Skip to main content

Advertisement

SpringerLink
Log in

A neuromuscular perspective of sarcopenia pathogenesis: deciphering the signaling pathways involved

  • Original Article
  • Published:
GeroScience Aims and scope Submit manuscript

Abstract

The escalation of life expectancy is accompanied by an increase in the prevalence of age-related conditions, such as sarcopenia. Sarcopenia, a muscle condition defined by low muscle strength, muscle quality or quantity, and physical performance, has a high prevalence among the elderly and is associated to increased mortality. The neuromuscular system has been emerging as a key contributor to sarcopenia pathogenesis. Indeed, the age-related degeneration of the neuromuscular junction (NMJ) function and structure may contribute to the loss of muscle strength and ultimately to the loss of muscle mass that characterize sarcopenia. The present mini-review discusses important signaling pathways involved in the function and maintenance of the NMJ, giving emphasis to the ones that might contribute to sarcopenia pathogenesis. Some conceivable biomarkers, such as C-terminal agrin fragment (CAF) and brain-derived neurotrophic factor (BDNF), and therapeutic targets, namely acetylcholine and calcitonin gene–related peptide (CGRP), can be retrieved, making way to future studies to validate their clinical use.

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. World Health Organization. Decade of healthy ageing: baseline report. Summary. Geneva: World Health Organization; 2021.

    Google Scholar 

  2. Cruz-Jentoft AJ, Bahat G, Bauer J, Boirie Y, Bruyère O, Cederholm T, et al. Sarcopenia: revised european consensus on definition and diagnosis. Age Ageing. 2019;48:16–31. https://doi.org/10.1093/ageing/afy169.

    Article  PubMed  Google Scholar 

  3. Rossi AP, Rubele S, D’Introno A, Zoico E, Brandimarte P, Amadio G, et al. An update on methods for sarcopenia diagnosis: from bench to bedside. Ital J Med. 2018;12:97–107. https://doi.org/10.4081/itjm.2018.995.

    Article  Google Scholar 

  4. Cruz-Jentoft AJ, Baeyens JP, Bauer JM, Boirie Y, Cederholm T, Landi F, et al. Sarcopenia: european consensus on definition and diagnosis. Age Ageing. 2010;39:412–23. https://doi.org/10.1093/ageing/afq034.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Yazar T, Olgun YH. Prevalance of sarcopenia according to decade. Clin Nutr ESPEN. 2019;29:137–41. https://doi.org/10.1016/j.clnesp.2018.11.005.

    Article  PubMed  Google Scholar 

  6. Beaudart C, Zaaria M, Pasleau F, Reginster J-Y, Bruyère O. Health outcomes of sarcopenia: a systematic review and meta-analysis. PLoS ONE. 2017;12:e0169548. https://doi.org/10.1371/journal.pone.0169548.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Wiedmer P, Jung T, Castro JP, Pomatto LCD, Sun PY, Davies KJA, et al. Sarcopenia – molecular mechanisms and open questions. Ageing Res Rev. 2021;65:101200. https://doi.org/10.1016/j.arr.2020.101200.

    Article  CAS  PubMed  Google Scholar 

  8. Ibebunjo C, Chick JM, Kendall T, Eash JK, Li C, Zhang Y, et al. Genomic and proteomic profiling reveals reduced mitochondrial function and disruption of the neuromuscular junction driving rat sarcopenia. Mol Cell Biol. 2013;33:194–212. https://doi.org/10.1128/mcb.01036-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Deschenes MR, Gaertner JR, O’Reilly S. The effects of sarcopenia on muscles with different recruitment patterns and myofiber profiles. Curr Aging Sci. 2013;6:266–72. https://doi.org/10.2174/18746098113066660035.

    Article  PubMed  Google Scholar 

  10. Rygiel KA, Picard M, Turnbull DM. The ageing neuromuscular system and sarcopenia: a mitochondrial perspective. J Physiol. 2016;594:4499–512. https://doi.org/10.1113/JP271212.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hepple RT, Rice CL. Innervation and neuromuscular control in ageing skeletal muscle. J Physiol. 2016;594:1965–78. https://doi.org/10.1113/JP270561.

    Article  CAS  PubMed  Google Scholar 

  12. Delmonico MJ, Harris TB, Visser M, Park SW, Conroy MB, Velasquez-Mieyer P, et al. Longitudinal study of muscle strength, quality, and adipose tissue infiltration. Am J Clin Nutr. 2009;90:1579–85. https://doi.org/10.3945/ajcn.2009.28047.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Mitchell WK, Williams J, Atherton P, Larvin M, Lund J, Narici M. Sarcopenia, dynapenia, and the impact of advancing age on human skeletal muscle size and strength; a quantitative review. Front Physiol. 2012;3:260. https://doi.org/10.3389/fphys.2012.00260.

    Article  PubMed  PubMed Central  Google Scholar 

  14. Santilli V, Bernetti A, Mangone M, Paoloni M. Clinical definition of sarcopenia. Clin Cases Miner Bone Metab. 2014;11:177–80.

    PubMed  PubMed Central  Google Scholar 

  15. Hayot M, Michaud A, Koechlin C, Caron M-A, LeBlanc P, Préfaut C, et al. Skeletal muscle microbiopsy: a validation study of a minimally invasive technique. Eur Respir J. 2005;25:431–40. https://doi.org/10.1183/09031936.05.00053404.

