Skip to main content
SpringerLink
Log in

Muscle Microdialysis to Investigate Inflammatory Biomarkers in Facioscapulohumeral Muscular Dystrophy

  • Published:
Molecular Neurobiology Aims and scope Submit manuscript

Abstract

Recent progresses in the understanding of facioscapulohumeral muscular dystrophy (FSHD) genetics opened the way to the development of targeted therapies. However, knowledge about pathophysiology of muscle damage is still limited and there is increasing need to identify biomarkers of disease activity in the perspective of clinical trial readiness.

We analyzed inflammatory mediators in the interstitial fluid of muscles with different MRI signal in FSHD patients, comparing muscles displaying early lesions on short-tau inversion recovery (STIR) sequences with normal ones. Patients with one T1-weighted normal and STIR hyperintense (STIR+) and contralateral T1-weighted and STIR normal (STIR-) lower limb muscle were asked to enter the study. Twelve consecutive patients, five controls, and one non-penetrant gene carrier underwent prolonged muscle microdialysis with high cut-off membranes. Microdialysates were analyzed using xMAP technology with a wide panel for cytokines, chemokines, and growth factors. A small number of inflammatory mediators were dysregulated in STIR+ versus STIR- and control muscles: CXCL13, upregulated in STIR+ muscles compared with controls (p < 0.01); CXCL5, downregulated in STIR+ compared with STIR- muscles (p < 0.05); and G-CSF, downregulated in STIR+ muscles compared with controls (p < 0.05). CXCL13 was also upregulated in the STIR+ muscles compared with the contralateral STIR- muscles of the same patient (p < 0.01).

These results support the evidence of a selective inflammatory process taking place in STIR+ FSHD muscles. The application of microdialysis could provide insights on novel mechanisms involved in muscle damage in FSHD and in other myopathies. Further studies are needed to validate these investigated molecules as tissue and circulating biomarkers.

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
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Tasca G, Monforte M, Ottaviani P, Pelliccioni M, Frusciante R, Laschena F et al (2016) Magnetic resonance imaging in a large cohort of facioscapulohumeral muscular dystrophy patients: pattern refinement and implications for clinical trials. Ann Neurol. doi:10.1002/ana.24640

    PubMed  Google Scholar 

  2. Tasca G, Monforte M, Iannaccone E, Laschena F, Ottaviani P, Leoncini E et al (2014) Upper girdle imaging in facioscapulohumeral muscular dystrophy. PLoS One 9:e100292

    Article  PubMed  PubMed Central  Google Scholar 

  3. Kan HE, Scheenen TW, Wohlgemuth M, Klomp DW, van Loosbroek-Wagenmans I, Padberg GW et al (2009) Quantitative MR imaging of individual muscle involvement in facioscapulohumeral muscular dystrophy. Neuromuscul Disord 19:357–362

    Article  PubMed  Google Scholar 

  4. Friedman SD, Poliachik SL, Carter GT, Budech CB, Bird TD, Shaw DW (2012) The magnetic resonance imaging spectrum of facioscapulohumeral muscular dystrophy. Muscle Nerve 45:500–506

    Article  PubMed  Google Scholar 

  5. Frisullo G, Frusciante R, Nociti V, Tasca G, Renna R, Iorio R et al (2011) CD8(+) T cells in facioscapulohumeral muscular dystrophy patients with inflammatory features at muscle MRI. J Clin Immunol 31:155–166

    Article  CAS  PubMed  Google Scholar 

  6. Hauerslev S, Ørngreen MC, Hertz JM, Vissing J, Krag TO (2013) Muscle regeneration and inflammation in patients with facioscapulohumeral muscular dystrophy. Acta Neurol Scand 128:194–201

    Article  CAS  PubMed  Google Scholar 

  7. Tasca G, Pescatori M, Monforte M, Mirabella M, Iannaccone E, Frusciante R et al (2012) Different molecular signatures in magnetic resonance imaging-staged facioscapulohumeral muscular dystrophy muscles. PLoS One 7:e38779

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Rooyackers O, Thorell A, Nygren J, Ljungqvist O (2004) Microdialysis methods for measuring human metabolism. Curr Opin Clin Nutr Metab Care 7:515–521

    Article  CAS  PubMed  Google Scholar 

  9. Winter CD, Pringle AK, Clough GF, Church MK (2004) Raised parenchymal interleukin-6 levels correlate with improved outcome after traumatic brain injury. Brain 127:315–320

    Article  PubMed  Google Scholar 

  10. Clough GF (2005) Microdialysis of large molecules. AAPS J 7:E686–E692

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Tawil R, Padberg GW, Shaw DW, van der Maarel SM, Tapscott SJ, FSHD WP (2016) Clinical trial preparedness in facioscapulohumeral muscular dystrophy: clinical, tissue, and imaging outcome measures 29-30 May 2015, Rochester, New York. Neuromuscul Disord 26:181–186

