Muscular Dystrophy and Rehabilitation Interventions with Regenerative Treatment

  • Nana Takenaka-NinagawaEmail author
  • Megumi Goto
  • Rukia Ikeda
  • Hidetoshi Sakurai
Regenerative Rehabilitation (CM Terzic, Section Editor)
Part of the following topical collections:
  1. Topical Collection on Regenerative Rehabilitation


Purpose of Review

This paper reviews the enhanced therapeutic effects of rehabilitation and regenerative medicine toward Duchenne muscular dystrophy.

Recent Findings

Duchenne muscular dystrophy (DMD) is one of the most severe forms of muscle disorders. Muscle in DMD patients is extremely fragile and can be damaged even during normal daily activity. There is little in the way of treatment for the disease and no cure. Some investigators have been developing cell therapies for DMD by generating muscle stem cells from human-induced pluripotent stem (iPS) cells and other progenitor/stem cells. Although reports have shown dystrophin protein restoration following cell transplantation in DMD models, improvement in motor function has not been achieved, and optimal methods that maximize the efficacy of the transplantation are still needed. Recently, some studies have reported that exercise with controlled load (treadmill running, voluntary running on a running wheel, swimming, etc.) improves the pathology of DMD. Thus, exercise is expected to enhance the effect of cell therapy for DMD, acting as a form of “regenerative rehabilitation.” Consistently, optimized muscle contraction training programs enhance the effect of cell transplantation therapy.


Cell transplantation therapy in combination with rehabilitation, which focuses on exercise therapy, may provide an effective radical treatment for DMD patients. This combination is described as regenerative rehabilitation.


Stem cell transplantation Duchenne muscular dystrophy Skeletal muscle Regenerative medicine Induced pluripotent stem cells Regenerative rehabilitation 


Compliance with Ethical Standards

Conflict of Interest

Nana Takenaka-Ninagawa, Megumi Goto, Rukia Ikeda, and Hidetoshi Sakurai declare no conflicts of interest relevant to this manuscript.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.


Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. 1.
    Yin H, Price F, Rudnicki MA. Satellite cells and the muscle stem cell niche. Physiol Rev. 2013;93(1):23–67. Scholar
  2. 2.
    Fairclough RJ, Wood MJ, Davies KE. Therapy for Duchenne muscular dystrophy: renewed optimism from genetic approaches. Nat Rev Genet. 2013;14(6):373–8. Scholar
  3. 3.
    Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51(6):919–28. Scholar
  4. 4.
    Davies KE, Nowak KJ. Molecular mechanisms of muscular dystrophies: old and new players. Nat Rev Mol Cell Biol. 2006;7(10):762–73. Scholar
  5. 5.
    Manzur AY, Muntoni F. Diagnosis and new treatments in muscular dystrophies. Postgrad Med J. 2009;85(1009):622–30. Scholar
  6. 6.
    Muntoni F, Torelli S, Ferlini A. Dystrophin and mutations: one gene, several proteins, multiple phenotypes. Lancet Neurol. 2003;2(12):731–40.CrossRefGoogle Scholar
  7. 7.
    Aartsma-Rus A, Krieg AM. FDA approves Eteplirsen for Duchenne muscular dystrophy: the next chapter in the Eteplirsen saga. Nucleic Acid Ther. 2017;27(1):1–3. Scholar
  8. 8.
    Echigoya Y, Aoki Y, Miskew B, Panesar D, Touznik A, Nagata T, et al. Long-term efficacy of systemic multiexon skipping targeting dystrophin exons 45-55 with a cocktail of vivo-morpholinos in mdx52 mice. Mol Ther Nucleic Acids. 2015;4:e225. Scholar
  9. 9.
    Echigoya Y, Nakamura A, Nagata T, Urasawa N, Lim KRQ, Trieu N, et al. Effects of systemic multiexon skipping with peptide-conjugated morpholinos in the heart of a dog model of Duchenne muscular dystrophy. Proc Natl Acad Sci U S A. 2017;114(16):4213–8. Scholar
  10. 10.
    Nelson CE, Hakim CH, Ousterout DG, Thakore PI, Moreb EA, Castellanos Rivera RM, et al. In vivo genome editing improves muscle function in a mouse model of Duchenne muscular dystrophy. Science. 2016;351(6271):403–7. Scholar
  11. 11.