    Article  CAS  PubMed  Google Scholar 

  16. Baguet A, Everaert I, Hespel P, Petrovic M, Achten E, Derave W. A new method for non-invasive estimation of human muscle fiber type composition. PLoS ONE. 2011;6:e21956. https://doi.org/10.1371/journal.pone.0021956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Rodríguez Cruz PM, Cossins J, Beeson D, Vincent A. The neuromuscular junction in health and disease: molecular mechanisms governing synaptic formation and homeostasis. Front Mol Neurosci. 2020;13:610964. https://doi.org/10.3389/fnmol.2020.610964.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Ham DJ, Rüegg MA. Causes and consequences of age-related changes at the neuromuscular junction. Curr Opin Physiol. 2018;4:32–9. https://doi.org/10.1016/j.cophys.2018.04.007.

    Article  Google Scholar 

  19. Mukund K, Subramaniam S. Skeletal muscle: a review of molecular structure and function, in health and disease. Wiley Interdiscip Rev Syst Biol Med. 2020;12:e1462. https://doi.org/10.1002/wsbm.1462.

    Article  PubMed  Google Scholar 

  20. Lepore E, Casola I, Dobrowolny G, Musarò A. Neuromuscular junction as an entity of nerve-muscle communication. Cells. 2019;8:906. https://doi.org/10.3390/cells8080906.

    Article  CAS  PubMed Central  Google Scholar 

  21. Rudolf R, Khan MM, Labeit S, Deschenes MR. Degeneration of neuromuscular junction in age and dystrophy. Front Aging Neurosci. 2014;6:00099. https://doi.org/10.3389/fnagi.2014.00099.

    Article  Google Scholar 

  22. Punga AR, Ruegg MA. Signaling and aging at the neuromuscular synapse: lessons learnt from neuromuscular diseases. Curr Opin Pharmacol. 2012;12:340–6. https://doi.org/10.1016/j.coph.2012.02.002.

    Article  CAS  PubMed  Google Scholar 

  23. Ham DJ, Börsch A, Lin S, Thürkauf M, Weihrauch M, Reinhard JR, et al. The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia. Nat Commun. 2020;11:4510. https://doi.org/10.1038/s41467-020-18140-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Valdez G, Tapia JC, Kang H, Clemenson GD, Gage FH, Lichtman JW, et al. Attenuation of age-related changes in mouse neuromuscular synapses by caloric restriction and exercise. Proc Natl Acad Sci U S A. 2010;107:14863–8. https://doi.org/10.1073/pnas.1002220107.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jones RA, Harrison C, Eaton SL, Llavero Hurtado M, Graham LC, Alkhammash L, et al. Cellular and molecular anatomy of the human neuromuscular junction. Cell Rep. 2017;21:2348–56. https://doi.org/10.1016/j.celrep.2017.11.008.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wokke JHJ, Jennekens FGI, van den Oord CJM, Veldman H, Smit LME, Leppink GJ. Morphological changes in the human end plate with age. J Neurol Sci. 1990;95:291–310. https://doi.org/10.1016/0022-510X(90)90076-Y.

    Article  CAS  PubMed  Google Scholar 

  27. Oda K. Age changes of motor innervation and acetylcholine receptor distribution on human skeletal muscle fibres. J Neurol Sci. 1984;66:327–38. https://doi.org/10.1016/0022-510X(84)90021-2.

    Article  CAS  PubMed  Google Scholar 

  28. da Orssatto LBR, Wiest MJ, Diefenthaeler F. Neural and musculotendinous mechanisms underpinning age-related force reductions. Mech Ageing Dev. 2018;175:17–23. https://doi.org/10.1016/j.mad.2018.06.005.

    Article  PubMed  Google Scholar 

  29. Roberts BM, Lavin KM, Many GM, Thalacker-Mercer A, Merritt EK, Bickel CS, et al. Human neuromuscular aging: sex differences revealed at the myocellular level. Exp Gerontol. 2018;106:116–24. https://doi.org/10.1016/j.exger.2018.02.023.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. St-Jean-Pelletier F, Pion CH, Leduc-Gaudet JP, Sgarioto N, Zovilé I, Barbat-Artigas S, et al. The impact of ageing, physical activity, and pre-frailty on skeletal muscle phenotype, mitochondrial content, and intramyocellular lipids in men. J Cachexia Sarcopenia Muscle. 2017;8:213–28. https://doi.org/10.1002/jcsm.12139.

    Article  PubMed  Google Scholar 

  31. Kwon YN, Yoon SS. Sarcopenia: neurological point of view. J Bone Metab. 2017;24:83–9. https://doi.org/10.11005/jbm.2017.24.2.83.

    Article  PubMed  PubMed Central  Google Scholar 

  32. Joanisse S, Nederveen JP, Snijders T, McKay BR, Parise G. Skeletal muscle regeneration, repair and remodelling in aging: the importance of muscle stem cells and vascularization. Gerontology. 2016;63:91–100. https://doi.org/10.1159/000450922.

