PubMed  CAS  Article  Google Scholar 

  106. 106.

    Zamir O, Hasselgren PO, von Allmen D, et al. In vivo administration of interleukin-1 alpha induces muscle proteolysis in normal and adrenalectomized rats. Metabolism 1993 Feb; 42 (2): 204–8

    PubMed  CAS  Article  Google Scholar 

  107. 107.

    Fan J, Wojnar MM, Theodorakis M, et al. Regulation of insulin-like growth factor (IGF)-I mRNA and peptideand IGF-binding proteins by interleukin-1. Am J Physiol 1996 Mar; 270 (3 Pt 2): 621–9

    Google Scholar 

  108. 108.

    Zsebo KM, Yuschenkoff VN, Schiffer S, et al. Vascular endothelial cells and granulopoiesis: interleukin-1 stimulates release of G-CSF and GM-CSF. Blood 1988 Jan;71 (1): 99–103

    PubMed  CAS  Google Scholar 

  109. 109.

    Allen RE, Boxhorn LK. Regulation of skeletal muscle satellite cell proliferation and differentiation by transforming growth factor-beta, insulin-like growth factor I,and fibroblast growth factor. J Cell Physiol 1989 Feb; 138 (2): 311–5

    PubMed  CAS  Article  Google Scholar 

  110. 110.

    Eskay RL, Grino M, Chen HT. Interleukins, signal transduction, and the immune system-mediated stress response. Adv Exp Med Biol 1990; 274: 331–43

    PubMed  CAS  Article  Google Scholar 

  111. 111.

    Tomiya A, Aizawa T, Nagatomi R, et al. Myofibers express IL-6 after eccentric exercise. Am J Sports Med 2004 Mar;32 (2): 503–8

    PubMed  Article  Google Scholar 

  112. 112.

    Caiozzo VJ, Haddad F, Baker MJ, et al. Microgravity-induced transformations of myosin isoforms and contractile properties of skeletal muscle. J Appl Physiol 1996;81 (1): 123–32

    PubMed  CAS  Google Scholar 

  113. 113.

    Cai YC, Yang GY, Nie Y, et al. Molecular alterations of p73 in human esophageal squamous cell carcinomas:loss of heterozygosity occurs frequently; loss ofimprinting and elevation of p73 expression may berelated to defective p53. Carcinogenesis 2000 Apr; 21 (4): 683–9

    PubMed  CAS  Article  Google Scholar 

  114. 114.

    Low QE, Drugea IA, Duffner LA, et al. Wound healing in MIP-1alpha(¯/¯) and MCP-1(¯/¯) mice. Am J Pathol 2001 Aug; 159 (2): 457–63

    PubMed  CAS  Article  Google Scholar 

  115. 115.

    Shireman PK, Contreras-Shannon V, Ochoa O, et al. MCP-1 deficiency causes altered inflammation with impaired skeletal muscle regeneration. J Leukoc Biol 2007; 81 (3): 775–85

    PubMed  CAS  Article  Google Scholar 

  116. 116.

    Lu B, Rutledge BJ, Gu L, et al. Abnormalities in monocyte recruitment and cytokine expression in monocyte chemoattractant protein 1-deficient mice. J Exp Med 1998 Feb 16; 187 (4): 601–8

    PubMed  CAS  Article  Google Scholar 

  117. 117.

    Warren GL, O’Farrell L, Summan M, et al. Role of CC chemokines in skeletal muscle functional restorationafter injury. Am J Physiol Cell Physiol 2004 May; 286 (5): 1031–6

    Article  Google Scholar 

  118. 118.

    Gimbrone Jr MA, Obin MS, Brock AF, et al. Endothelial interleukin-8: a novel inhibitor of leukocyte-endothelialinteractions. Science 1989 Dec 22; 246 (4937): 1601–3

    PubMed  CAS  Article  Google Scholar 

  119. 119.

    Stratos I, Rotter R, Eipel C, et al. Granulocyte-colony stimulating factor (G-CSF) enhances muscle proliferationand strength following skeletal muscle injury in rats.J Appl Physiol 2007; 103 (5): 1857–63

    PubMed  CAS  Article  Google Scholar 

  120. 120.

