Skip to main content
SpringerLink
Log in

Amyotrophic Lateral Sclerosis and Skeletal Muscle: An Update

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Amyotrophic lateral sclerosis (ALS) is the most frequent adult-onset motor neuron disease characterized by degeneration of upper and lower motor neurons (MNs), generalized weakness and muscle atrophy. The “neurocentric” view of ALS assumes that the disease primarily affects motor neurons, while muscle alterations only represent a consequence, in the periphery, of motor neuron loss. However, this outlook was recently challenged by evidence suggesting that non-neural cells such as microglia, astrocytes, peripheral blood mononuclear cells (PBMCs) and skeletal muscle fibres participate in triggering motor neuron degeneration, and this stressed the concept that alterations in different cell types may act together to exacerbate the disease. In this review, we will summarize the most recent findings on the alterations of skeletal muscle fibres found in ALS, with particular attention to the relationship between mutant SOD1 and skeletal muscle. We will analyze changes in muscle function, in the expression of myogenic regulatory factors, and also mitochondrial dysfunction, SOD1 aggregation and proteasome activity.

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

Fig. 1

Similar content being viewed by others

References

  1. Pette D, Staron RS (1990) Cellular and molecular diversities of mammalian skeletal muscle fibers. Rev Physiol Biochem Pharmacol 116:1–76

    CAS  PubMed  Google Scholar 

  2. Bottinelli R, Betto R, Schiaffino S, Reggiani C (1994) Maximum shortening velocity and coexistence of myosin heavy chain isoforms in single skinned fast fibres of rat skeletal muscle. J Muscle Res Cell Motil 15:413–419

    Article  CAS  PubMed  Google Scholar 

  3. McCullagh KJ, Calabria E, Pallafacchina G, Ciciliot S, Serrano AL, Argentini C, Kalhovde JM, Lomo T, Schiaffino S (2004) NFAT is a nerve activity sensor in skeletal muscle and controls activity-dependent myosin switching. Proc Natl Acad Sci U S A 101:10590–10595

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  4. Jackman RW, Kandarian SC (2004) The molecular basis of skeletal muscle atrophy. Am J Physiol Cell Physiol 287:C834–C843

    Article  CAS  PubMed  Google Scholar 

  5. Boillée S, Velde CV, Cleveland DW (2006) ALS: a disease of motor neurons and their nonneuronal neighbors. Neuron 52:39–59

    Article  PubMed  Google Scholar 

  6. Bruijn L, Miller TM, Cleveland DW (2004) Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annu Rev Neurosci 27:723–749

    Article  CAS  PubMed  Google Scholar 

  7. Dobrowolny G, Aucello M, Rizzuto E et al (2008) Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab 8:425–436

    Article  CAS  PubMed  Google Scholar 

  8. Yamanaka K, Chun SJ, Boillée S, Fujimori-Tonou N, Yamashita H, Gutmann DH, Takahashi R, Misawa H, Cleveland DW (2008) Astrocytes as determinants of disease progression in inherited amyotrophic lateral sclerosis. Nat Neurosci 11:251–253

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  9. Clement AM, Nguyen MD, Roberts EA et al (2003) Wild-type nonneuronal cells extend survival of SOD1 mutant motor neurons in ALS mice. Science 302:113–117, Erratum in: Science. 2003; 302: 568

    Article  CAS  PubMed  Google Scholar 

  10. Beers DR, Henkel JS, Xiao Q, Zhao W, Wang J, Yen AA, Siklos L, McKercher SR, Appel SH (2006) Wild-type microglia extend survival in PU.1 knockout mice with familial amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 103:16021–16026

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  11. Di Giorgio FP, Carrasco MA, Siao MC, Maniatis T, Eggan K (2007) Non-cell autonomous effect of glia on motor neurons in an embryonic stem cell-based ALS model. Nat Neurosci 10:608–614

    Article  PubMed Central  PubMed  Google Scholar 

  12. Nagai M, Re DB, Nagata T, Chalazonitis A, Jessell TM, Wichterle H, Przedborski S (2007) Astrocytes expressing ALS-linked mutated SOD1 release factors selectively toxic to motor neurons. Nat Neurosci 10:615–622