    Nelson CE, Wu Y, Gemberling MP, Oliver ML, Waller MA, Bohning JD, et al. Long-term evaluation of AAV-CRISPR genome editing for Duchenne muscular dystrophy. Nat Med. 2019;25(3):427–32. Scholar
  12. 12.
    Long C, Amoasii L, Mireault AA, McAnally JR, Li H, Sanchez-Ortiz E, et al. Postnatal genome editing partially restores dystrophin expression in a mouse model of muscular dystrophy. Science. 2016;351(6271):400–3. Scholar
  13. 13.
    Amoasii L, Hildyard JCW, Li H, Sanchez-Ortiz E, Mireault A, Caballero D, et al. Gene editing restores dystrophin expression in a canine model of Duchenne muscular dystrophy. Science. 2018;362(6410):86–91. Scholar
  14. 14.
    Iyer PS, Mavoungou LO, Ronzoni F, Zemla J, Schmid-Siegert E, Antonini S, et al. Autologous cell therapy approach for Duchenne muscular dystrophy using PiggyBac transposons and Mesoangioblasts. Mol Ther. 2018;26(4):1093–108. Scholar
  15. 15.
    Henssen AG, Henaff E, Jiang E, Eisenberg AR, Carson JR, Villasante CM, et al. Genomic DNA transposition induced by human PGBD5. Elife. 2015;4.
  16. 16.
    Ivics Z. Endogenous Transposase source in human cells mobilizes piggyBac transposons. Mol Ther. 2016;24(5):851–4. Scholar
  17. 17.
    Partridge TA, Morgan JE, Coulton GR, Hoffman EP, Kunkel LM. Conversion of mdx myofibres from dystrophin-negative to -positive by injection of normal myoblasts. Nature. 1989;337(6203):176–9. Scholar
  18. 18.
    Skuk D, Goulet M, Roy B, Chapdelaine P, Bouchard JP, Roy R, et al. Dystrophin expression in muscles of duchenne muscular dystrophy patients after high-density injections of normal myogenic cells. J Neuropathol Exp Neurol. 2006;65(4):371–86. Scholar
  19. 19.
    Tedesco FS, Hoshiya H, D'Antona G, Gerli MF, Messina G, Antonini S, et al. Stem cell-mediated transfer of a human artificial chromosome ameliorates muscular dystrophy. Sci Transl Med. 2011;3(96):96–78. Scholar
  20. 20.
    Benedetti S, Uno N, Hoshiya H, Ragazzi M, Ferrari G, Kazuki Y, et al. Reversible immortalisation enables genetic correction of human muscle progenitors and engineering of next-generation human artificial chromosomes for Duchenne muscular dystrophy. EMBO Mol Med. 2018;10(2):254–75. Scholar
  21. 21.
    Darabi R, Arpke RW, Irion S, Dimos JT, Grskovic M, Kyba M, et al. Human ES- and iPS-derived myogenic progenitors restore DYSTROPHIN and improve contractility upon transplantation in dystrophic mice. Cell Stem Cell. 2012;10(5):610–9. Scholar
  22. 22.
    Goudenege S, Lebel C, Huot NB, Dufour C, Fujii I, Gekas J, et al. Myoblasts derived from normal hESCs and dystrophic hiPSCs efficiently fuse with existing muscle fibers following transplantation. Mol Ther. 2012;20(11):2153–67. Scholar
  23. 23.
    • Chal J, Oginuma M, Al Tanoury Z, Gobert B, Sumara O, Hick A, et al. Differentiation of pluripotent stem cells to muscle fiber to model Duchenne muscular dystrophy. Nat Biotechnol. 2015;33(9):962–9. demonstrates the generation of Pax7 positive muscle progenitors by a stepwise myogenic differentitation protocol from pluripotent stem cells without forced gene expression. CrossRefPubMedGoogle Scholar
  24. 24.
    Kim J, Magli A, Chan SSK, Oliveira VKP, Wu J, Darabi R, et al. Expansion and purification are critical for the therapeutic application of pluripotent stem cell-derived myogenic progenitors. Stem Cell Reports. 2017;9(1):12–22. Scholar
  25. 25.