    Article  PubMed  Google Scholar 

  33. Li M, Larsson L. Force-generating capacity of human myosin isoforms extracted from single muscle fibre segments. J Physiol. 2010;588:5105–14. https://doi.org/10.1113/jphysiol.2010.199067.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Verdijk LB, Snijders T, Beelen M, Savelberg HHCM, Meijer K, Kuipers H, et al. Characteristics of muscle fiber type are predictive of skeletal muscle mass and strength in elderly men. J Am Geriatr Soc. 2010;58:2069–75. https://doi.org/10.1111/j.1532-5415.2010.03150.x.

    Article  PubMed  Google Scholar 

  35. Covault J, Sanes JR. Neural cell adhesion molecule (N-CAM) accumulates in denervated and paralyzed skeletal muscles. Proc Natl Acad Sci U S A. 1985;82:4544–8. https://doi.org/10.1073/pnas.82.13.4544.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hendrickse P, Galinska M, Hodson-Tole E, Degens H. An evaluation of common markers of muscle denervation in denervated young-adult and old rat gastrocnemius muscle. Exp Gerontol. 2018;106:159–64. https://doi.org/10.1016/j.exger.2018.03.007.

    Article  CAS  PubMed  Google Scholar 

  37. Gillon A, Sheard P. Elderly mouse skeletal muscle fibres have a diminished capacity to upregulate NCAM production in response to denervation. Biogerontology. 2015;16:811–23. https://doi.org/10.1007/s10522-015-9608-6.

    Article  CAS  PubMed  Google Scholar 

  38. Soendenbroe C, Heisterberg MF, Schjerling P, Karlsen A, Kjaer M, Andersen JL, et al. Molecular indicators of denervation in aging human skeletal muscle. Muscle Nerve. 2019;60:453–63. https://doi.org/10.1002/mus.26638.

    Article  CAS  PubMed  Google Scholar 

  39. Edström E, Ulfhake B. Sarcopenia is not due to lack of regenerative drive in senescent skeletal muscle. Aging Cell. 2005;4:65–77. https://doi.org/10.1111/j.1474-9728.2005.00145.x.

    Article  CAS  PubMed  Google Scholar 

  40. Chen J, Mizushige T, Nishimune H. Active zone density is conserved during synaptic growth but impaired in aged mice. J Comp Neurol. 2012;520:434–52. https://doi.org/10.1002/cne.22764.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Hurtado E, Cilleros V, Nadal L, Simó A, Obis T, Garcia N, et al. Muscle contraction regulates BDNF/TrkB signaling to modulate synaptic function through presynaptic cPKCα and cPKCβi. Front Mol Neurosci. 2017;10:147. https://doi.org/10.3389/fnmol.2017.00147.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Nishimune H, Numata T, Chen J, Aoki Y, Wang Y, Starr MP, et al. Active zone protein Bassoon co-localizes with presynaptic calcium channel, modifies channel function, and recovers from aging related loss by exercise. PLoS ONE. 2012;7:e38029. https://doi.org/10.1371/journal.pone.0038029.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Ross JA, Webster RG, Lechertier T, Reynolds LE, Turmaine M, Bencze M, et al. Multiple roles of integrin-α3 at the neuromuscular junction. J Cell Sci. 2017;130:1772–84. https://doi.org/10.1242/jcs.201103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Chen J, Billings SE, Nishimune H. Calcium channels link the muscle-derived synapse organizer laminin β2 to Bassoon and CAST/Erc2 to organize presynaptic active zones. J Neurosci. 2011;31:512–25. https://doi.org/10.1523/JNEUROSCI.3771-10.2011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Waites CL, Leal-Ortiz SA, Okerlund N, Dalke H, Fejtova A, Altrock WD, et al. Bassoon and Piccolo maintain synapse integrity by regulating protein ubiquitination and degradation. EMBO J. 2013;32:954–69. https://doi.org/10.1038/emboj.2013.27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Ivanova D, Dirks A, Fejtova A. Bassoon and piccolo regulate ubiquitination and link presynaptic molecular dynamics with activity-regulated gene expression. J Physiol. 2016;594:5441–8. https://doi.org/10.1113/JP271826.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Shi L, Fu AKY, Ip NY. Molecular mechanisms underlying maturation and maintenance of the vertebrate neuromuscular junction. Trends Neurosci. 2012;35:441–53. https://doi.org/10.1016/j.tins.2012.04.005.

    Article  CAS  PubMed  Google Scholar 

  48. Nishimune H, Badawi Y, Mori S, Shigemoto K. Dual-color STED microscopy reveals a sandwich structure of Bassoon and Piccolo in active zones of adult and aged mice. Sci Rep. 2016;6:27. https://doi.org/10.1038/srep27935.

    Article  CAS  Google Scholar 

  49. Casati M, Costa AS, Capitanio D, Ponzoni L, Ferri E, Agostini S, et al. The biological foundations of sarcopenia: established and promising markers. Front Med. 2019;6:184. https://doi.org/10.3389/fmed.2019.00184.

    Article  Google Scholar 

  50. Antonucci F, Corradini I, Fossati G, Tomasoni R, Menna E, Matteoli M. SNAP-25, a known presynaptic protein with emerging postsynaptic functions. Front Synaptic Neurosci. 2016;8:7. https://doi.org/10.3389/fnsyn.2016.00007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Simó A, Cilleros-Mañé V, Just-Borràs L, Hurtado E, Nadal L, Tomàs M, et al. nPKCε mediates SNAP-25 phosphorylation of Ser-187 in basal conditions and after synaptic activity at the neuromuscular junction. Mol Neurobiol. 2019;56:5346–64. https://doi.org/10.1007/s12035-018-1462-5.

