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Muscle Fiber Regeneration in Long-Term Denervated Muscles: Basics and Clinical Perspectives

  • Ugo Carraro
  • Helmut Kern
  • Sandra Zampieri
  • Paolo Gargiulo
  • Amber Pond
  • Francesco Piccione
  • Stefano Masiero
  • Franco Bassetto
  • Vincenzo VindigniEmail author
Chapter

Abstract

The differentiation of muscle fibers regenerating in the absence of the nerve is remarkable in animal experiments and is also evident in muscle biopsies harvested from human patients. During the last 20 years, clinical studies have employed long impulse biphasic electrical stimulation as a first-step treatment for humans living with long-term denervated muscles subsequent to spinal cord injury (SCI). Trophic and functional recovery from severe atrophy/degeneration occurs in long-term denervated degenerating muscles (DDM) treated with h-bFES at between 1 and 5 years from SCI. This fact has sound foundations based on muscle biopsy analyses and on quantitative muscle color computed tomography (QMC-CT). If myogenesis in patients could be modulated during the many months needed to recover tetanic contractility of denervated muscles, then it should be possible to substantially abbreviate the time needed to achieve functional recovery of long-term denervated human muscle by h-bFES, using the commercial muscle stimulator and the large electrodes now available. The future will tell if induced muscle fiber regeneration and h-bFES will be useful even at 10 years after SCI, i.e., in the vast majority of the people in need of them.

Keywords

Muscle stem cells Satellite cells Muscle regeneration Nerve regeneration 

Notes

Acknowledgements

This work was supported by Italian Ministero per l’Università e la RicercaScientifica eTecnologica (M.U.R.S.T.), the EU Commission Shared Cost Project RISE (Contract no. QLG5-CT-2001-02191), the Austrian Ministry of Science, and the Ludwig Boltzmann Society (Vienna). U. Carraro thanks the IRCCS Fondazione Ospedale San Camillo, Venice (Italy), for scientific support and hospitality.

