Skip to main content

Advertisement

SpringerLink
Log in

Muscle-Bone Crosstalk in Amyotrophic Lateral Sclerosis

  • Muscle and Bone (L Bonewald and M Hamrick, Section Editors)
  • Published:
Current Osteoporosis Reports Aims and scope Submit manuscript

Abstract

Amyotrophic lateral sclerosis (ALS), also called Lou Gehrig’s disease, is a fatal neuromuscular disorder characterized by degeneration of motor neurons and by skeletal muscle atrophy. Although the death of motor neurons is a pathological hallmark of ALS, the potential role of other organs in disease progression remains to be elucidated. Skeletal muscle and bone are the two largest organs in the human body. They are responsible not only for locomotion but also for maintaining whole body normal metabolism and homeostasis. Patients with ALS display severe muscle atrophy, which may reflect intrinsic defects in mitochondrial respiratory function and calcium (Ca) signaling in muscle fibers, in addition to the role of axonal withdrawal associated with ALS progression. Incidence of fractures is high in ALS patients, indicating there are potential bone defects in individuals with this condition. There is a lifelong interaction between skeletal muscle and bone. The severe muscle degeneration that occurs during ALS progression may potentially have a significant impact on bone function, and the defective bone may also contribute significantly to neuromuscular degeneration in the course of the disease. Due to the nature of the rapid and severe neuromuscular symptoms, a majority of studies on ALS have focused on neurodegeneration. Just a few studies have explored the possible contribution of muscle defects, even fewer on bone defects, and fewer still on possible muscle-bone crosstalk in ALS. This review article discusses current studies on bone defects and potential defects in muscle-bone crosstalk in ALS.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

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

  1. Alonso A, Logroscino G, Jick SS, Hernan MA. Incidence and lifetime risk of motor neuron disease in the United Kingdom: a population-based study. Eur J Neurol. 2009;16:745–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  2. Pasinelli P, Brown RH. Molecular biology of amyotrophic lateral sclerosis: insights from genetics. Nat Rev Neurosci. 2006;7:710–23.

    Article  CAS  PubMed  Google Scholar 

  3. McGoldrick P, Joyce PI, Fisher EM, Greensmith L. Rodent models of amyotrophic lateral sclerosis. Biochim Biophys Acta. 2013;1832:1421–36.

    Article  CAS  PubMed  Google Scholar 

  4. Baloh RH. How do the RNA-binding proteins TDP-43 and FUS relate to amyotrophic lateral sclerosis and frontotemporal degeneration, and to each other? Curr Opin Neurol. 2012;25:701–7.

    Article  CAS  PubMed  Google Scholar 

  5. Gurney ME, Pu H, Chiu AY, Dal Canto MC, Polchow CY, Alexander DD, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science. 1994;264:1772–5.

    Article  CAS  PubMed  Google Scholar 

  6. Boillee S, Vande Velde C, Cleveland DW. ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron. 2006;52:39–59.

    Article  CAS  PubMed  Google Scholar 

  7. Fischer LR, Culver DG, Tennant P, Davis AA, Wang M, Castellano-Sanchez A, et al. Amyotrophic lateral sclerosis is a distal axonopathy: evidence in mice and man. Exp Neurol. 2004;185:232–40.

    Article  PubMed  Google Scholar 

  8. Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P. Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci. 2000;20:2534–42.

    CAS  PubMed  Google Scholar 

  9. Luo G, Yi J, Ma C, Xiao Y, Yi F, Yu T, et al. Defective mitochondrial dynamics is an early event in skeletal muscle of an amyotrophic lateral sclerosis mouse model. PLoS One. 2013;8:e82112. ALS-linked mutation directly impairs mitochondrial dynamics in skeletal muscle. The study supports that the skeletal muscle defects caused by ALS mutation may actively contribute to ALS pathogenesis.