    Article  CAS  PubMed  Google Scholar 

  52. Islamov RR, Samigullin DV, Rizvanov AA, Bondarenko NI, Nikolskiy EE. Synaptosome-associated protein 25 (SNAP25) synthesis in terminal buttons of mouse motor neuron. Dokl Biochem Biophys. 2015;464:272–4. https://doi.org/10.1134/S1607672915050026.

    Article  CAS  PubMed  Google Scholar 

  53. Giniatullin AR, Darios F, Shakirzyanova A, Davletov B, Giniatullin R. SNAP25 is a pre-synaptic target for the depressant action of reactive oxygen species on transmitter release. J Neurochem. 2006;98:1789–97. https://doi.org/10.1111/j.1471-4159.2006.03997.x.

    Article  CAS  PubMed  Google Scholar 

  54. Kaneai N, Arai M, Takatsu H, Fukui K, Urano S. Vitamin E inhibits oxidative stress-induced denaturation of nerve terminal proteins involved in neurotransmission. J Alzheimer’s Dis. 2012;28:183–9. https://doi.org/10.3233/JAD-2011-111133.

    Article  CAS  Google Scholar 

  55. Liguori I, Russo G, Curcio F, Bulli G, Aran L, Della-Morte D, et al. Oxidative stress, aging, and diseases. Clin Interv Aging. 2018;13:757–72. https://doi.org/10.2147/CIA.S158513.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Baumann CW, Kwak D, Liu HM, Thompson LV. Age-induced oxidative stress: how does it influence skeletal muscle quantity and quality? J Appl Physiol. 2016;121:1047–52. https://doi.org/10.1152/japplphysiol.00321.2016.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Kalinkovich A, Livshits G. Sarcopenia - the search for emerging biomarkers. Ageing Res Rev. 2015;22:58–71. https://doi.org/10.1016/j.arr.2015.05.001.

    Article  CAS  PubMed  Google Scholar 

  58. Uchitomi R, Hatazawa Y, Senoo N, Yoshioka K, Fujita M, Shimizu T, et al. Metabolomic analysis of skeletal muscle in aged mice. Sci Rep. 2019;9:10425. https://doi.org/10.1038/s41598-019-46929-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sugita S, Fleming LL, Wood C, Vaughan SK, Gomes MPSM, Camargo W, et al. VAChT overexpression increases acetylcholine at the synaptic cleft and accelerates aging of neuromuscular junctions. Skelet Muscle. 2016;6:31. https://doi.org/10.1186/s13395-016-0105-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Vaughan SK, Sutherland NM, Valdez G. Attenuating cholinergic transmission increases the number of satellite cells and preserves muscle mass in old age. Front Aging Neurosci. 2019;11:262. https://doi.org/10.3389/fnagi.2019.00262.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Cetin H, Beeson D, Vincent A, Webster R. The structure, function, and physiology of the fetal and adult acetylcholine receptor in muscle. Front Mol Neurosci. 2020;13:581097. https://doi.org/10.3389/fnmol.2020.581097.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Bao Z, Cui C, Chow SK-H, Qin L, Wong RMY, Cheung W-H. AChRs degeneration at NMJ in aging-associated sarcopenia – a systematic review. Front Aging Neurosci. 2020;12:597811. https://doi.org/10.3389/fnagi.2020.597811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Soendenbroe C, Bechshøft CJL, Heisterberg MF, Jensen SM, Bomme E, Schjerling P, et al. Key components of human myofibre denervation and neuromuscular junction stability are modulated by age and exercise. Cells. 2020;9:893. https://doi.org/10.3390/cells9040893.

    Article  CAS  PubMed Central  Google Scholar 

  64. Witzemann V, Brenner H-R, Sakmann B. Neural factors regulate AChR subunit mRNAs at rat neuromuscular synapses. J Cell Biol. 1991;114:125–41. https://doi.org/10.1083/jcb.114.1.125.

    Article  CAS  PubMed  Google Scholar 

  65. Caron M-A, Charette SJ, Maltais F, Debigaré R. Variability of protein level and phosphorylation status caused by biopsy protocol design in human skeletal muscle analyses. BMC Res Notes. 2011;4:488. https://doi.org/10.1186/1756-0500-4-488.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Apel PJ, Alton T, Northam C, Ma J, Callahan M, Sonntag WE, et al. How age impairs the response of the neuromuscular junction to nerve transection and repair: an experimental study in rats. J Orthop Res. 2009;27:385–93. https://doi.org/10.1002/jor.20773.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Aare S, Spendiff S, Vuda M, Elkrief D, Perez A, Wu Q, et al. Failed reinnervation in aging skeletal muscle. Skelet Muscle. 2016;6:29. https://doi.org/10.1186/s13395-016-0101-y.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Zhao K, Shen C, Li L, Wu H, Xing G, Dong Z, et al. Sarcoglycan alpha mitigates neuromuscular junction decline in aged mice by stabilizing LRP4. J Neurosci. 2018;38:8860–73. https://doi.org/10.1523/JNEUROSCI.0860-18.2018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cisterna BA, Vargas AA, Puebla C, Fernández P, Escamilla R, Lagos CF, et al. Active acetylcholine receptors prevent the atrophy of skeletal muscles and favor reinnervation. Nat Commun. 2020;11:1073. https://doi.org/10.1038/s41467-019-14063-8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Ma J, Shen J, Garrett JP, Lee CA, Li Z, Elsaidi GA, et al. Gene expression of myogenic regulatory factors, nicotinic acetylcholine receptor subunits, and GAP-43 in skeletal muscle following denervation in a rat model. J Orthop Res. 2007;25:1498–505. https://doi.org/10.1002/jor.20414.