    •• Hicks MR, Hiserodt J, Paras K, Fujiwara W, Eskin A, Jan M, et al. ERBB3 and NGFR mark a distinct skeletal muscle progenitor cell in human development and hPSCs. Nat Cell Biol. 2018;20(1):46–57. shows the effect of transplantation treatment with patient-derived iPS cells induced to differentiate without forced gene expression. CrossRefPubMedGoogle Scholar
  26. 26.
    Law PK, Goodwin TG, Fang Q, Hall TL, Quinley T, Vastagh G, et al. First human myoblast transfer therapy continues to show dystrophin after 6 years. Cell Transplant. 1997;6(1):95–100. Scholar
  27. 27.
    Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda K, et al. Induction of pluripotent stem cells from adult human fibroblasts by defined factors. Cell. 2007;131(5):861–72. Scholar
  28. 28.
    Kazuki Y, Hiratsuka M, Takiguchi M, Osaki M, Kajitani N, Hoshiya H, et al. Complete genetic correction of ips cells from Duchenne muscular dystrophy. Mol Ther. 2010;18(2):386–93. Scholar
  29. 29.
    Kazuki Y, Hoshiya H, Takiguchi M, Abe S, Iida Y, Osaki M, et al. Refined human artificial chromosome vectors for gene therapy and animal transgenesis. Gene Ther. 2011;18(4):384–93. Scholar
  30. 30.
    Jinek M, Chylinski K, Fonfara I, Hauer M, Doudna JA, Charpentier E. A programmable dual-RNA-guided DNA endonuclease in adaptive bacterial immunity. Science. 2012;337(6096):816–21. Scholar
  31. 31.
    Li HL, Fujimoto N, Sasakawa N, Shirai S, Ohkame T, Sakuma T, et al. Precise correction of the dystrophin gene in duchenne muscular dystrophy patient induced pluripotent stem cells by TALEN and CRISPR-Cas9. Stem Cell Reports. 2015;4(1):143–54. Scholar
  32. 32.
    Liao HK, Hatanaka F, Araoka T, Reddy P, Wu MZ, Sui Y, et al. In vivo target gene activation via CRISPR/Cas9-mediated trans-epigenetic modulation. Cell. 2017;171(7):1495–507 e15. Scholar
  33. 33.
    Okita K, Matsumura Y, Sato Y, Okada A, Morizane A, Okamoto S, et al. A more efficient method to generate integration-free human iPS cells. Nat Methods. 2011;8(5):409–12. Scholar
  34. 34.
    Leung DG, Wagner KR. Therapeutic advances in muscular dystrophy. Ann Neurol. 2013;74(3):404–11. Scholar
  35. 35.
    Hyzewicz J, Ruegg UT, Takeda S. Comparison of experimental protocols of physical exercise for mdx mice and Duchenne muscular dystrophy patients. J Neuromuscul Dis. 2015;2(4):325–42. Scholar
  36. 36.
    Markert CD, Ambrosio F, Call JA, Grange RW. Exercise and Duchenne muscular dystrophy: toward evidence-based exercise prescription. Muscle Nerve. 2011;43(4):464–78. Scholar
  37. 37.
    Weller B, Karpati G, Carpenter S. Dystrophin-deficient mdx muscle fibers are preferentially vulnerable to necrosis induced by experimental lengthening contractions. J Neurol Sci. 1990;100(1–2):9–13. Scholar
  38. 38.
    Vilquin JT, Brussee V, Asselin I, Kinoshita I, Gingras M, Tremblay JP. Evidence of mdx mouse skeletal muscle fragility in vivo by eccentric running exercise. Muscle Nerve. 1998;21(5):567–76. Scholar
  39. 39.
    Bulfield G, Siller WG, Wight PA, Moore KJ. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci U S A. 1984;81(4):1189–92. Scholar
  40. 40.
    Gordon BS, Lowe DA, Kostek MC. Exercise increases utrophin protein expression in the mdx mouse model of Duchenne muscular dystrophy. Muscle Nerve. 2014;49(6):915–8. Scholar
  41. 41.
    Hyzewicz J, Tanihata J, Kuraoka M, Ito N, Miyagoe-Suzuki Y, Takeda S. Low intensity training of mdx mice reduces carbonylation and increases expression levels of proteins involved in energy metabolism and muscle contraction. Free Radic Biol Med. 2015;82:122–36. Scholar
  42. 42.