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Van Damme P, Bogaert E, Dewil M et al (2007) Astrocytes regulate GluR2 expression in motor neurons and their vulnerability to excitotoxicity. Proc Natl Acad Sci U S A 104:14825–14830

    Article  PubMed Central  PubMed  Google Scholar 

  14. Cassina P, Cassina A, Pehar M et al (2008) Mitochondrial dysfunction in SOD1G93A-bearing astrocytes promotes motor neuron degeneration: prevention by mitochondrial-targeted antioxidants. J Neurosci 28:4115–4122

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  15. Rossi D, Brambilla L, Valori CF, Roncoroni C, Crugnola A, Yokota T, Bredesen DE, Volterra A (2008) Focal degeneration of astrocytes in amyotrophic lateral sclerosis. Cell Death Differ 15:1691–1700

    Article  CAS  PubMed  Google Scholar 

  16. Di Giorgio FP, Boulting GL, Bobrowicz S, Eggan KC (2008) Human embryonic stem cell-derived motor neurons are sensitive to the toxic effect of glial cells carrying an ALS-causing mutation. Cell Stem Cell 3:637–648

    Article  PubMed  Google Scholar 

  17. Marchetto MC, Muotri AR, Mu Y, Smith AM, Cezar GG, Gage FH (2008) Non-cell-autonomous effect of human SOD1 G37R astrocytes on motor neurons derived from human embryonic stem cells. Cell Stem Cell 3:649–657

    Article  CAS  PubMed  Google Scholar 

  18. Díaz-Amarilla P, Olivera-Bravo S, Trias E, Cragnolini A, Martínez-Palma L, Cassina P, Beckman J, Barbeito L (2011) Phenotypically aberrant astrocytes that promote motoneuron damage in a model of inherited amyotrophic lateral sclerosis. Proc Natl Acad Sci U S A 108:18126–18131

    Article  PubMed Central  PubMed  Google Scholar 

  19. Haidet-Phillips AM, Hester ME, Miranda CJ et al (2011) Astrocytes from familial and sporadic ALS patients are toxic to motor neurons. Nat Biotechnol 29:824–828

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Papadeas ST, Kraig SE, O'Banion C, Lepore AC, Maragakis NJ (2011) Astrocytes carrying the superoxide dismutase 1 (SOD1G93A) mutation induce wild-type motor neuron degeneration in vivo. Proc Natl Acad Sci U S A 108:17803–17808

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  21. Wang L, Gutmann DH, Roos RP (2011) Astrocyte loss of mutant SOD1 delays ALS disease onset and progression in G85R transgenic mice. Hum Mol Genet 20:286–293

    Article  CAS  PubMed  Google Scholar 

  22. Martorana F, Brambilla L, Valori CF, Bergamaschi C, Roncoroni C, Aronica E, Volterra A, Bezzi P, Rossi D (2012) The BH4 domain of Bcl-X(L) rescues astrocyte degeneration in amyotrophic lateral sclerosis by modulating intracellular calcium signals. Hum Mol Genet 21:826–840

    Article  CAS  PubMed  Google Scholar 

  23. Cova E, Cereda C, Galli A, Curti D, Finotti C, Di Poto C, Corato M, Mazzini G, Ceroni M (2006) Modified expression of Bcl-2 and SOD1 proteins in lymphocytes from sporadic ALS patients. Neurosci Lett 399:186–190

    Article  CAS  PubMed  Google Scholar 

  24. Barber SC, Shaw PJ (2010) Oxidative stress in ALS: key role in motor neuron injury and therapeutic target. Free Rad Biol Med 48:629–641

    Article  CAS  PubMed  Google Scholar 

  25. Barber SC, Mead RJ, Shaw PJ (2006) Oxidative stress in ALS: a mechanism of neurodegeneration and a therapeutic target. Biochim Biophys Acta 1762:1051–1067

    Article  CAS  PubMed  Google Scholar 

  26. Ticozzi N, Tiloca C, Morelli C, Colombrita C, Poletti B, Doretti A, Maderna L, Messina S, Ratti A, Silani V (2011) Genetics of familial amyotrophic lateral sclerosis. Arch Ital Biol 149:65–82