    Article  PubMed Central  PubMed  Google Scholar 

  10. Yi J, Ma C, Li Y, Weisleder N, Rios E, Ma J, et al. Mitochondrial calcium uptake regulates rapid calcium transients in skeletal muscle during excitation-contraction (E-C) coupling. J Biol Chem. 2011;286:32436–43. First study demonstrates that defective mitochondrial control in Ca signaling plays a key role in skeletal muscle degeneration during ALS progression.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Zhou J, Yi J, Fu R, Liu E, Siddique T, Rios E, et al. Hyperactive intracellular calcium signaling associated with localized mitochondrial defects in skeletal muscle of an animal model of amyotrophic lateral sclerosis. J Biol Chem. 2010;285:705–12.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  12. Neel BA, Lin Y, Pessin JE. Skeletal muscle autophagy: a new metabolic regulator. Trends Endocrinol Metab. 2013;24:635–43.

    Article  CAS  PubMed  Google Scholar 

  13. Gonzalez de Aguilar JL, Niederhauser-Wiederkehr C, Halter B, De Tapia M, Di Scala F, Demougin P, et al. Gene profiling of skeletal muscle in an amyotrophic lateral sclerosis mouse model. Physiol Genomics. 2008;32:207–18.

    Article  CAS  PubMed  Google Scholar 

  14. Xiao Y, Ma C, Yi J, Wu S, Luo G, Xu X, et al. Suppressed autophagy flux in skeletal muscle of an amyotrophic lateral sclerosis mouse model during disease progression. Physiol Rep. 2015;3.

  15. Nguyen QT, Son YJ, Sanes JR, Lichtman JW. Nerve terminals form but fail to mature when postsynaptic differentiation is blocked: in vivo analysis using mammalian nerve-muscle chimeras. J Neurosci. 2000;20:6077–86.

    CAS  PubMed  Google Scholar 

  16. Dobrowolny G, Giacinti C, Pelosi L, Nicoletti C, Winn N, Barberi L, et al. Muscle expression of a local Igf-1 isoform protects motor neurons in an ALS mouse model. J Cell Biol. 2005;168:193–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Wong M, Martin LJ. Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet. 2010;19:2284–302.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  18. Dobrowolny G, Aucello M, Rizzuto E, Beccafico S, Mammucari C, Boncompagni S, et al. Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab. 2008;8:425–36.

    Article  CAS  PubMed  Google Scholar 

  19. Raisz LG. Physiology and pathophysiology of bone remodeling. Clin Chem. 1999;45:1353–8.

    CAS  PubMed  Google Scholar 

  20. Bonewald LF, Kiel DP, Clemens TL, Esser K, Orwoll ES, O’Keefe RJ, et al. Forum on bone and skeletal muscle interactions: summary of the proceedings of an ASBMR workshop. J Bone Miner Res. 2013;28:1857–65.

    Article  PubMed Central  PubMed  Google Scholar 

  21. Edwards MH, Gregson CL, Patel HP, Jameson KA, Harvey NC, Sayer AA, et al. Muscle size, strength, and physical performance and their associations with bone structure in the Hertfordshire Cohort Study. J Bone Miner Res. 2013;28:2295–304.

    Article  PubMed Central  PubMed  Google Scholar 

  22. Hamrick M. JMNI special issue: basic science and mechanisms of muscle-bone interactions. J Musculoskelet Neuronal Interact. 2010;10:1–2.

    CAS  PubMed  Google Scholar 

  23. Kaji H. Interaction between muscle and bone. J Bone Metab. 2014;21:29–40.

    Article  PubMed Central  PubMed  Google Scholar 

  24. Lang TF. The bone-muscle relationship in men and women. J Osteoporos. 2011;2011:702735.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Lebrasseur NK, Achenbach SJ, Melton LJ, Lebrasseur NK, Achenbach SJ, Melton 3rd LJ, et al. Skeletal muscle mass is associated with bone geometry and microstructure and serum insulin-like growth factor binding protein-2 levels in adult women and men. J Bone Miner Res. 2012;27:2159–69. A recent study on potential muscle-bone interaction.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  26. Shackelford LC, LeBlanc AD, Driscoll TB, Evans HJ, Rianon NJ, Smith SM, et al. Resistance exercise as a countermeasure to disuse-induced bone loss. J Appl Physiol. 2014;97:119–29.

    Article  Google Scholar 

  27. Hamrick MW, McNeil PL, Patterson SL. Role of muscle-derived growth factors in bone formation. J Musculoskelet Neuronal Interact. 2010;10:64–70.