References

  1. 1.
    Kern H, Carraro U. Home-based Functional Electrical Stimulation (h-b FES) for long-term denervated human muscle: History, basics, results and perspectives of the Vienna Rehabilitation Strategy. Eur J Transl Myol. 2014;24:27–40.Google Scholar
  2. 2.
    Carraro U, Kern H, Gava P, Hofer C, Loefler S, Gargiulo P, Edmunds K, Árnadóttir D, Zampieri S, Ravara B, Gava F, Nori A, Gobbo V, Masiero S, Marcante A, Baba A, Piccione F, Schils S, Pond A, Mosole S. Recovery from muscle weakness by exercise and FES: lessons from Masters, active or sedentary seniors and SCI patients. Aging Clin Exp Res. 2017;29(4):579–90.PubMedCrossRefGoogle Scholar
  3. 3.
    Kern H, Boncompagni S, Rossini K, Mayr W, Fanò G, Zanin ME, Podhorska-Okolow M, Protasi F, Carraro U. Long-term denervation in humans causes degeneration of both contractile and excitation-contraction coupling apparatus that can be reversed by functional electrical stimulation (FES). A role for myofiber regeneration? J Neuropathol Exp Neurol. 2004;63:919–31.PubMedCrossRefGoogle Scholar
  4. 4.
    Kern H, Rossini K, Carraro U, Mayr W, Vogelauer M, Hoellwarth U, Hofer C. Muscle biopsies show that FES of denervated muscles reverses human muscle degeneration from permanent spinal motoneuron lesion. J Rehabil Res Dev. 2005;42:43–53.PubMedCrossRefGoogle Scholar
  5. 5.
    Carraro U, Rossini K, Mayr W, Kern H. Muscle fiber regeneration in human permanent lower motoneuron denervation: relevance to safety and effectiveness of FES-training, which induces muscle recovery in SCI subjects. Artif Organs. 2005;29:187–91.PubMedCrossRefGoogle Scholar
  6. 6.
    Kern H, Salmons S, Mayr W, Rossini K, Carraro U. Recovery of long-term denervated human muscles induced by electrical stimulation. Muscle Nerve. 2005;31(1):98–101.PubMedCrossRefGoogle Scholar
  7. 7.
    Boncompagni S, Kern H, Rossini K, Hofer C, Mayr W, Carraro U, Protasi F. Structural differentiation of skeletal muscle fibers in the absence of innervation in humans. Proc Natl Acad Sci U S A. 2007;104:19339–44.PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Kern H, Carraro U, Adami N, Hofer C, Loefler S, Vogelauer M, Mayr W, Rupp R, Zampieri S. One year of home-based Functional Electrical Stimulation (FES) in complete lower motor neuron paraplegia: recovery of tetanic contractility drives the structural improvements of denervated muscle. Neurol Res. 2010;32:5–12.PubMedCrossRefGoogle Scholar
  9. 9.
    Kern H, Carraro U, Adami N, Biral D, Hofer C, Forstner C, Mödlin M, Vogelauer M, Pond A, Boncompagni S, Paolini C, Mayr W, Protasi F, Zampieri S. Home-based functional electrical stimulation rescues permanently denervated muscles in paraplegic patients with complete lower motor neuron lesion. Neurorehabil Neural Repair. 2010;24:709–21.PubMedCrossRefGoogle Scholar
  10. 10.
    Zealear DL, Rodriguez RJ, Kenny T, Billante MJ, Cho Y, Billante CR, Garren KC. Electrical stimulation of a denervated muscle promotes selective reinnervation by native over foreign motoneurons. J Neurophysiol. 2002;87:2195–9.PubMedCrossRefGoogle Scholar
  11. 11.
    Willand MP. Electrical stimulation enhances reinnervation after nerve injury. Eur J Transl Myol. 2015;25(4):243–8.PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Willand MP, Rosa E, Michalski B, Zhang JJ, Gordon T, Fahnestock M, Borschel GH. Electrical muscle stimulation elevates intramuscular BDNF and GDNF mRNA following peripheral nerve injury and repair in rats. Neuroscience. 2016;334:93–104.PubMedCrossRefGoogle Scholar
  13. 13.