    Article  CAS  PubMed  Google Scholar 

  71. Chen A, Bai L, Zhong K, Shu X, Wang A, Xiao Y, et al. APC2CDH1 negatively regulates agrin signaling by promoting the ubiquitination and proteolytic degradation of DOK7. FASEB J. 2020;34:12009–23. https://doi.org/10.1096/fj.202000485R.

    Article  CAS  PubMed  Google Scholar 

  72. Rimer M. Emerging roles for MAP kinases in agrin signaling. Commun Integr Biol. 2011;4:143–6. https://doi.org/10.4161/psb.4.2.14357.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Landi F, Calvani R, Lorenzi M, Martone AM, Tosato M, Drey M, et al. Serum levels of C-terminal agrin fragment (CAF) are associated with sarcopenia in older multimorbid community-dwellers: results from the ilSIRENTE study. Exp Gerontol. 2016;79:31–6. https://doi.org/10.1016/j.exger.2016.03.012.

    Article  CAS  PubMed  Google Scholar 

  74. Ohno K, Ohkawara B, Ito M. Agrin-LRP4-MuSK signaling as a therapeutic target for myasthenia gravis and other neuromuscular disorders. Expert Opin Ther Targets. 2017;21:949–58. https://doi.org/10.1080/14728222.2017.1369960.

    Article  CAS  PubMed  Google Scholar 

  75. Nishimune H, Shigemoto K. Pratical anatomy of the neuromuscular junction in health and disease. Neurol Clin. 2018;36:231–40. https://doi.org/10.1016/j.ncl.2018.01.009.

    Article  PubMed  PubMed Central  Google Scholar 

  76. Naguib M, Flood P, McArdle JJ, Brenner HR. Advances in neurobiology of the neuromuscular junction: implications for the anesthesiologist. Anesthesiology. 2002;96:202–31. https://doi.org/10.1097/00000542-200201000-00035.

    Article  CAS  PubMed  Google Scholar 

  77. Blasco A, Gras S, Mòdol-Caballero G, Tarabal O, Casanovas A, Piedrafita L, et al. Motoneuron deafferentation and gliosis occur in association with neuromuscular regressive changes during ageing in mice. J Cachexia Sarcopenia Muscle. 2020;11:1628–60. https://doi.org/10.1002/jcsm.12599.

    Article  PubMed  PubMed Central  Google Scholar 

  78. Dunne V, Maselli RA. Identification of pathogenic mutations in the human rapsyn gene. J Hum Genet. 2003;48:204–7. https://doi.org/10.1007/s10038-003-0005-7.

    Article  CAS  PubMed  Google Scholar 

  79. Bolliger MF, Zurlinden A, Lüscher D, Bütikofer L, Shakhova O, Francolini M, et al. Specific proteolytic cleavage of agrin regulates maturation of the neuromuscular junction. J Cell Sci. 2010;123:3944–55. https://doi.org/10.1242/jcs.072090.

    Article  CAS  PubMed  Google Scholar 

  80. Reif R, Sales S, Hettwer S, Dreier B, Gisler C, Wölfel J, et al. Specific cleavage of agrin by neurotrypsin, a synaptic protease linked to mental retardation. FASEB J. 2007;21:3468–78. https://doi.org/10.1096/fj.07-8800com.

    Article  CAS  PubMed  Google Scholar 

  81. Hettwer S, Dahinden P, Kucsera S, Farina C, Ahmed S, Fariello R, et al. Elevated levels of a C-terminal agrin fragment identifies a new subset of sarcopenia patients. Exp Gerontol. 2013;48:69–75. https://doi.org/10.1016/j.exger.2012.03.002.

    Article  CAS  PubMed  Google Scholar 

  82. Marzetti E, Calvani R, Lorenzi M, Marini F, D’Angelo E, Martone AM, et al. Serum levels of C-terminal agrin fragment (CAF) are associated with sarcopenia in older hip fractured patients. Exp Gerontol. 2014;60:79–82. https://doi.org/10.1016/j.exger.2014.10.003.

    Article  CAS  PubMed  Google Scholar 

  83. Bütikofer L, Zurlinden A, Bolliger MF, Kunz B, Sonderegger P. Destabilization of the neuromuscular junction by proteolytic cleavage of agrin results in precocious sarcopenia. FASEB J. 2011;25:4378–93. https://doi.org/10.1096/fj.11-191262.