    PubMed  Google Scholar 

  27. Kwiatkowski TJ Jr, Bosco DA, Leclerc AL et al (2009) Mutations in the FUS/TLS gene on chromosome 16 cause familial amyotrophic lateral sclerosis. Science 323:1205–1208

    Article  CAS  PubMed  Google Scholar 

  28. Strong MJ, Volkening K, Hammond R, Yang W, Strong W, Leystra-Lantz C, Shoesmith C (2007) TDP43 is a human low molecular weight neurofilament (hNFL) mRNA-binding protein. Mol Cell Neurosci 35:320–327

    Article  CAS  PubMed  Google Scholar 

  29. Deng HX, Chen W, Hong ST et al (2011) Mutations in UBQLN2 cause dominant X-linked juvenile and adult-onset ASL and ALS/dementia. Nature 477:211–215

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Renton AE, Majounie E, Waite A et al (2011) A hexanucleotide repeat expansion in the C9ORF72 is the cause of the chromosome 9p21-linked ALS-FTD. Neuron 72:257–268

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. DeJesus-Hernandez M, Mackenzie IR, Boeve BF et al (2011) Expanded GGGGCC hexanucleotide repeat in noncoding region of C9ORF72 causes chromosome 9p-linked FTD and ALS. Neuron 72:245–256

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  32. Wong M, Martin LJ (2010) Skeletal muscle-restricted expression of human SOD1 causes motor neuron degeneration in transgenic mice. Hum Mol Genet 19:2284–2302

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Da Cruz S, Parone PA, Lopes VS et al (2012) Elevated PGC-1α activity sustains mitochondrial biogenesis and muscle function without extending survival in a mouse model of inherited ALS. Cell Metab 15:778–786

    Article  PubMed Central  PubMed  Google Scholar 

  34. Krivickas LS, Yang JI, Kim SK, Frontera WR (2002) Skeletal muscle fibre function and rate of disease progression in amyotrophic lateral sclerosis. Muscle Nerve 26:636–643

    Article  PubMed  Google Scholar 

  35. Hegedus J, Putman CT, Tyreman N, Gordon T (2008) Preferential motor unit loss in the SOD1G93A transgenic mouse model of amyotrophic lateral sclerosis. J Physiol 586(14):3337–3351

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Hegedus J, Putman CT, Gordon T (2007) Time course of preferential motor unit loss in the SOD1G93A mouse model of amyotrophic lateral sclerosis. Neurobiol Dis 28:154–164

    Article  CAS  PubMed  Google Scholar 

  37. Frey D, Schneider C, Xu L, Borg J, Spooren W, Caroni P (2000) Early and selective loss of neuromuscular synapse subtypes with low sprouting competence in motoneuron diseases. J Neurosci 20:2534–2542

    CAS  PubMed  Google Scholar 

  38. Schaefer AM, Sanes JR, Lichtman JW (2005) A compensatory subpopulation of motor neurons in a mouse model of amyotrophic lateral sclerosis. J Comp Neurol 490:209–219

    Article  PubMed  Google Scholar 

  39. Derave W, Van Den Bosch L, Lemmens G, Eijnde BO, Robberecht W, Hespel P (2003) Skeletal muscle properties in a transgenic mouse model for amyotrophic lateral sclerosis: effects of creatine treatment. Neurobiol Dis 13:264–272

    Article  CAS  PubMed  Google Scholar 

  40. Atkin JD, Scott RL, West JM, Lopes E, Quah AK, Cheema SS (2005) Properties of slow- and fast-twitch muscle fibres in a mouse model of amyotrophic lateral sclerosis. Neuromuscul Disord 15:377–388

    Article  PubMed  Google Scholar 

  41. Tedesco FS, Dellavalle A, Diaz-Manera J, Messina G, Cossu G (2010) Repairing skeletal muscle: regenerative potential of skeletal muscle stem cells. J Clin Invest 120:11–19

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Le Grand F, Rudnicki M (2007) Satellite and stem cells in muscle growth and repair. Development 134:3953–3957