    Hyzewicz J, Tanihata J, Kuraoka M, Nitahara-Kasahara Y, Beylier T, Ruegg UT, et al. Low-intensity training and the C5a complement antagonist NOX-D21 rescue the mdx phenotype through modulation of inflammation. Am J Pathol. 2017;187(5):1147–61. Scholar
  43. 43.
    Jansen M, van Alfen N, Geurts AC, de Groot IJ. Assisted bicycle training delays functional deterioration in boys with Duchenne muscular dystrophy: the randomized controlled trial "no use is disuse". Neurorehabil Neural Repair. 2013;27(9):816–27. Scholar
  44. 44.
    Alemdaroglu I, Karaduman A, Yilmaz OT, Topaloglu H. Different types of upper extremity exercise training in Duchenne muscular dystrophy: effects on functional performance, strength, endurance, and ambulation. Muscle Nerve. 2015;51(5):697–705. Scholar
  45. 45.
    Call JA, McKeehen JN, Novotny SA, Lowe DA. Progressive resistance voluntary wheel running in the mdx mouse. Muscle Nerve. 2010;42(6):871–80. Scholar
  46. 46.
    Hulmi JJ, Oliveira BM, Silvennoinen M, Hoogaars WM, Pasternack A, Kainulainen H, et al. Exercise restores decreased physical activity levels and increases markers of autophagy and oxidative capacity in myostatin/activin-blocked mdx mice. Am J Physiol Endocrinol Metab. 2013;305(2):E171–82. Scholar
  47. 47.
    Selsby JT, Acosta P, Sleeper MM, Barton ER, Sweeney HL. Long-term wheel running compromises diaphragm function but improves cardiac and plantarflexor function in the mdx mouse. J Appl Physiol (1985). 2013, 115(5):660–6. Scholar
  48. 48.
    Nozaki S, Kawai M, Shimoyama R, Futamura N, Matsumura T, Adachi K, et al. Range of motion exercise of temporo-mandibular joint with hot pack increases occlusal force in patients with Duchenne muscular dystrophy. Acta Myol. 2010;29(3):392–7.PubMedPubMedCentralGoogle Scholar
  49. 49.
    Rodrigues MR, Carvalho CR, Santaella DF, Lorenzi-Filho G, Marie SK. Effects of yoga breathing exercises on pulmonary function in patients with Duchenne muscular dystrophy: an exploratory analysis. J Bras Pneumol. 2014;40(2):128–33. Scholar
  50. 50.
    Baltgalvis KA, Call JA, Cochrane GD, Laker RC, Yan Z, Lowe DA. Exercise training improves plantar flexor muscle function in mdx mice. Med Sci Sports Exerc. 2012;44(9):1671–9. Scholar
  51. 51.
    Hourde C, Joanne P, Medja F, Mougenot N, Jacquet A, Mouisel E, et al. Voluntary physical activity protects from susceptibility to skeletal muscle contraction-induced injury but worsens heart function in mdx mice. Am J Pathol. 2013;182(5):1509–18. Scholar
  52. 52.
    Fontana S, Schillaci O, Frinchi M, Giallombardo M, Morici G, Di Liberto V, et al. Reduction in mdx mouse muscle degeneration by low-intensity endurance exercise: a proteomic analysis in quadriceps muscle of exercised compared with sedentary mdx mice. Biosci Rep. 2015;35(3).
  53. 53.
    Delacroix C, Hyzewicz J, Lemaitre M, Friguet B, Li Z, Klein A, et al. Improvement of dystrophic muscle fragility by short-term voluntary exercise through activation of Calcineurin pathway in mdx mice. Am J Pathol. 2018;188(11):2662–73. Scholar
  54. 54.
    • Lindsay A, Larson AA, Verma M, Ervasti JM, Lowe DA. Isometric resistance training increases strength and alters histopathology of dystrophin-deficient mouse skeletal muscle. J Appl Physiol (1985). 2019;126(2):363–75. focuses on the adaptive responses of mdx mouse skeletal muscle to isometric contraction training and reports that in the absence of dystrophin, strength and muscle histopathology are improved. Importantly, there was no indication that the isometric exercise training was deleterious to dystrophin-deficient muscle. CrossRefGoogle Scholar
  55. 55.