    PubMed Central  CAS  PubMed  Google Scholar 

  28. Blitz E, Viukov S, Sharir A, Shwartz Y, Galloway JL, Pryce BA, et al. Bone ridge patterning during musculoskeletal assembly is mediated through SCX regulation of Bmp4 at the tendon-skeleton junction. Dev Cell. 2009;17:861–73.

    Article  PubMed Central  PubMed  Google Scholar 

  29. Kahn J, Shwartz Y, Blitz E, Krief S, Sharir A, Breitel DA, et al. Muscle contraction is necessary to maintain joint progenitor cell fate. Dev Cell. 2009;16:734–43.

    Article  CAS  PubMed  Google Scholar 

  30. Sharir A, Stern T, Rot C, Shahar R, Zelzer E. Muscle force regulates bone shaping for optimal load-bearing capacity during embryogenesis. Development. 2011;138:3247–59. A recent study provides the evidence on the role of muscle contraction in regulating bone morphology.

    Article  CAS  PubMed  Google Scholar 

  31. Shwartz Y, Farkas Z, Stern T, Aszodi A, Zelzer E. Muscle contraction controls skeletal morphogenesis through regulation of chondrocyte convergent extension. Dev Biol. 2012;370:154–63.

    Article  CAS  PubMed  Google Scholar 

  32. Lee JY, Qu-Petersen Z, Cao B, Kimura S, Jankowski R, Cummins J, et al. Clonal isolation of muscle-derived cells capable of enhancing muscle regeneration and bone healing. J Cell Biol. 2000;150:1085–100.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  33. Li H, Johnson NR, Usas A, Lu A, Poddar M, Wang Y, et al. Sustained release of bone morphogenetic protein 2 via coacervate improves the osteogenic potential of muscle-derived stem cells. Stem Cells Transl Med. 2013;2:667–77. A recent study on possible muscle-bone interaction in osteogenesis.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  34. Oishi T, Uezumi A, Kanaji A, Yamamoto N, Yamaguchi A, Yamada H, et al. Osteogenic differentiation capacity of human skeletal muscle-derived progenitor cells. PLoS One. 2013;8:e56641. A recent study on the possible role of muscle-derived progenitor cells in osteogenesis.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  35. Sun JS, Wu SY, Lin FH. The role of muscle-derived stem cells in bone tissue engineering. Biomaterials. 2005;26:3953–60.

    Article  CAS  PubMed  Google Scholar 

  36. Bikle DD, Sakata T, Halloran BP. The impact of skeletal unloading on bone formation. Gravit Space Biol Bull. 2003;16:45–54.

    PubMed  Google Scholar 

  37. Robling AG, Niziolek PJ, Baldridge LA, Condon KW, Allen MR, Alam I, et al. Mechanical stimulation of bone in vivo reduces osteocyte expression of Sost/sclerostin. J Biol Chem. 2008;283:5866–75.

    Article  CAS  PubMed  Google Scholar 

  38. Khatri IA, Chaudhry US, Seikaly MG, Browne RH, Iannaccone ST. Low bone mineral density in spinal muscular atrophy. J Clin Neuromuscul Dis. 2008;10:11–7.

    Article  PubMed  Google Scholar 

  39. Larson CM, Henderson RC. Bone mineral density and fractures in boys with Duchenne muscular dystrophy. J Pediatr Orthop. 2000;20:71–4.

    CAS  PubMed  Google Scholar 

  40. Rufo A, Del Fattore A, Capulli M, Carvello F, De Pasquale L, Ferrari S, et al. Mechanisms inducing low bone density in Duchenne muscular dystrophy in mice and humans. J Bone Miner Res. 2011;26:1891–903. A recent study on the potential muscle-bone interaction in muscular dystrophic diseases.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Vestergaard P, Glerup H, Steffensen BF, Rejnmark L, Rahbek J, Moseklide L. Fracture risk in patients with muscular dystrophy and spinal muscular atrophy. J Rehabil Med. 2001;33:150–5.

    Article  CAS  PubMed  Google Scholar 

  42. Sato Y, Honda Y, Asoh T, Kikuyama M, Oizumi K. Hypovitaminosis D and decreased bone mineral density in amyotrophic lateral sclerosis. Eur Neurol. 1997;37:225–9.