    Pette D, Vrbová G. The contribution of neuromuscular stimulation in elucidating muscle plasticity revisited. Eur J Transl Myol. 2017;27(1):33–9.CrossRefGoogle Scholar
  14. 14.
    Carraro U, Franceschi C. Apoptosis of skeletal and cardiac muscles and physical exercise. Aging (Milano). 1997;9(1-2):19–34.Google Scholar
  15. 15.
    Carraro U, Sandri M. Apoptosis of skeletal muscles during development and disease. Int J Biochem Cell Biol. 1999;31(12):1373–90.PubMedCrossRefGoogle Scholar
  16. 16.
    Borisov AB, Carlson BM. Cell death in denervated skeletal muscle is distinct from classical apoptosis. Anat Rec. 2000;258(3):305–18.PubMedCrossRefGoogle Scholar
  17. 17.
    Borisov AB, Dedkov EI, Carlson BM. Interrelations of myogenic response, progressive atrophy of muscle fibers, and cell death in denervated skeletal muscle. Anat Rec. 2001;264:203–18.PubMedCrossRefGoogle Scholar
  18. 18.
    Carlson BM, Borisov AI, Dekov EI, Dow D, Kostrominova TY. The biology and restorative capacity of long-term denervated skeletal muscle. Basic Appl Myol. 2002;12:247–54.Google Scholar
  19. 19.
    Jakubiec-Puka A, Kordowska J, Catani C, Carraro U. Myosin heavy chain isoform composition in striated muscle after denervation and self- reinnervation. Eur J Biochem. 1990;193:623–8.PubMedCrossRefGoogle Scholar
  20. 20.
    Talmadge RJ, Roy RR, Bodine-Fowler SC, Pierotti DJ, Edgerton VR. Adaptations in myosin heavy chain profile in chronically unloaded muscles. Basic Appl Biol. 1995;5:119–34.Google Scholar
  21. 21.
    Carraro U, Morale D, Mussini I, Lucke S, Cantini M, Betto R, Catani C, Dalla Libera L, Danieli-Betto D, Noventa D. Chronic denervation of rat diaphragm: maintenance of fiber heterogeneity with associated increasing uniformity of myosin isoforms. J Cell Biol. 1985;100:161–74.PubMedCrossRefPubMedCentralGoogle Scholar
  22. 22.
    Carraro U, Catani C, Biral D. Selective maintenance of neurotrophically regulated proteins in denervated rat diaphragm. Exp Neurol. 1979;63(3):468–75.PubMedCrossRefPubMedCentralGoogle Scholar
  23. 23.
    Carraro U, Catani C, DallaLibera L. Myosin light and heavy chains in rat gastrocnemius and diaphragm muscles after chronic denervation or reinnervation. Exp Neurol. 1981;72(2):401–12.PubMedCrossRefPubMedCentralGoogle Scholar
  24. 24.
    Lewis DM, Schmalbruch H. Contractile properties of a neurally regenerated compared with denervated muscles of rat. J Muscle Res Cell Motil. 1994;15(3):267–77.PubMedCrossRefPubMedCentralGoogle Scholar
  25. 25.
    Schmalbruch H, Lewis DM. A comparison of the morphology of denervated with aneurally regenerated soleus muscle of rat. J Muscle Res Cell Motil. 1994;15(3):256–66.PubMedCrossRefPubMedCentralGoogle Scholar
  26. 26.
    Carraro U, Catani C, Degani A, Rizzi C. Myosin expression in denervated fast-and slow-twitch muscles: fiber modulation and substitution. In: Pette D, editor. The dynamic state of muscle fibers. Berlin: Walter de Gruyter; 1990. p. 247–62.CrossRefGoogle Scholar
  27. 27.
    Bacou F, Rouanet P, Barjot C, Janmot C, Vigneron P, d’Albis A. Expression of myosin isoforms in denervated, cross-reinnervated, and electrically stimulated rabbit muscles. Eur J Biochem. 1996;236(2):539–47.PubMedCrossRefPubMedCentralGoogle Scholar
  28. 28.