    Madihally SV, Toner M, Yarmush ML, et al. Interferon gamma modulates trauma-induced muscle wasting andimmune dysfunction. Ann Surg 2002; 236 (5): 649–57

    PubMed  Article  Google Scholar 

  121. 121.

    Olsson T, Kelic S, Edlund C, et al. Neuronal interferongamma immunoreactive molecule: bio activities and purification.Eur J Immunol 1994 Feb; 24 (2): 308–14

    PubMed  CAS  Article  Google Scholar 

  122. 122.

    Florini JR, Ewton DZ, Magri KA. Hormones, growth factors, and myogenic differentiation. Annu Rev Physiol 1991; 53: 201–16

    PubMed  CAS  Article  Google Scholar 

  123. 123.

    Yamada S, Buffinger N, DiMario J, et al. Fibroblast growth factor is stored in fiber extracellular matrix andplays a role in regulating muscle hypertrophy. Med SciSports Exerc 1989 Oct; 21 (5 Suppl.): 173–80

    Google Scholar 

  124. 124.

    Florini JR, Magri KA, Ewton DZ, et al. ‘spontaneous’ differentiation of skeletal myoblasts is dependent uponautocrine secretion of insulin-like growth factor-II. J Biol Chem 1991 Aug 25; 266 (24): 15917–23

    PubMed  CAS  Google Scholar 

  125. 125.

    DeVol DL, Rotwein P, Sadow JL, et al. Activation of insulin like growth factor gene expression during work-inducedskeletal muscle growth. Am J Physiol 1990 Jul; 259 (1 Pt 1): 89–95

    Google Scholar 

  126. 126.

    Gustafsson T, Ameln H, Fischer H, et al. VEGF-A splice variants and related receptor expression in human skeletal muscle following submaximal exercise. J Appl Physiol 2005 Jun; 98 (6): 2137–46

    PubMed  CAS  Article  Google Scholar 

  127. 127.

    Mirshahi F, Pourtau J, Li H, et al. SDF-1 activity on microvascular endothelial cells: consequences on angiogenesisin in vitro and in vivo models. Thromb Res 2000 Sep 15; 99 (6): 587–94

    PubMed  CAS  Article  Google Scholar 

  128. 128.

    Kucia M, Ratajczak J, Reca R, et al. Tissue-specific muscle, neural and liver stem/progenitor cells reside in thebone marrow, respond to an SDF-1 gradient and aremobilized into peripheral blood during stress and tissueinjury. Blood Cells Mol Dis 2004 Jan-Feb; 32 (1): 52–7

    PubMed  CAS  Article  Google Scholar 

  129. 129.

    Massague J, Cheifetz S, Endo T, et al. Type beta transforming growth factor is an inhibitor of myogenic differentiation. Proc Natl Acad Sci USA 1986 Nov; 83 (21): 8206–10

    PubMed  CAS  Article  Google Scholar 

  130. 130.

    Kurek JB, Bennett TM, Bower JJ, et al. Leukaemia inhibitory factor (LIF) production in a mouse model ofspinal trauma. Neuro sci Lett 1998 Jun 12; 249 (1): 1–4

    CAS  Article  Google Scholar 

  131. 131.

    Kami K, Morikawa Y, Kawai Y, et al. Leukemia inhibitory factor, glial cell line-derived neurotrophic factor, andtheir receptor expressions following muscle crush injury. Muscle Nerve 1999 Nov; 22 (11): 1576–86

    PubMed  CAS  Article  Google Scholar 

  132. 132.

    Spangenburg EE, Booth FW. Multiple signaling pathways mediate LIF-induced skeletal muscle satellite cell proliferation. Am J Physiol Cell Physiol 2002 Jul; 283 (1): 204–11

    Google Scholar 

  133. 133.

    Kovacs EJ, DiPietro LA. Fibrogenic cytokines and connective tissue production. FASEB J 1994 Aug; 8 (11): 854–61

    PubMed  CAS  Google Scholar 

  134. 134.

    Kobayashi S, Satomura K, Levsky JM, et al. Expression pattern of macrophage migration inhibitory factorduring embryogenesis. Mech Dev 1999 Jun; 84 (1-2): 153–6

    PubMed  CAS  Article  Google Scholar 

  135. 135.