    Article  CAS  PubMed  Google Scholar 

  84. Hettwer S, Lin S, Kucsera S, Haubitz M, Oliveri F, Fariello RG, et al. Injection of a soluble fragment of neural agrin (NT-1654) considerably improves the muscle pathology caused by the disassembly of the neuromuscular junction. PLoS ONE. 2014;9:e88739. https://doi.org/10.1371/journal.pone.0088739.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Colombo E, Bedogni F, Lorenzetti I, Landsberger N, Previtali SC, Farina C. Autocrine and immune cell-derived BDNF in human skeletal muscle: implications for myogenesis and tissue regeneration. J Pathol. 2013;231:190–8. https://doi.org/10.1002/path.4228.

    Article  CAS  PubMed  Google Scholar 

  86. Sakuma K, Yamaguchi A. The recent understanding of the neurotrophin’s role in skeletal muscle adaptation. J Biomed Biotechnol. 2011;2011:201696. https://doi.org/10.1155/2011/201696.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Leßmann V, Brigadski T. Mechanisms, locations, and kinetics of synaptic BDNF secretion: an update. Neurosci Res. 2009;65:11–22. https://doi.org/10.1016/j.neures.2009.06.004.

    Article  CAS  PubMed  Google Scholar 

  88. Greising SM, Stowe JM, Sieck GC, Mantilla CB. Role of TrkB kinase activity in aging diaphragm neuromuscular junctions. Exp Gerontol. 2015;72:184–91. https://doi.org/10.1016/j.exger.2015.10.013.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Miyazaki S, Iino N, Koda R, Narita I, Kaneko Y. Brain-derived neurotrophic factor is associated with sarcopenia and frailty in Japanese hemodialysis patients. Geriatr Gerontol Int. 2020. https://doi.org/10.1111/ggi.14089.

    Article  PubMed  Google Scholar 

  90. Shimada H, Makizako H, Doi T, Yoshida D, Tsutsumimoto K, Anan Y, et al. A large, cross-sectional observational study of serum BDNF, cognitive function, and mild cognitive impairment in the elderly. Front Aging Neurosci. 2014;6:69. https://doi.org/10.3389/fnagi.2014.00069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Kwak JY, Hwang H, Kim S-K, Choi JY, Lee S-M, Bang H, et al. Prediction of sarcopenia using a combination of multiple serum biomarkers. Sci Rep. 2018;8:8574. https://doi.org/10.1038/s41598-018-26617-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Gómez-Pinilla F, Ying Z, Roy RR, Molteni R, Edgerton VR. Voluntary exercise induces a BDNF-mediated mechanism that promotes neuroplasticity. J Neurophysiol. 2002;88:2187–95. https://doi.org/10.1152/jn.00152.2002.

    Article  PubMed  Google Scholar 

  93. Matthews VB, Åström MB, Chan MHS, Bruce CR, Krabbe KS, Prelovsek O, et al. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase. Diabetologia. 2009;52:1409–18. https://doi.org/10.1007/s00125-009-1364-1.

    Article  CAS  PubMed  Google Scholar 

  94. Gomes M, Figueiredo D, Teixeira L, Poveda V, Paúl C, Santos-Silva A, et al. Physical inactivity among older adults across Europe based on the SHARE database. Age Ageing. 2017;46:71–7. https://doi.org/10.1093/ageing/afw165.

    Article  PubMed  Google Scholar 

  95. Nagano M, Suzuki H. Quantitative analyses of expression of GDNF and neurotrophins during postnatal development in rat skeletal muscles. Neurosci Res. 2003;45:391–9. https://doi.org/10.1016/S0168-0102(03)00010-5.

    Article  CAS  PubMed  Google Scholar 

  96. McCullough MJ, Peplinski NG, Kinnell KR, Spitsbergen JM. Glial cell line-derived neurotrophic factor (GDNF) protein content in rat skeletal muscle is altered by increased physical activity in vivo and in vitro. Neuroscience. 2011;174:234–44. https://doi.org/10.1016/j.neuroscience.2010.11.016.

    Article  CAS  PubMed  Google Scholar 

  97. Victoria Vega A, Avila G. CGRP, a vasodilator neuropeptide that stimulates neuromuscular transmission and EC coupling. Curr Vasc Pharmacol. 2010;8:394–403. https://doi.org/10.2174/157016110791112287.

    Article  Google Scholar 

  98. Buffelli M, Pasino E, Cangiano A. In vivo acetylcholine receptor expression induced by calcitonin gene-related peptide in rat soleus muscle. Neuroscience. 2001;104:561–7. https://doi.org/10.1016/S0306-4522(01)00090-2.

    Article  CAS  PubMed  Google Scholar 

  99. Parnow A, Gharakhanlou R, Gorginkaraji Z, Rajabi S, Eslami R, Hedayati M, et al. Effects of endurance and resistance training on calcitonin gene-related peptide and acetylcholine receptor at slow and fast twitch skeletal muscles and sciatic nerve in male wistar rats. Int J Pept. 2012;2012:962651. https://doi.org/10.1155/2012/962651.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Machado J, Manfredi LH, Silveira WA, Gonçalves DAP, Lustrino D, Zanon NM, et al. Calcitonin gene-related peptide inhibits autophagic-lysosomal proteolysis through cAMP/PKA signaling in rat skeletal muscles. Int J Biochem Cell Biol. 2016;72:40–50. https://doi.org/10.1016/j.biocel.2015.12.011.