    Mauro A. Satellite cell of skeletal muscle fibers. J Biophys Biochem Cytol. 1961;9:493–5.PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Yin H, Price F, Rudnicki MA. Satellite cells and the muscle stem cell niche. Physiol Rev. 2013;93:23–67.PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Gundersen K, Bruusgaard JC. Nuclear domains during muscle atrophy: nuclei lost or paradigm lost? J Physiol. 2008;586(Pt 11):2675–81.PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    Yablonka-Reuveni Z. The skeletal muscle satellite cell: still young and fascinating at 50. J Histochem Cytochem. 2011;59(12):1041–59.PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Mussini I, Favaro G, Carraro U. Maturation, dystrophic changes and the continuous production of fibers in skeletal muscle regenerating in the absence of nerve. J Neurophatol Exp Neurol. 1987;46:315–31.CrossRefGoogle Scholar
  33. 33.
    Allen DL, Monke SR, Talmadge RJ, Roy RR, Edgerton VR. Plasticity of myonuclear number in hypertrophied and atrophied mammalian skeletal muscle fibers. J Appl Physiol. 1995;78:1969–76.PubMedCrossRefGoogle Scholar
  34. 34.
    Billington L, Carlson BM. The recovery of long-term denervated rat muscles after Marcaine treatment and grafting. Anat Rec. 1996;144(1-2):147–55.Google Scholar
  35. 35.
    Dedkov AR, Kostrominova TY, Borisov AB, Carlson BM. Reparative myogenesis in long-term denervated skeletal muscles of adult rats results in a reduction of the satellite cell population. Anat Rec. 2001;263:139–54.PubMedCrossRefGoogle Scholar
  36. 36.
    Jejurikar SS, Marcelo CL, Kuzon WM Jr. Skeletal muscle denervation increases satellite cell susceptibility to apoptosis. Plast Reconstr Surg. 2002;110(1):160–8.PubMedCrossRefGoogle Scholar
  37. 37.
    Lewis DM, Schmalbruch H. Effects of age on aneural regeneration of soleus muscle in rat. J Physiol (Lond). 1995;488(2):483–92.CrossRefGoogle Scholar
  38. 38.
    Rodrigues AC, Schmalbruch H. Satellite cells and myonuclei in long-term denervated rat muscle. Anat Rec. 1995;243(4):430–7.CrossRefGoogle Scholar
  39. 39.
    Yoshimura K, Harii K. A regenerative change during muscle adaptation to denervation in rats. J Surg Res. 1999;81(2):139–46.PubMedCrossRefGoogle Scholar
  40. 40.
    Schmalbruch H, Lewis DM. Dynamics of nuclei of muscle fibers and connective tissue cells in normal and denervated rat muscles. Muscle Nerve. 2000;23(4):617–26.PubMedCrossRefGoogle Scholar
  41. 41.
    Hnik P. Rate of denervation muscle atrophy. In: Gutmann E, editor. The denervated muscle. Prague: Publishing House of Czechoslovak Academy of Science; 1962. p. 341–71.CrossRefGoogle Scholar
  42. 42.
    Gallucci V, Novello F, Margreth A, Aloisi M. Biochemical correlates of discontinuous muscle regeneration in rat. Br J Exp Pathol. 1966;47:215–27.PubMedCentralPubMedGoogle Scholar
  43. 43.
    Carraro U, DallaLibera L, Catani C. Myosin light and heavy chains in muscle regenerating in absence of the nerve: transient appearance of the embryonic light chains. Exp Neurol. 1983;79:106–17.PubMedCrossRefGoogle Scholar
  44. 44.
    Carraro U, Catani C. A sensitive SDS PAGE method separating heavy chain isoforms of rat skeletal muscles reveals the heterogeneous nature of the embryonic myosin. Biochem Biophys Res Commun. 1983;116:793–802.PubMedCrossRefGoogle Scholar
  45. 45.
    Carraro U, Rossini K, Zanin ME, Rizzi C, Mayr W, Kern H. Induced myogenesis in long-term permanent denervation: perspective role in functional electrical stimulation of denervated legs in humans. Basic Appl Myol. 2002;12(2):53–64.Google Scholar
  46. 46.
    Gulati AK. Long-term retention of regenerative capacity after denervation of skeletal muscle, and dependency of late differentiation on innervation. Anat Rec. 1988;220:429–34.PubMedCrossRefGoogle Scholar
  47. 47.
    Lu DX, Huang SK, Carlson BM. Electron microscopic study of long-term denervated rat skeletal muscle. Anat Rec. 1997;248(3):355–6.PubMedCrossRefGoogle Scholar