    Begum N, Pash JM, Bhorjee JS. Expression and synthesis of high mobility group chromosomal proteins in different rat skeletal cell lines during myogenesis. J Biol Chem 1990 Jul 15; 265 (20): 11936–41

    PubMed  CAS  Google Scholar 

  136. 136.

    Lundberg K, Karlson JR, Ingebrigtsen K, et al. On the presence of the chromosomal proteinsHMGI andHMGY in rat organs. Biochim Biophys Acta 1989 Dec 22; 1009 (3): 277–9

    PubMed  CAS  Article  Google Scholar 

  137. 137.

    Kami K, Morikawa Y, Sekimoto M, et al. Gene expression of receptors for IL-6, LIF, and CNTF in regeneratingskeletal muscles. J Histochem Cytochem 2000 Sep; 48 (9): 1203–13

    PubMed  CAS  Article  Google Scholar 

  138. 138.

    Darmani H, Crossan J, McLellan SD, et al. Expression of nitric oxide synthase and transforming growth factorbetain crush-injured tendon and synovium. Mediators Inflamm 2004 Dec; 13 (5-6): 299–305

    PubMed  CAS  Article  Google Scholar 

  139. 139.

    Squarzoni S, Sabatelli P, Capanni C, et al. Emerin increase in regenerating muscle fibers. Eur J Histochem 2005 Oct-Dec; 49 (4): 355–62

    PubMed  CAS  Google Scholar 

  140. 140.

    Vignaud A, Cebrian J, Martelly I, et al. Effect of antiinflammatory and antioxidant drugs on the long-termrepair of severely injured mouse skeletal muscle. Exp Physiol 2005 Jul; 90 (4): 487–95

    PubMed  CAS  Article  Google Scholar 

  141. 141.

    Kvist H, Jarvinen M, Sorvari T. Effect of mobilization and immobilization on the healing of contusion injury inmuscle: a preliminary report of a histological study inrats. Scand J Rehabil Med 1974; 6 (3): 134–40

    PubMed  CAS  Google Scholar 

  142. 142.

    Stratton SA, Heckmann R, Francis RS. Therapeutic ultrasound, its effects on the integrity of a nonpenetrating wound. J Orthop Sports Phys Ther 1984; 5: 278–81

    PubMed  CAS  Google Scholar 

  143. 143.

    Nossuli TO, Lakshminarayanan V, Baumgarten G, et al. A chronic mouse model of myocardial ischemia-reperfusion:essential in cytokine studies. Am J Physiol Heart Circ Physiol 2000 Apr; 278 (4): 1049–55

    Google Scholar 

  144. 144.

    Akimau P, Yoshiya K, Hosotsubo H, et al. New experimental model of crush injury of the hindlimbs in rats.J Trauma 2005 Jan; 58 (1): 51–8

    PubMed  Article  Google Scholar 

  145. 145.

    Rubinstein I, Abassi Z, Coleman R, et al. Involvement of nitric oxide system in experimental muscle crush injury. J Clin Invest 1998 Mar 15; 101 (6): 1325–33

    PubMed  CAS  Article  Google Scholar 

  146. 146.

    Rawlins M, Gullichsen E, Kuttila K, et al. Central hemodynamic changes in experimental muscle crush injury inpigs. Eur Surg Res 1999; 31 (1): 9–18

    PubMed  CAS  Article  Google Scholar 

  147. 147.

    Merrick MA, Rankin JM, Andres FA, et al. A preliminary examination of cryotherapy and secondary injury inskeletal muscle. Med Sci Sports Exerc 1999 Nov; 31 (11):1516–21

    PubMed  CAS  Article  Google Scholar 

  148. 148.

    Collins RA, Grounds MD. The role of tumor necrosis factor-alpha (TNF-alpha) in skeletal muscle regeneration.Studies in TNF-alpha(¯/¯) and TNFalpha(¯/¯)/LT-alpha(¯/¯) mice. J Histo chem Cyto chem 2001 Aug; 49 (8): 989–1001

    CAS  Article  Google Scholar 

  149. 149.