    Fernandes DC, Cardoso-Nascimento JJA, Garcia BCC, Costa KB, Rocha-Vieira E, Oliveira MX, et al. Low intensity training improves redox status and reduces collagen fibers on dystrophic muscle. J Exerc Rehabil. 2019;15(2):213–23. Scholar
  56. 56.
    • Zelikovich AS, Quattrocelli M, Salamone IM, Kuntz NL, EM MN. Moderate exercise improves function and increases adiponectin in the mdx mouse model of muscular dystrophy. Sci Rep. 2019;9(1):5770. this study, 4–5-month-old mdx mice were trained on a treadmill for 30 minutes 3 times a week for 6 months at low intensity (4 m / min) and moderate intensity (8 m / min). Compared to the non-intervention group, the results of the hind limb grip test and TA muscle strength increased, and the fatigue resistance was improved by the muscle fatigue test (10 times with isometric muscle contraction). In addition to muscle strength, excrcise had a positive effect on respiratory and cardiac functions. CrossRefPubMedPubMedCentralGoogle Scholar
  57. 57.
    Grange RW, Call JA. Recommendations to define exercise prescription for Duchenne muscular dystrophy. Exerc Sport Sci Rev. 2007;35(1):12–7. Scholar
  58. 58.
    Gianola S, Pecoraro V, Lambiase S, Gatti R, Banfi G, Moja L. Efficacy of muscle exercise in patients with muscular dystrophy: a systematic review showing a missed opportunity to improve outcomes. PLoS One. 2013;8(6):e65414. Scholar
  59. 59.
    •• Spaulding HR, Selsby JT. Is exercise the right medicine for dystrophic muscle? Med Sci Sports Exerc. 2018;50(9):1723–32. reviews the results of exercise intervention studies for DMD patients and mdx mice. The data are summarized to show whether the pathology of DMD was improved or worsened. CrossRefPubMedGoogle Scholar
  60. 60.
    Hayes A, Williams DA. Beneficial effects of voluntary wheel running on the properties of dystrophic mouse muscle. J Appl Physiol (1985). 1996;80(2):670–9. Scholar
  61. 61.
    Dupont-Versteegden EE. Exercise and clenbuterol as strategies to decrease the progression of muscular dystrophy in mdx mice. J Appl Physiol (1985). 1996;80(3):734–41. Scholar
  62. 62.
    Dupont-Versteegden EE, McCarter RJ, Katz MS. Voluntary exercise decreases progression of muscular dystrophy in diaphragm of mdx mice. J Appl Physiol (1985). 1994;77(4):1736–41. Scholar
  63. 63.
    Hayes A, Williams DA. Contractile function and low-intensity exercise effects of old dystrophic (mdx) mice. Am J Phys. 1998;274(4):C1138–44. Scholar
  64. 64.
    Frinchi M, Macaluso F, Licciardi A, Perciavalle V, Coco M, Belluardo N, et al. Recovery of damaged skeletal muscle in mdx mice through low-intensity endurance exercise. Int J Sports Med. 2014;35(1):19–27. Scholar
  65. 65.
    De Luca A, Nico B, Liantonio A, Didonna MP, Fraysse B, Pierno S, et al. A multidisciplinary evaluation of the effectiveness of cyclosporine a in dystrophic mdx mice. Am J Pathol. 2005;166(2):477–89. Scholar
  66. 66.
    De Luca A, Pierno S, Liantonio A, Cetrone M, Camerino C, Fraysse B, et al. Enhanced dystrophic progression in mdx mice by exercise and beneficial effects of taurine and insulin-like growth factor-1. J Pharmacol Exp Ther. 2003;304(1):453–63. Scholar
  67. 67.
    Burdi R, Didonna MP, Pignol B, Nico B, Mangieri D, Rolland JF, et al. First evaluation of the potential effectiveness in muscular dystrophy of a novel chimeric compound, BN 82270, acting as calpain-inhibitor and anti-oxidant. Neuromuscul Disord. 2006;16(4):237–48. Scholar
  68. 68.