  48. 48.
    Gross JG, Morgan JE. Muscle precursor cells injected into irradiated mdx mouse muscle persist after serial injury. Muscle Nerve. 1999;22(2):174–85.PubMedCrossRefGoogle Scholar
  49. 49.
    Gross JG, Bou-Gharios G, Morgan JE. Potentiation of myoblast transplantation by host muscle irradiation is dependent on the rate of radiation delivery. Cell Tissue Res. 1999;298(2):371–5.PubMedCrossRefGoogle Scholar
  50. 50.
    Putman CT, Dusterhoft S, Pette D. Satellite cell proliferation in low frequency-stimulated fast muscle of hypothyroid rat. Am J Physiol Cell. 2000;279(3):C682–C90.CrossRefGoogle Scholar
  51. 51.
    Kadi F, Schjerling P, Andersen LL, Charifi N, Madsen JL, Christensen LR, Andersen JL. The effects of heavy resistance training and detraining on satellite cells in human skeletal muscles. J Physiol. 2004;558(Pt 3):1005–12.PubMedPubMedCentralCrossRefGoogle Scholar
  52. 52.
    Best TM, Gharaibeh B, Huard J. Stem cells, angiogenesis and muscle healing: a potential role in massage therapies? Br J Sports Med. 2013;47(9):556–60.CrossRefGoogle Scholar
  53. 53.
    Kern H, Hofer C, Mödlin M, Forstner C, Raschka- Höger D, Mayr W, Stöhr H. Denervated muscles in humans: limitations and problems of currently used functional electrical stimulation training protocols. Artif Organs. 2002;26(3):216–8.PubMedCrossRefGoogle Scholar
  54. 54.
    Franceschini M, Cerrel Bazo H, Lauretani F, Agosti M, Pagliacci MC. Age influences rehabilitative outcomes in patients with spinal cord injury (SCI). Aging Clin Exp Res. 2011;23(3):202–8.PubMedCrossRefGoogle Scholar
  55. 55.
    Huang H, Sun T, Chen L, Moviglia G, Chernykh E, von Wild K, Deda H, Kang KS, Kumar A, Jeon SR, Zhang S, Brunelli G, Bohbot A, Soler MD, Li J, Cristante AF, Xi H, Onose G, Kern H, Carraro U, Saberi H, Sharma HS, Sharma A, He X, Muresanu D, Feng S, Otom A, Wang D, Iwatsu K, Lu J, Al-Zoubi A. Consensus of clinical neurorestorative progress in patients with complete chronic spinal cord injury. Cell Transplant. 2014;23(Suppl 1):S5–17.PubMedCrossRefGoogle Scholar
  56. 56.
    Valencic V, Vodovnik L, Stefancic M, Jelnikar T. Improved motor response due to chronic electrical stimulation of denervated tibialis anterior muscle in humans. Muscle Nerve. 1986;9:612–7.PubMedCrossRefGoogle Scholar
  57. 57.
    Hofer C, Mayr W, Stöhr H, Unger E, Kern H. A stimulator for functional activation of denervated muscles. Artif Organs. 2002;26(3):276–9.PubMedCrossRefGoogle Scholar
  58. 58.
    Edmunds KJ, Árnadóttir Í, Gíslason MK, Carraro U, Gargiulo P. Nonlinear trimodal regression analysis of radiodensitometric distributions to quantify sarcopenic and sequelae muscle degeneration. Comput Math Methods Med. 2016;2016:8932950.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Edmunds KJ, Gargiulo P. Imaging approaches in functional assessment of implantable myogenic biomaterials and engineered muscle tissue. Eur J Transl Myol. 2015;25(2):4847.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Nieman K, Hoffmann U. Cardiac computed tomography in patients with acute chest pain. Eur Heart J. 2015;36:906–14.PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Gargiulo P, Reynisson PJ, Helgason B, Kern H, Mayr W, Ingvarsson P, Helgason T, Carraro U. Muscle, tendons, and bone: structural changes during denervation and FES treatment. Neurol Res. 2011;33:750–8.PubMedCrossRefGoogle Scholar
  62. 62.