    Article  CAS  PubMed  Google Scholar 

  43. Sato Y, Honda Y, Iwamoto J. Etidronate for fracture prevention in amyotrophic lateral sclerosis: a randomized controlled trial. Bone. 2006;39:1080–6.

    Article  CAS  PubMed  Google Scholar 

  44. Majka SM, Jackson KA, Kienstra KA, Majesky MW, Goodell MA, Hirschi KK. Distinct progenitor populations in skeletal muscle are bone marrow derived and exhibit different cell fates during vascular regeneration. J Clin Invest. 2003;111:71–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  45. Sassoli C, Pini A, Chellini F, Mazzanti B, Nistri S, Nosi D, et al. Bone marrow mesenchymal stromal cells stimulate skeletal myoblast proliferation through the paracrine release of VEGF. PLoS One. 2012;7:e37512. A recent study on the potential role of bone in myogenesis.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  46. Koh SH, Baik W, Noh MY, Cho GW, Kim HY, Kim KS, et al. The functional deficiency of bone marrow mesenchymal stromal cells in ALS patients is proportional to disease progression rate. Exp Neurol. 2012;233:472–80. A recent study on the deficiency of bone marrow mesenchymal stromal cells in ALS patients.

    Article  CAS  PubMed  Google Scholar 

  47. Cho GW, Noh MY, Kim HY, Koh SH, Kim KS, Kim SH. Bone marrow-derived stromal cells from amyotrophic lateral sclerosis patients have diminished stem cell capacity. Stem Cells Dev. 2010;19:1035–42.

    Article  CAS  PubMed  Google Scholar 

  48. Blanquer M, Moraleda JM, Iniesta F, Gomez-Espuch J, Meca-Lallana J, Villaverde R, et al. Neurotrophic bone marrow cellular nests prevent spinal motoneuron degeneration in amyotrophic lateral sclerosis patients: a pilot safety study. Stem Cells. 2012;30:1277–85.

    Article  CAS  PubMed  Google Scholar 

  49. Lin C, Jiang X, Dai Z, Guo X, Weng T, Wang J, et al. Sclerostin mediates bone response to mechanical unloading through antagonizing Wnt/beta-catenin signaling. J Bone Miner Res. 2009;24:1651–61.

    Article  CAS  PubMed  Google Scholar 

  50. Di Monaco M, Vallero F, Di Monaco R, Tappero R. Prevalence of sarcopenia and its association with osteoporosis in 313 older women following a hip fracture. Arch Gerontol Geriatr. 2011;52:71–4.

    Article  PubMed  Google Scholar 

  51. Galli C, Passeri G, Macaluso GM. Osteocytes and WNT: the mechanical control of bone formation. J Dent Res. 2010;89:331–43.

    Article  CAS  PubMed  Google Scholar 

  52. Tu X, Rhee Y, Condon KW, Bivi N, Allen MR, Dwyer D, et al. Sost downregulation and local Wnt signaling are required for the osteogenic response to mechanical loading. Bone. 2012;50:209–17.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  53. Zhao L, Shim JW, Dodge TR, Robling AG, Yokota H. Inactivation of Lrp5 in osteocytes reduces young’s modulus and responsiveness to the mechanical loading. Bone. 2013;54:35–43.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Bivi N, Pacheco-Costa R, Brun LR, Murphy TR, Farlow NR, Robling AG, et al. Absence of Cx43 selectively from osteocytes enhances responsiveness to mechanical force in mice. J Orthop Res. 2013;31:1075–81.

    Article  CAS  PubMed  Google Scholar 

  55. Javaheri B, Stern AR, Lara N, Dallas M, Zhao H, Liu Y, et al. Deletion of a single beta-catenin allele in osteocytes abolishes the bone anabolic response to loading. J Bone Miner Res. 2014;29:705–15. A recent molecular mechanism study on muscle-bone interaction.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  56. Zhu K, Yi J, Xiao Y, Lai Y, Song P, Zheng W, et al. Impaired bone homeostasis in amyotrophic lateral sclerosis mice with muscle atrophy. J Biol Chem. 2015. The first study to explore the muscle-bone crosstalk in ALS disease progression.

  57. Bonewald LF, Johnson ML. Osteocytes, mechanosensing and Wnt signaling. Bone. 2008;42:606–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Clevers H, Nusse R. Wnt/beta-catenin signaling and disease. Cell. 2012;149:1192–205.