    Article  PubMed  Google Scholar 

  12. Khan IH, Krishnan VV, Ziman M, Janatpour K, Wun T, Luciw PA et al (2009) A comparison of multiplex suspension array large-panel kits for profiling cytokines and chemokines in rheumatoid arthritis patients. Cytometry B Clin Cytom 76:159–168

    Article  PubMed  PubMed Central  Google Scholar 

  13. Fu Q, Zhu J, Van Eyk JE (2010) Comparison of multiplex immunoassay platforms. Clin Chem 56:314–318

    Article  CAS  PubMed  Google Scholar 

  14. Gabriëls J, Beckers MC, Ding H, De Vriese A, Plaisance S, van der Maarel SM et al (1999) Nucleotide sequence of the partially deleted D4Z4 locus in a patient with FSHD identifies a putative gene within each 3.3 kb element. Gene 236:25–32

    Article  PubMed  Google Scholar 

  15. Dixit M, Ansseau E, Tassin A, Winokur S, Shi R, Qian H et al (2007) DUX4, a candidate gene of facioscapulohumeral muscular dystrophy, encodes a transcriptional activator of PITX1. Proc Natl Acad Sci U S A 104:18157–18162

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Lemmers RJ, van der Vliet PJ, Klooster R, Sacconi S, Camano P, Dauwerse JG et al (2010) A unifying genetic model for facioscapulohumeral muscular dystrophy. Science 329:1650–1653

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Snider L, Geng LN, Lemmers RJ, Kyba M, Ware CB, Nelson AM et al (2010) Facioscapulohumeral dystrophy: incomplete suppression of a retrotransposed gene. PLoS Genet 6:e1001181

    Article  PubMed  PubMed Central  Google Scholar 

  18. Geng LN, Yao Z, Snider L, Fong AP, Cech JN, Young JM et al (2012) DUX4 activates germline genes, retroelements, and immune mediators: implications for facioscapulohumeral dystrophy. Dev Cell 22:38–51

    Article  CAS  PubMed  Google Scholar 

  19. Munsat TL, Piper D, Cancilla P, Mednick J (1972) Inflammatory myopathy with facioscapulohumeral distribution. Neurology 22:335–347

    Article  CAS  PubMed  Google Scholar 

  20. Figarella-Branger D, Pellissier JF, Serratrice G, Pouget J, Bianco N (1989) Immunocytochemical study of the inflammatory forms of facioscapulohumeral myopathies and correlation with other types of myositis. Ann Pathol 9:100–108

    CAS  PubMed  Google Scholar 

  21. Arahata K, Ishihara T, Fukunaga H, Orimo S, Lee JH, Goto K et al (1995) Inflammatory response in facioscapulohumeral muscular dystrophy (FSHD): immunocytochemical and genetic analyses. Muscle Nerve 2:S56–S66

    Article  CAS  PubMed  Google Scholar 

  22. Honda H, Mano Y, Takahashi A (1987) Inflammatory changes in affected muscles of facioscapulohumeral dystrophy. J Neurol 234:408–411

    Article  CAS  PubMed  Google Scholar 

  23. Fitzsimons RB (1994) Facioscapulohumeral dystrophy: the role of inflammation. Lancet 344:902–903

    Article  CAS  PubMed  Google Scholar 

  24. Macaione V, Aguennouz M, Rodolico C, Mazzeo A, Patti A, Cannistraci E et al (2007) RAGE-NF-kappaB pathway activation in response to oxidative stress in facioscapulohumeral muscular dystrophy. Acta Neurol Scand 115:115–121

    Article  CAS  PubMed  Google Scholar 

  25. Olausson P, Gerdle B, Ghafouri N, Larsson B, Ghafouri B (2012) Identification of proteins from interstitium of trapezius muscle in women with chronic myalgia using microdialysis in combination with proteomics. PLoS One 7:e52560

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Li Z-W, Zhao L, Han Q-C, Zhu X (2016) CXCL13 inhibits microRNA-23a through PI3K/AKT signaling pathway in adipose tissue derived-mesenchymal stem cells. Biomed Pharmacother 83:876–880

    Article  CAS  PubMed  Google Scholar 

  27. Dmitriev P, Kiseleva E, Kharchenko O, Ivashkin E, Pichugin A, Dessen P et al (2016) Dux4 controls migration of mesenchymal stem cells through the Cxcr4-Sdf1 axis. Oncotarget 7:65090–65108