    Carraro U, Edmunds KJ, Gargiulo P. 3D false color computed tomography for diagnosis and follow-up of permanent denervated human muscles submitted to home-based functional electrical stimulation. Eur J Transl Myol. 2015;25:129–40.CrossRefGoogle Scholar
  63. 63.
    Edmunds KJ, Gíslason MK, Arnadottir ID, Marcante A, Piccione F, Gargiulo P. Quantitative computed tomography and image analysis for advanced muscle assessment. Eur J Transl Myol. 2016;26(2):6015.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Kern H, Barberi L, Löfler S, Sbardella S, Burggraf S, Fruhmann H, Carraro U, Mosole S, Sarabon N, Vogelauer M, Mayr W, Krenn M, Cvecka J, Romanello V, Pietrangelo L, Protasi F, Sandri M, Zampieri S, Musaro A. Electrical stimulation counteracts muscle decline in seniors. Front Aging Neurosci. 2014;6:189.PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Zampieri S, Pietrangelo L, Loefler S, Fruhmann H, Vogelauer M, Burggraf S, Pond A, Grim-Stieger M, Cvecka J, Sedliak M, Tirpáková V, Mayr W, Sarabon N, Rossini K, Barberi L, De Rossi M, Romanello V, Boncompagni S, Musarò A, Sandri M, Protasi F, Carraro U, Kern H. Lifelong physical exercise delays age-associated skeletal muscle decline. J Gerontol A Biol Sci Med Sci. 2015;70(2):163–73.PubMedCrossRefPubMedCentralGoogle Scholar
  66. 66.
    Zampieri S, Mosole S, Löfler S, Fruhmann H, Burggraf S, Cvečka J, Hamar D, Sedliak M, Tirptakova V, Šarabon N, Mayr W, Kern H. Physical exercise in aging: nine weeks of leg press or electrical stimulation training in 70 years old sedentary elderly people. Eur J Transl Myol. 2015;25(4):237–42.PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Zampieri S, Mammucari C, Romanello V, Barberi L, Pietrangelo L, Fusella A, Mosole S, Gherardi G, Höfer C, Löfler S, Sarabon N, Cvecka J, Krenn M, Carraro U, Kern H, Protasi F, Musarò A, Sandri M, Rizzuto R. Physical exercise in aging human skeletal muscle increases mitochondrial calcium uniporter expression levels and affects mitochondria dynamics. Physiol Rep. 2016;4(24):e13005.PubMedPubMedCentralCrossRefGoogle Scholar
  68. 68.
    Kern H, Hofer C, Loefler S, Zampieri S, Gargiulo P, Baba A, Marcante A, Piccione F, Pond A, Carraro U. Atrophy, ultra-structural disorders, severe atrophy and degeneration of denervated human muscle in SCI and Aging. Implications for their recovery by Functional Electrical Stimulation, updated 2017. Neurol Res. 2017;13:1–7.Google Scholar
  69. 69.
    Carraro U, Gava K, Baba A, Piccione F, Marcante A. Fighting muscle weakness in advanced aging by take-home strategies: Safe anti-aging full-body in-bed gym and functional electrical stimulation (FES) for mobility compromised elderly people. Biol Eng Med. 2016;1:1–4.CrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Ugo Carraro
    • 1
    • 2
  • Helmut Kern
    • 3
  • Sandra Zampieri
    • 4
  • Paolo Gargiulo
    • 5
  • Amber Pond
    • 6
  • Francesco Piccione
    • 1
  • Stefano Masiero
    • 4
  • Franco Bassetto
    • 4
  • Vincenzo Vindigni
    • 7
    Email author
  1. 1.IRCCS Fondazione Ospedale San CamilloVenezia-LidoItaly
  2. 2.Department of NeurorehabilitationFoundation San Camillo Hospital, I.R.C.C.S.VeniceItaly
  3. 3.Physiko- und RheumatherapieSt. PoeltenAustria
  4. 4.Interdepartmental Research Centre of MyologyUniversity of PadovaPadovaItaly
  5. 5.Clinical Engineering and Information TechnologyLandspitali—University HospitalReykjavikIceland
  6. 6.Anatomy DepartmentSouthern Illinois University School of MedicineCarbondaleUSA
  7. 7.Unit of Plastic Surgery, Department of NeuroscienceUniversity of PadovaPadovaItaly

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