    Burdi R, Rolland JF, Fraysse B, Litvinova K, Cozzoli A, Giannuzzi V, et al. Multiple pathological events in exercised dystrophic mdx mice are targeted by pentoxifylline: outcome of a large array of in vivo and ex vivo tests. J Appl Physiol (1985). 2009;106(4):1311–24. Scholar
  69. 69.
    Camerino GM, Cannone M, Giustino A, Massari AM, Capogrosso RF, Cozzoli A, et al. Gene expression in mdx mouse muscle in relation to age and exercise: aberrant mechanical-metabolic coupling and implications for pre-clinical studies in Duchenne muscular dystrophy. Hum Mol Genet. 2014;23(21):5720–32. Scholar
  70. 70.
    Hall JE, Kaczor JJ, Hettinga BP, Isfort RJ, Tarnopolsky MA. Effects of a CRF2R agonist and exercise on mdx and wildtype skeletal muscle. Muscle Nerve. 2007;36(3):336–41. Scholar
  71. 71.
    Schill KE, Altenberger AR, Lowe J, Periasamy M, Villamena FA, Rafael-Fortney JA, et al. Muscle damage, metabolism, and oxidative stress in mdx mice: impact of aerobic running. Muscle Nerve. 2016;54(1):110–7. Scholar
  72. 72.
    Radley-Crabb H, Terrill J, Shavlakadze T, Tonkin J, Arthur P, Grounds M. A single 30 min treadmill exercise session is suitable for 'proof-of concept studies' in adult mdx mice: a comparison of the early consequences of two different treadmill protocols. Neuromuscul Disord. 2012;22(2):170–82. Scholar
  73. 73.
    Morales MG, Cabrera D, Cespedes C, Vio CP, Vazquez Y, Brandan E, et al. Inhibition of the angiotensin-converting enzyme decreases skeletal muscle fibrosis in dystrophic mice by a diminution in the expression and activity of connective tissue growth factor (CTGF/CCN-2). Cell Tissue Res. 2013;353(1):173–87. Scholar
  74. 74.
    Pessina P, Cabrera D, Morales MG, Riquelme CA, Gutierrez J, Serrano AL, et al. Novel and optimized strategies for inducing fibrosis in vivo: focus on Duchenne muscular dystrophy. Skelet Muscle. 2014;4:7. Scholar
  75. 75.
    Haycock JW, MacNeil S, Jones P, Harris JB, Mantle D. Oxidative damage to muscle protein in Duchenne muscular dystrophy. Neuroreport. 1996;8(1):357–61. Scholar
  76. 76.
    Ragusa RJ, Chow CK, Porter JD. Oxidative stress as a potential pathogenic mechanism in an animal model of Duchenne muscular dystrophy. Neuromuscul Disord. 1997;7(6–7):379–86.CrossRefGoogle Scholar
  77. 77.
    Rodriguez MC, Tarnopolsky MA. Patients with dystrophinopathy show evidence of increased oxidative stress. Free Radic Biol Med. 2003;34(9):1217–20.CrossRefGoogle Scholar
  78. 78.
    Disatnik MH, Dhawan J, Yu Y, Beal MF, Whirl MM, Franco AA, et al. Evidence of oxidative stress in mdx mouse muscle: studies of the pre-necrotic state. J Neurol Sci. 1998;161(1):77–84. Scholar
  79. 79.
    Franco AA, Odom RS, Rando TA. Regulation of antioxidant enzyme gene expression in response to oxidative stress and during differentiation of mouse skeletal muscle. Free Radic Biol Med. 1999;27(9–10):1122–32.CrossRefGoogle Scholar
  80. 80.
    Disatnik MH, Chamberlain JS, Rando TA. Dystrophin mutations predict cellular susceptibility to oxidative stress. Muscle Nerve. 2000;23(5):784–92. Scholar
  81. 81.
    Dalle-Donne I, Scaloni A, Giustarini D, Cavarra E, Tell G, Lungarella G, et al. Proteins as biomarkers of oxidative/nitrosative stress in diseases: the contribution of redox proteomics. Mass Spectrom Rev. 2005;24(1):55–99. Scholar
  82. 82.
    Renjini R, Gayathri N, Nalini A, Srinivas Bharath MM. Oxidative damage in muscular dystrophy correlates with the severity of the pathology: role of glutathione metabolism. Neurochem Res. 2012;37(4):885–98. Scholar
  83. 83.