    Article  CAS  PubMed  Google Scholar 

  59. Day TF, Guo X, Garrett-Beal L, Yang Y. Wnt/beta-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev Cell. 2005;8:739–50.

    Article  CAS  PubMed  Google Scholar 

  60. Li X, Zhang Y, Kang H, Liu W, Liu P, Zhang J, et al. Sclerostin binds to LRP5/6 and antagonizes canonical Wnt signaling. J Biol Chem. 2005;280:19883–7.

    Article  CAS  PubMed  Google Scholar 

  61. ten Dijke P, Krause C, de Gorter DJ, Lowik CW, van Bezooijen RL. Osteocyte-derived sclerostin inhibits bone formation: its role in bone morphogenetic protein and Wnt signaling. J Bone Joint Surg Am. 2008;90 Suppl 1:31–5.

    Article  PubMed  Google Scholar 

  62. Kawamura N, Kugimiya F, Oshima Y, Ohba S, Ikeda T, Saito T, et al. Akt1 in osteoblasts and osteoclasts controls bone remodeling. PLoS One. 2007;2:e1058.

    Article  PubMed Central  PubMed  Google Scholar 

  63. Ge C, Xiao G, Jiang D, Franceschi RT. Critical role of the extracellular signal-regulated kinase-MAPK pathway in osteoblast differentiation and skeletal development. J Cell Biol. 2007;176:709–18.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  64. Xiao G, Jiang D, Thomas P, Benson MD, Guan K, Karsenty G, et al. MAPK pathways activate and phosphorylate the osteoblast-specific transcription factor, Cbfa1. J Biol Chem. 2000;275:4453–9.

    Article  CAS  PubMed  Google Scholar 

  65. Kim HJ, Kim JH, Bae SC, Choi JY, Kim HJ, Ryoo HM. The protein kinase C pathway plays a central role in the fibroblast growth factor-stimulated expression and transactivation activity of Runx2. J Biol Chem. 2003;278:319–26.

    Article  CAS  PubMed  Google Scholar 

  66. Nakashima T, Hayashi M, Fukunaga T, Kurata K, Oh-Hora M, Feng JQ, et al. Evidence for osteocyte regulation of bone homeostasis through RANKL expression. Nat Med. 2011;17:1231–4.

    Article  CAS  PubMed  Google Scholar 

  67. Xiong J, Onal M, Jilka RL, Weinstein RS, Manolagas SC, O’Brien CA. Matrix-embedded cells control osteoclast formation. Nat Med. 2011;17:1235–41.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  68. Wijenayaka AR, Kogawa M, Lim HP, Bonewald LF, Findlay DM, Atkins GJ. Sclerostin stimulates osteocyte support of osteoclast activity by a RANKL-dependent pathway. PLoS One. 2011;6:e25900.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  69. Brotto M, Johnson ML. Endocrine crosstalk between muscle and bone. Curr Osteoporos Rep. 2014;12:135–41.

    Article  PubMed Central  PubMed  Google Scholar 

Download references

Compliance with Ethics Guidelines

Conflict of Interest

The authors of this paper declare they have no conflicts of interest.

Human and Animal Rights and Informed Consent

This article contains no studies with human or animal subjects performed by the author.

Author information

Authors and Affiliations

  1. Department of Physiology, Kansas City University of Medicine and Biosciences, 1750 Independence Ave., Kansas City, MO, 64106, USA

    Jingsong Zhou & Jianxun Yi

  2. Department of Oral and Craniofacial Sciences, University of Missouri at Kansas City School of Dentistry, 650 East 25th Street, Kansas City, MO, 64108, USA

    Jianxun Yi & Lynda Bonewald

Authors
  1. Jingsong Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Jianxun Yi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Lynda Bonewald
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Jingsong Zhou or Lynda Bonewald.

Additional information

This article is part of the Topical Collection on Muscle and Bone

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhou, J., Yi, J. & Bonewald, L. Muscle-Bone Crosstalk in Amyotrophic Lateral Sclerosis. Curr Osteoporos Rep 13, 274–279 (2015). https://doi.org/10.1007/s11914-015-0281-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11914-015-0281-0

Keywords

Search

Navigation