    Article  CAS  PubMed  Google Scholar 

  101. Matteoli M, Balbi S, Sala C, Chini B, Cimino M, Vitadello M, et al. Developmentally regulated expression of calcitonin gene-related peptide at mammalian neuromuscular junction. J Mol Neurosci. 1990;2:175–84. https://doi.org/10.1007/BF02896842.

    Article  CAS  PubMed  Google Scholar 

  102. Tarabal O. Regulation of motoneuronal calcitonin gene-related peptide (CGRP) during axonal growth and neuromuscular synaptic plasticity induced by botulinum toxin in rats. Eur J Neurosci. 1996;8:829–36. https://doi.org/10.1111/j.1460-9568.1996.tb01269.x.

    Article  CAS  PubMed  Google Scholar 

  103. Machado J, Silveira WA, Gonçalves DA, Schavinski AZ, Khan MM, Zanon NM, et al. α−calcitonin gene-related peptide inhibits autophagy and calpain systems and maintains the stability of neuromuscular junction in denervated muscles. Mol Metab. 2019;28:91–106. https://doi.org/10.1016/j.molmet.2019.06.024.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Baraldo M, Geremia A, Pirazzini M, Nogara L, Solagna F, Türk C, et al. Skeletal muscle mTORC1 regulates neuromuscular junction stability. J Cachexia Sarcopenia Muscle. 2020;11:208–25. https://doi.org/10.1002/jcsm.12496.

    Article  PubMed  Google Scholar 

  105. Joseph GA, Wang SX, Jacobs CE, Zhou W, Kimble GC, Tse HW, et al. Partial inhibition of mTORC1 in aged rats counteracts the decline in muscle mass and reverses molecular signaling associated with sarcopenia. Mol Cell Biol. 2019;39:e00141-e219. https://doi.org/10.1128/MCB.00141-19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Edwards BJ, Perry HM, Kaiser FE, Morley JE, Kraenzle D, Stevenson R, et al. Relationship of age and calcitonin gene-related peptide to postprandial hypotension. Mech Ageing Dev. 1996;87:61–73. https://doi.org/10.1016/0047-6374(96)01688-0.

    Article  CAS  PubMed  Google Scholar 

  107. Holahan MR. A shift from a pivotal to supporting role for the growth-associated protein (GAP-43) in the coordination of axonal structural and functional plasticity. Front Cell Neurosci. 2017;11:1–19. https://doi.org/10.3389/fncel.2017.00266.

    Article  CAS  Google Scholar 

  108. Hesselmans LFGM, Jennekens FGI, van den Oord CJM, Oestreicher AB, Veldman H, Gispen WH. A light and electron microscopical study of B-50 (GAP-43) in human intramuscular nerve and neuromuscular junctions during development. J Neurol Sci. 1989;89:301–11. https://doi.org/10.1016/0022-510X(89)90031-2.

    Article  CAS  PubMed  Google Scholar 

  109. Aigner L, Arber S, Kapfhammer JP, Laux T, Schneider C, Botteri F, et al. Overexpression of the neural growth-associated protein GAP-43 induces nerve sprouting in the adult nervous system of transgenic mice. Cell. 1995;83:269–78. https://doi.org/10.1016/0092-8674(95)90168-X.

    Article  CAS  PubMed  Google Scholar 

  110. Woolf CJ, Reynolds ML, Chong MS, Emson P, Irwin N, Benowitz LI. Denervation of the motor endplate results in the rapid expression by terminal Schwann cells of the growth-associated protein GAP-43. J Neurosci. 1992;12:3999–4010. https://doi.org/10.1523/jneurosci.12-10-03999.1992.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Caprara GA, Morabito C, Perni S, Navarra R, Guarnieri S, Mariggiò MA. Evidence for altered Ca2+ handling in growth associated protein 43-knockout skeletal muscle. Front Physiol. 2016;7:493. https://doi.org/10.3389/fphys.2016.00493.

    Article  PubMed  PubMed Central  Google Scholar 

  112. Guarnieri S, Morabito C, Paolini C, Boncompagni S, Pilla R, Fanò-Illic G, et al. Growth associated protein 43 is expressed in skeletal muscle fibers and is localized in proximity of mitochondria and calcium release units. PLoS ONE. 2013;8:e53267. https://doi.org/10.1371/journal.pone.0053267.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Johnson H, Mossberg K, Arvidsson U, Piehl F, Hökfelt T, Ulfhake B. Increase in α-CGRP and GAP-43 in aged motoneurons: a study of peptides, growth factors, and ChAT mRNA in the lumbar spinal cord of senescent rats with symptoms of hindlimb incapacities. J Comp Neurol. 1995;359:69–89. https://doi.org/10.1002/cne.903590106.

    Article  CAS  PubMed  Google Scholar 

  114. Verzè L, Buffo A, Rossi F, Oestreicher AB, Gispen WH, Strata P. Increase of B-50/GAP-43 immunoreactivity in uninjured muscle nerves of MDX mice. Neuroscience. 1996;70:807–15. https://doi.org/10.1016/S0306-4522(96)83017-X.

    Article  PubMed  Google Scholar 

  115. Heuß D, Engelhardt A, Göbel H, Neundörfer B. Light-microscopic study of phosphoprotein B-50 in myopathies. Virchows Arch. 1995;426:69–76. https://doi.org/10.1007/BF00194700.