    Kaczor JJ, Hall JE, Payne E, Tarnopolsky MA. Low intensity training decreases markers of oxidative stress in skeletal muscle of mdx mice. Free Radic Biol Med. 2007;43(1):145–54. Scholar
  84. 84.
    Kharraz Y, Guerra J, Mann CJ, Serrano AL, Munoz-Canoves P. Macrophage plasticity and the role of inflammation in skeletal muscle repair. Mediat Inflamm. 2013;2013:491497. Scholar
  85. 85.
    Rigamonti E, Zordan P, Sciorati C, Rovere-Querini P, Brunelli S. Macrophage plasticity in skeletal muscle repair. Biomed Res Int. 2014;2014:560629. Scholar
  86. 86.
    Madaro L, Bouche M. From innate to adaptive immune response in muscular dystrophies and skeletal muscle regeneration: the role of lymphocytes. Biomed Res Int. 2014;2014:438675. Scholar
  87. 87.
    • Dort J, Fabre P, Molina T, Dumont NA. Macrophages are key regulators of stem cells during skeletal muscle regeneration and diseases. Stem cells Int. 2019;2019:4761427. reviews how macrophages are involved in DMD muscle regeneration. CrossRefPubMedPubMedCentralGoogle Scholar
  88. 88.
    Summan M, Warren GL, Mercer RR, Chapman R, Hulderman T, Van Rooijen N, et al. Macrophages and skeletal muscle regeneration: a clodronate-containing liposome depletion study. Am J Physiol Regul Integr Comp Physiol. 2006;290(6):R1488–95. Scholar
  89. 89.
    Arnold L, Henry A, Poron F, Baba-Amer Y, van Rooijen N, Plonquet A, et al. Inflammatory monocytes recruited after skeletal muscle injury switch into antiinflammatory macrophages to support myogenesis. J Exp Med. 2007;204(5):1057–69. Scholar
  90. 90.
    Perdiguero E, Sousa-Victor P, Ruiz-Bonilla V, Jardi M, Caelles C, Serrano AL, et al. p38/MKP-1-regulated AKT coordinates macrophage transitions and resolution of inflammation during tissue repair. J Cell Biol. 2011;195(2):307–22. Scholar
  91. 91.
    Deng B, Wehling-Henricks M, Villalta SA, Wang Y, Tidball JG. IL-10 triggers changes in macrophage phenotype that promote muscle growth and regeneration. J Immunol. 2012;189(7):3669–80. Scholar
  92. 92.
    Saclier M, Yacoub-Youssef H, Mackey AL, Arnold L, Ardjoune H, Magnan M, et al. Differentially activated macrophages orchestrate myogenic precursor cell fate during human skeletal muscle regeneration. Stem Cells. 2013;31(2):384–96. Scholar
  93. 93.
    Wehling M, Spencer MJ, Tidball JG. A nitric oxide synthase transgene ameliorates muscular dystrophy in mdx mice. J Cell Biol. 2001;155(1):123–31. Scholar
  94. 94.
    Villalta SA, Nguyen HX, Deng B, Gotoh T, Tidball JG. Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. Hum Mol Genet. 2009;18(3):482–96. Scholar
  95. 95.
    • Lemos DR, Babaeijandaghi F, Low M, Chang CK, Lee ST, Fiore D, et al. Nilotinib reduces muscle fibrosis in chronic muscle injury by promoting TNF-mediated apoptosis of fibro/adipogenic progenitors. Nat Med. 2015;21(7):786–94. shows the involvement of macrophages in the pathology of DMD. mdx mice express unusually high TGF-b1, suggesting unusually high levels of M2 macrophages to suppress the apoptosis of FAPs (fibro-adipogenic progenitors) and cause fibrosis. CrossRefPubMedGoogle Scholar
  96. 96.
    Capote J, Kramerova I, Martinez L, Vetrone S, Barton ER, Sweeney HL, et al. Osteopontin ablation ameliorates muscular dystrophy by shifting macrophages to a pro-regenerative phenotype. J Cell Biol. 2016;213(2):275–88. Scholar
  97. 97.