    Fisher BD, Baracos VE, Shnitka TK, et al. Ultrastructural events following acute muscle trauma. Med Sci Sports Exerc 1990 Apr; 22 (2): 185–93

    PubMed  CAS  Google Scholar 

  150. 150.

    Kami K, Masuhara M, Kashiba H, et al. Changes of vinculin and extracellular matrix components following blunt trauma to rat skeletal muscle. Med Sci Sports Exerc 1993 Jul; 25 (7): 832–40

    PubMed  CAS  Article  Google Scholar 

  151. 151.

    Kami K, Senba E. In vivo activation of STAT3 signaling in satellite cells and myo fibers in regenerating ratskeletal muscles. J Histochem Cyto chem 2002 Dec; 50 (12): 1579–89

    CAS  Article  Google Scholar 

  152. 152.

    Crisco JJ, Hentel KD, Jackson WO, et al. Maximal contraction lessens impact response in a muscle contusionmodel. J Bio mech 1996 Oct; 29 (10): 1291–6

    CAS  Google Scholar 

  153. 153.

    Markert CD, Merrick MA, Kirby TE, et al. Nonthermal ultrasound and exercise in skeletal muscle regeneration. Arch Phys Med Rehabil 2005 Jul; 86 (7): 1304–10

    PubMed  Article  Google Scholar 

  154. 154.

    Wilkin LD, Merrick MA, Kirby TE, et al. Influence of therapeutic ultrasound on skeletal muscle regeneration following blunt contusion. Int J Sports Med 2004 Jan; 25 (1): 73–7

    PubMed  CAS  Article  Google Scholar 

  155. 155.

    Wright-Carpenter T, Klein P, Schaferhoff P, et al. Treatment of muscle injuries by local administration of autologous conditioned serum: a pilot study on sports men with muscle strains. Int J Sports Med 2004 Nov; 25 (8): 588–93

    PubMed  CAS  Article  Google Scholar 

  156. 156.

    Mathieu-Costello O, Hepple RT. Muscle structural capacity for oxygen flux from capillary to fiber mitochondria. Exerc Sport Sci Rev 2002 Apr; 30 (2): 80–4

    PubMed  Article  Google Scholar 

  157. 157.

    Lexell J, Jarvis JC, Currie J, et al. Fibre type composition of rabbit tibialis anterior and extensor digitorum longus muscles. J Anat 1994 Aug; 185 (Pt 1): 95–101

    PubMed  Google Scholar 

  158. 158.

    Sorokin LM, Maley MA, Moch H, et al. Laminin alpha4 and integrin alpha6 are upregulated in regeneratingdy/dy skeletal muscle: comparative expression of lamininand integrin is forms in muscles regenerating after crush injury. Exp Cell Res 2000 May 1; 256 (2): 500–14

    PubMed  CAS  Article  Google Scholar 

  159. 159.

    Thorsson O, Rantanen J, Hurme T, et al. Effects of nonsteroidal antiinflammatory medication on satellite cell proliferation during muscle regeneration. Am J Sports Med 1998; 26 (2): 172–6

    PubMed  CAS  Google Scholar 

  160. 160.

    Wang LC, Kernell D. Proximo-distal organization and fibre type regionalization in rat hind limb muscles. J Muscle Res Cell Motil 2000; 21 (6): 587–98

    PubMed  CAS  Article  Google Scholar 

  161. 161.

    Plomgaard P, Penkowa M, Pedersen BK. Fiber type specific expression of TNF-alpha, IL-6 and IL-18 inhuman skeletal muscles. Exerc Immunol Rev 2005; 11: 53–63

    PubMed  Google Scholar 

  162. 162.

    Febbraio MA, Pedersen BK. Contraction-induced myokine production and release: is skeletal muscle an endocrine organ? Exerc Sport Sci Rev 2005 Jul; 33 (3): 114–9

    PubMed  Article  Google Scholar 

  163. 163.

    Pedersen BK, Fischer CP. Beneficial health effects of exercise: the role of IL-6 as a myokine. Trends Pharmacol Sci 2007 Apr; 28 (4): 152–6

    PubMed  CAS  Article  Google Scholar 

  164. 164.