    Article  PubMed  Google Scholar 

  43. Buckingham M (2007) Skeletal muscle progenitor cells and the role of Pax genes. C R Biol 330:530–533

    Article  CAS  PubMed  Google Scholar 

  44. Asakura A, Komaki M, Rudnicki M (2001) Muscle satellite cells are multipotential stem cells that exhibit myogenic, osteogenic, and adipogenic differentiation. Differentiation 68:245–253

    Article  CAS  PubMed  Google Scholar 

  45. Seale P, Rudnicki MA (2000) A new look at the origin, function, and ‘stem-cell’ status of muscle satellite cells. Dev Biol 218:115–124

    Article  CAS  PubMed  Google Scholar 

  46. Rudnicki MA, Le Grand F, McKinnel I, Kuang S (2008) The molecular regulation of muscle stem cell function. Cold Spring Harb Symp Quant Biol 73:323–331

    Article  CAS  PubMed  Google Scholar 

  47. Manzano R, Toivonen JM, Olivan S, Calvo AC, Moreno-Igoa M, Muñoz MJ, Zaragoza P, García-Redondo A, Osta R (2011) Altered expression of myogenic regulatory factors in the mouse model of amyotrophic lateral sclerosis. Neurodegener Dis 8:386–396

    Article  CAS  PubMed  Google Scholar 

  48. Manzano R, Toivonen JM, Calvo AC, Oliván S, Zaragoza P, Muñoz MJ, Montarras D, Osta R (2012) Quantity and activation of myofiber-associated satellite cells in a mouse model of amyotrophic lateral sclerosis. Stem Cell Rev 8:279–287

    Article  PubMed  Google Scholar 

  49. Manzano R, Toivonen JM, Calvo AC, Oliván S, Zaragoza P, Rodellar C, Montarras D, Osta R (2013) Altered in vitro proliferation of mouse SOD1-G93A skeletal muscle satellite cells. Neurodegener Dis 11:153–164

    Article  CAS  PubMed  Google Scholar 

  50. Dupuis L, Muller A, Meininger V, Loeffler JP (2004) Molecular mechanisms of amyotrophic lateral sclerosis: recent contributions from studies in animal models (in French). Rev Neurol (Paris) 160:35–43

    Article  CAS  Google Scholar 

  51. Cleveland DW, Rothstein JD (2001) From Charcot to Lou Gehrig: deciphering selective motor neuron death in ALS. Nat Rev Neurosci 2:806–819

    Article  CAS  PubMed  Google Scholar 

  52. Afifi AK, Aleu FP, Goodgold J, MacKay B (1966) Ultrastructure of atrophic muscle in amyotrophic lateral sclerosis. Neurology 16:475–481

    Article  CAS  PubMed  Google Scholar 

  53. Sasaki S, Iwata M (1996) Ultrastructural study of synapses in the anterior horn neurons of patients with amyotrophic lateral sclerosis. Neurosci Lett 204:53–56

    Article  CAS  PubMed  Google Scholar 

  54. Chung MJ, Suh YL (2002) Ultrastructural changes of mitochondria in the skeletal muscle of patients with amyotrophic lateral sclerosis. Ultrastruct Pathol 26:3–7

    Article  PubMed  Google Scholar 

  55. Vielhaber S, Kunz D, Winkler K, Wiedemann FR, Kirches E, Feistner H, Heinze HJ, Elger CE, Schubert W, Kunz WS (2000) Mitochondrial DNA abnormalities in skeletal muscle of patients with sporadic amyotrophic lateral sclerosis. Brain 23:1339–1348

    Article  Google Scholar 

  56. Dupuis L, di Scala F, Rene F, de Tapia M, Oudart H, Pradat PF, Meininger V, Loeffler JP (2003) Up-regulation of mitochondrial uncoupling protein 3 reveals an early muscular metabolic defect in amyotrophic lateral sclerosis. FASAB J 17:2091–2093

    CAS  Google Scholar 

  57. Desport JC, Preux PM, Magy L, Boirie Y, Vallat JM, Beaufrère B, Couratier P (2001) Factors correlated with hypermetabolism in patients with amyotrophic lateral sclerosis. Am J Clin Nutr 74:328–334