    Juban G, Saclier M, Yacoub-Youssef H, Kernou A, Arnold L, Boisson C, Ben Larbi S, Magnan M, Cuvellier S, Théret M, Petrof BJ, Desguerre I, Gondin J, Mounier R, Chazaud B AMPK activation regulates LTBP4-dependent TGF-beta1 secretion by pro-inflammatory macrophages and controls fibrosis in Duchenne muscular dystrophy. Cell Rep 2018;25(8):2163–2176 e6. Scholar
  98. 98.
    Ambrosio F, Ferrari RJ, Distefano G, Plassmeyer JM, Carvell GE, Deasy BM, et al. The synergistic effect of treadmill running on stem-cell transplantation to heal injured skeletal muscle. Tissue Eng Part A. 2010;16(3):839–49. Scholar
  99. 99.
    Ambrosio F, Kadi F, Lexell J, Fitzgerald GK, Boninger ML, Huard J. The effect of muscle loading on skeletal muscle regenerative potential: an update of current research findings relating to aging and neuromuscular pathology. Am J Phys Med Rehabil. 2009;88(2):145–55. Scholar
  100. 100.
    Kadi F, Charifi N, Denis C, Lexell J, Andersen JL, Schjerling P, et al. The behaviour of satellite cells in response to exercise: what have we learned from human studies? Pflugers Arch. 2005;451(2):319–27. Scholar
  101. 101.
    Payne TR, Oshima H, Okada M, Momoi N, Tobita K, Keller BB, et al. A relationship between vascular endothelial growth factor, angiogenesis, and cardiac repair after muscle stem cell transplantation into ischemic hearts. J Am Coll Cardiol. 2007;50(17):1677–84. Scholar
  102. 102.
    Stillwell E, Vitale J, Zhao Q, Beck A, Schneider J, Khadim F, Elson G, Altaf A, Yehia G, Dong JH, Liu J, Mark W, Bhaumik M, Grange R, Fraidenraich D Blastocyst injection of wild type embryonic stem cells induces global corrections in mdx mice. PLoS One 2009;4(3):e4759. doi: Scholar
  103. 103.
    Neri M, Torelli S, Brown S, Ugo I, Sabatelli P, Merlini L, et al. Dystrophin levels as low as 30% are sufficient to avoid muscular dystrophy in the human. Neuromuscul Disord. 2007;17(11–12):913–8. Scholar
  104. 104.
    van den Bergen JC, Wokke BH, Janson AA, van Duinen SG, Hulsker MA, Ginjaar HB, et al. Dystrophin levels and clinical severity in Becker muscular dystrophy patients. J Neurol Neurosurg Psychiatry. 2014;85(7):747–53. Scholar
  105. 105.
    Godfrey C, Muses S, McClorey G, Wells KE, Coursindel T, Terry RL, et al. How much dystrophin is enough: the physiological consequences of different levels of dystrophin in the mdx mouse. Hum Mol Genet. 2015;24(15):4225–37. Scholar
  106. 106.
    • Itoh Y, Murakami T, Mori T, Agata N, Kimura N, Inoue-Miyazu M, et al. Training at non-damaging intensities facilitates recovery from muscle atrophy. Muscle Nerve. 2017;55(2):243–53. shows that muscle hypertrophy and strength improvement occur when isometric contraction training load is performed on wild-type mice and includes a description of the mechanism and optimum load strength. CrossRefPubMedGoogle Scholar
  107. 107.
    Filareto A, Parker S, Darabi R, Borges L, Iacovino M, Schaaf T, et al. An ex vivo gene therapy approach to treat muscular dystrophy using inducible pluripotent stem cells. Nat Commun. 2013;4:1549. Scholar
  108. 108.
    Distefano G, Ferrari RJ, Weiss C, Deasy BM, Boninger ML, Fitzgerald GK, et al. Neuromuscular electrical stimulation as a method to maximize the beneficial effects of muscle stem cells transplanted into dystrophic skeletal muscle. PLoS One. 2013;8(3):e54922. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2020

Authors and Affiliations

  • Nana Takenaka-Ninagawa
    • 1
    • 2
    Email author
  • Megumi Goto
    • 1
  • Rukia Ikeda
    • 1
  • Hidetoshi Sakurai
    • 1
  1. 1.Center for iPS cell Research and ApplicationKyoto UniversityKyotoJapan
  2. 2.Japan Society for the Promotion of Science (JSPS)TokyoJapan

Personalised recommendations