    Brenner IK, Natale VM, Vasiliou P, et al. Impact of three different types of exercise on components of the inflammatory response. Eur J Appl Physiol Occup Physiol 1999 Oct; 80 (5): 452–60

    PubMed  CAS  Article  Google Scholar 

  165. 165.

    Hirose L, Nosaka K, Newton M, et al. Changes in inflammatory mediators following eccentric exercise of theel bow flexors. Exerc Immunol Rev 2004; 10: 75–90

    PubMed  Google Scholar 

  166. 166.

    Smith JK, Grisham MB, Granger DN, et al. Free radical defense mechanisms and neutrophil infiltration in postis chemics keletal muscle. Am J Physiol 1989 Mar; 256 (3 Pt 2): 789–93

    Google Scholar 

  167. 167.

    Toft AD, Jensen LB, Bruunsgaard H, et al. Cytokine response to eccentric exercise in young and elderly humans. Am J Physiol Cell Physiol 2002 Jul; 283 (1): 289–95

    Google Scholar 

  168. 168.

    McBrier NM, Lekan JM, Druhan LJ, et al. Therapeutic ultrasound decreases mechano-growth factor messenger ribonucleic acid expression after muscle contusion injury. Arch Phys Med Rehabil 2007 Jul; 88 (7): 936–40

    PubMed  Article  Google Scholar 

  169. 169.

    Barnard W, Bower J, Brown MA, et al. Leukemia inhibitory factor (LIF) infusion stimulates skeletal muscle regeneration after injury: injured muscle expresses LIFm RNA. J Neurol Sci 1994 May; 123 (1-2): 108–13

    PubMed  CAS  Article  Google Scholar 

  170. 170.

    Rantanen J, Thorsson O, Wollmer P, et al. Effects of therapeutic ultrasound on the regeneration of skeletal myofibers after experimental muscle injury. Am J Sports Med 1999 Jan-Feb; 27 (1): 54–9

    PubMed  CAS  Google Scholar 

  171. 171.

    Jarvinen M, Lehto M, Sorvari T, et al. Effect of some anti inflammatory agents on the healing of ruptured muscle an experimental study in rats. J Sports Traumatol Relat Res 1992; 14: 19–28

    Google Scholar 

  172. 172.

    Menth-Chiari WA, Curl WW, Rosencrance E, et al. Contusion of skeletal muscle increases leukocyte-endothelial cell interactions: an intravital-microscopy study in rats.J Trauma 1998 Oct; 45 (4): 709–14

    PubMed  CAS  Article  Google Scholar 

  173. 173.

    Lee H, Natsui H, Akimoto T, et al. Effects of cryotherapy after contusion using real-time intravital microscopy. Med Sci Sports Exerc 2005 Jul; 37 (7): 1093–8

    PubMed  Article  Google Scholar 

  174. 174.

    Schaser KD, Stover JF, Melcher I, et al. Local cooling restores microcirculatory hemo dynamics after closedsoft-tissue trauma in rats. J Trauma 2006 Sep; 61 (3): 642–9

    PubMed  Article  Google Scholar 

  175. 175.

    Barlow Y, Willoughby J. Pathophysiology of soft tissue repair. Br Med Bull 1992 Jul; 48 (3): 698–711

    PubMed  CAS  Google Scholar 

  176. 176.

    Wong CW, Seow HF, Liu AH, et al. Modulation of immune responses by bovine beta-casein. Immunol Cell Biol 1996 Aug; 74 (4): 323–9

    PubMed  CAS  Article  Google Scholar 

Download references

Acknowledgements

No sources of funding were used to assist in the preparation of this review. The authors have no conflicts of interest that are directly relevant to the content of this review. No other persons beside the authors contributed to this review.

Author information

Affiliations

Authors

Corresponding author

Correspondence to Carine Smith.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Smith, C., Kruger, M.J., Smith, R.M. et al. The Inflammatory Response to Skeletal Muscle Injury. Sports Med 38, 947–969 (2008). https://doi.org/10.2165/00007256-200838110-00005

Download citation

Keywords

  • Satellite Cell
  • Muscle Injury
  • Muscle Regeneration
  • Secondary Damage
  • Impact Surface