    CAS  PubMed  Google Scholar 

  58. Beal MF (2000) Mitochondria and the pathogenesis of ALS. Brain 123:1291–1292

    Article  PubMed  Google Scholar 

  59. Vielhaber S, Kudin A, Winkler K, Wiedemann F, Schröder R, Feistner H, Heinze HJ, Elger CE, Kunz WS (2003) Is there mitochondrial dysfunction in ALS muscle? Ann Neurol 53:686–687

    Article  PubMed  Google Scholar 

  60. Echaniz-Laguna A, Zoll J, Ribera F, Tranchant C, Warter JM, Lonsdorfer J, Lampert E (2002) Mitochondrial respiratory chain function in skeletal muscle of ALS patients. Ann Neurol 52:623–627

    Article  CAS  PubMed  Google Scholar 

  61. Turner BJ, Lopes EC, Cheema SS (2003) Neuromuscular accumulation of mutant superoxide dismutase 1 aggregates in a transgenic mouse of familial amyotrophic lateral sclerosis. Neurosci Lett 350:132–136

    Google Scholar 

  62. Wei R, Bhattacharya A, Chintalaramulu N, Jernigan AL, Liu Y, Van Remmen H, Chaudhuri AR (2012) Protein misfolding, mitochondrial dysfunction and muscle loss are not directly dependent on soluble and aggregation state of mSOD1 protein in skeletal muscle of ALS. Biochem Biophys Res Commun 417:1275–1279

    Article  CAS  PubMed  Google Scholar 

  63. Onesto E, Rusmini P, Crippa V, Ferri N, Zito A, Galbiati M, Poletti A (2011) Muscle cells and motoneurons differentially remove mutant SOD1 causing familial amyotrophic lateral sclerosis. J Neurochem 118:266–280

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  64. Sau D, De Biasi S, Vitellaro-Zuccarello L et al (2007) Mutation of SOD1 in ALS: a gain of a loss of function. Hum Mole Genet 16:1604–1618

    Article  CAS  Google Scholar 

  65. Cashman NR, Durham HD, Blusztajn JK, Cashman NR, Durham HD, Blusztajn JK, Oda K, Tabira T, Shaw IT, Dahrouge S, Antel JP (1992) Neuroblastoma × spinal cord (NSC) hybrid cell lines resemble developing motor neurons. Dev Dyn 194:209–221

    Article  CAS  PubMed  Google Scholar 

  66. Sorarú G, Orsetti V, Buratti E, Baralle F, Cima V, Volpe M, D'Ascenzo C, Palmieri A, Koutsikos K, Pegoraro E, Angelini C (2010) TDP-43 in skeletal muscle of patients affected with amyotrophic lateral sclerosis. Amyotroph Lateral Scler 11:240–243

    Article  PubMed  Google Scholar 

  67. Hernandez Lain A, Millecamps S, Dubourg O et al (2011) Abnormal TDP-43 and FUS proteins in muscles of sporadic IBM: similarities in a TARDBP-linked ALS patient. J Neurol Neurosurg Psychiatry 82:1414–1416

    Article  PubMed  Google Scholar 

Download references

Conflict of Interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Laboratory of Experimental Neurobiology, National Neurological Institute C. Mondino, via Mondino 2, 27100, Pavia, Italy

    O. Pansarasa & C. Cereda

  2. Laboratory for Research on Neurodegenerative Disorders, IRCCS Salvatore Maugeri Foundation, via S. Maugeri 10/10A, 27100, Pavia, Italy

    D. Rossi

  3. Child Neurology and Psychiatry Unit, National Neurological Institute C. Mondino, via Mondino 2, 27100, Pavia, Italy

    A. Berardinelli

Authors
  1. O. Pansarasa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D. Rossi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. A. Berardinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C. Cereda
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to O. Pansarasa.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pansarasa, O., Rossi, D., Berardinelli, A. et al. Amyotrophic Lateral Sclerosis and Skeletal Muscle: An Update. Mol Neurobiol 49, 984–990 (2014). https://doi.org/10.1007/s12035-013-8578-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-013-8578-4

Keywords

Search

Navigation