    Article  PubMed  Google Scholar 

  116. Yoshimoto Y, Ikemoto-Uezumi M, Hitachi K, Fukada S, Uezumi A. Methods for accurate assessment of myofiber maturity during skeletal muscle regeneration. Front Cell Dev Biol. 2020;8:267. https://doi.org/10.3389/fcell.2020.00267.

    Article  PubMed  PubMed Central  Google Scholar 

  117. Sousa-Victor P, García-Prat L, Muñoz-Cánoves P. Control of satellite cell function in muscle regeneration and its disruption in ageing. Nat Rev Mol Cell Biol. 2021. https://doi.org/10.1038/s41580-021-00421-2.

    Article  PubMed  Google Scholar 

  118. Sajko Š, Kubínová L, Cvetko E, Kreft M, Wernig A, Eržen I. Frequency of M-cadherin-stained satellite cells declines in human muscles during aging. J Histochem Cytochem. 2004;52:179–85. https://doi.org/10.1177/002215540405200205.

    Article  CAS  PubMed  Google Scholar 

  119. Shefer G, Van de Mark DP, Richardson JB, Yablonka-Reuveni Z. Satellite-cell pool size does matter: defining the myogenic potency of aging skeletal muscle. Dev Biol. 2006;294:50–66. https://doi.org/10.1016/j.ydbio.2006.02.022.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Arpke RW, Shams AS, Collins BC, Larson AA, Lu N, Lowe DA, et al. Preservation of satellite cell number and regenerative potential with age reveals locomotory muscle bias. Skelet Muscle. 2021;11:22. https://doi.org/10.1186/s13395-021-00277-2.

    Article  PubMed  PubMed Central  Google Scholar 

  121. Collins CA, Zammit PS, Ruiz AP, Morgan JE, Partridge TA. A population of myogenic stem cells that survives skeletal muscle aging. Stem Cells. 2007;25:885–94. https://doi.org/10.1634/stemcells.2006-0372.

    Article  CAS  PubMed  Google Scholar 

  122. Sousa-Victor P, Gutarra S, García-Prat L, Rodriguez-Ubreva J, Ortet L, Ruiz-Bonilla V, et al. Geriatric muscle stem cells switch reversible quiescence into senescence. Nature. 2014;506:316–21. https://doi.org/10.1038/nature13013.

    Article  CAS  PubMed  Google Scholar 

  123. Liu W, Klose A, Forman S, Paris ND, Wei-LaPierre L, Cortés-Lopéz M, et al. Loss of adult skeletal muscle stem cells drives age-related neuromuscular junction degeneration. Elife. 2017;6:e26464. https://doi.org/10.7554/eLife.26464.

    Article  PubMed  PubMed Central  Google Scholar 

  124. Liu W, Wei-LaPierre L, Klose A, Dirksen RT, Chakkalakal JV. Inducible depletion of adult skeletal muscle stem cells impairs the regeneration of neuromuscular junctions. Elife. 2015;4:e09221. https://doi.org/10.7554/eLife.09221.

    Article  PubMed Central  Google Scholar 

  125. Snijders T, Nederveen JP, McKay BR, Joanisse S, Verdijk LB, van Loon LJC, et al. Satellite cells in human skeletal muscle plasticity. Front Physiol. 2015;6:283. https://doi.org/10.3389/fphys.2015.00283.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Funding

This work was supported by CIAFEL (UIDB/00617/2020), LAQV (UIDB/50006/2020), and CITAB (UIDB/04033/2020) research units and by A.M.P.’s fellowship (SFRH/BD/144396/2019) through national funds by the Portuguese Foundation for Science and Technology (FCT) and co-financed by the European Regional Development Fund (FEDER), within the PT2020 Partnership Agreement.

Author information

Authors and Affiliations

  1. CIAFEL, Faculty of Sport, University of Porto, Dr. Plácido da Costa 91, 4200-450, Porto, Portugal

    Alexandra Moreira-Pais & José A. Duarte

  2. LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, 3810-193, Aveiro, Portugal

    Alexandra Moreira-Pais & Rita Ferreira

  3. Centre for Research and Technology of Agro Environmental and Biological Sciences (CITAB), Inov4Agro, University of Trás-Os-Montes and Alto Douro (UTAD), Quinta de Prados, 5000-801, Vila Real, Portugal

    Alexandra Moreira-Pais & Paula A. Oliveira

  4. TOXRUN – Toxicology Research Unit, University Institute of Health Sciences, CESPU, CRL, Gandra, Portugal

    José A. Duarte

Authors
  1. Alexandra Moreira-Pais
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Rita Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Paula A. Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. José A. Duarte
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

A.M.P. conducted the literature search and drafted the manuscript, and R.F., P.A.O., and J.A.D. critically revised the work.

Corresponding author

Correspondence to Alexandra Moreira-Pais.

Ethics declarations

Conflict of interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Moreira-Pais, A., Ferreira, R., Oliveira, P. et al. A neuromuscular perspective of sarcopenia pathogenesis: deciphering the signaling pathways involved. GeroScience 44, 1199–1213 (2022). https://doi.org/10.1007/s11357-021-00510-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-021-00510-2

Keywords

Search

Navigation