    Article  PubMed  PubMed Central  Google Scholar 

  28. Legler DF, Loetscher M, Roos RS, Clark-Lewis I, Baggiolini M, Moser B (1998) B cell-attracting chemokine 1, a human CXC chemokine expressed in lymphoid tissues, selectively attracts B lymphocytes via BLR1/CXCR5. J Exp Med 187:655–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. De Paepe B, Creus KK, De Bleecker JL (2009) Role of cytokines and chemokines in idiopathic inflammatory myopathies. Curr Opin Rheumatol 21:610–616

    Article  CAS  PubMed  Google Scholar 

  30. Housley WJ, Pitt D, Hafler DA (2015) Biomarkers in multiple sclerosis. Clin Immunol 161:51–58

    Article  CAS  PubMed  Google Scholar 

  31. Pícha D, Moravcová L, Smíšková D (2016) Prospective study on the chemokine CXCL13 in neuroborreliosis and other aseptic neuroinfections. J Neurol Sci 368:214–220

    Article  PubMed  Google Scholar 

  32. Schiffer L, Worthmann K, Haller H, Schiffer M (2015) CXCL13 as a new biomarker of systemic lupus erythematosus and lupus nephritis - from bench to bedside. Clin Exp Immunol 179:85–89

    Article  CAS  PubMed  Google Scholar 

  33. Jones JD, Hamilton BJ, Challener GJ, de Brum-Fernandes AJ, Cossette P, Liang P et al (2014) Serum C-X-C motif chemokine 13 is elevated in early and established rheumatoid arthritis and correlates with rheumatoid factor levels. Arthritis Res Ther 16:R103

    Article  PubMed  PubMed Central  Google Scholar 

  34. Nishikawa A, Suzuki K, Kassai Y, Gotou Y, Takiguchi M, Miyazaki T et al (2016) Identification of definitive serum biomarkers associated with disease activity in primary Sjögren’s syndrome. Arthritis Res Ther 18:106

    Article  PubMed  PubMed Central  Google Scholar 

  35. Monach PA (2014) Biomarkers in vasculitis. Curr Opin Rheumatol 26:24–30

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zhang Q, Cao DL, Zhang ZJ, Jiang BC, Gao YJ (2016) Chemokine CXCL13 mediates orofacial neuropathic pain via CXCR5/ERK pathway in the trigeminal ganglion of mice. J Neuroinflammation 13:183

    Article  PubMed  PubMed Central  Google Scholar 

  37. Huber AK, Irani DN (2015) Targeting CXCL13 during neuroinflammation. Adv Neuroimmune Biol 6:1–8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Müller G, Lipp M (2003) Concerted action of the chemokine and lymphotoxin system in secondary lymphoid-organ development. Curr Opin Immunol 15:217–224

    Article  PubMed  Google Scholar 

  39. Yang T, Wang S, Zheng Q, Wang L, Li Q, Wei M et al (2016) Increased plasma levels of epithelial neutrophil-activating peptide 78/CXCL5 during the remission of neuromyelitis optica. BMC Neurol 16:96

    Article  PubMed  PubMed Central  Google Scholar 

  40. Zhao Y, Zhang H (2016) Update on the mechanisms of homing of adipose tissue-derived stem cells. Cytotherapy 18:816–827

    Article  CAS  PubMed  Google Scholar 

  41. Rando A, Gasco S, de la Torre M, García-Redondo A, Zaragoza P, Toivonen JM et al (2017) Granulocyte colony-stimulating factor ameliorates skeletal muscle dysfunction in amyotrophic lateral sclerosis mice and improves proliferation of SOD1-G93A myoblasts in vitro. Neurodegener Dis 17:1–13

    Article  CAS  PubMed  Google Scholar 

  42. Hayashiji N, Yuasa S, Miyagoe-Suzuki Y, Hara M, Ito N, Hashimoto H et al (2015) G-CSF supports long-term muscle regeneration in mouse models of muscular dystrophy. Nat Commun 6:6745

    Article  CAS  PubMed  Google Scholar 

  43. Statland J, Donlin-Smith CM, Tapscott SJ, van der Maarel S, Tawil R (2014) Multiplex screen of serum biomarkers in facioscapulohumeral muscular dystrophy. J Neuromuscul Dis 1:181–190

    PubMed Central  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge the FSHD Italia ONLUS Association.

Compliance with Ethical Standards

This protocol is in agreement with the Declaration of Helsinki and was approved by the Ethics Committee of our Institution. All involved subjects gave their written informed consent.

Funding

This study was supported by a grant from the FSH Society (FSHS-82013-05) and fundings from the Don Carlo Gnocchi ONLUS Foundation, Ricerca corrente 2014, to GT.

Conflict of Interest

Pursuant to the terms of a Master Academic Services Agreement with the Catholic University of the Sacred Heart, M. Monforte and E. Ricci have provided central reading services for MRI scans generated in aTyr’s clinical trials of Resolaris (ATYR1940). E. Ricci is the site principal investigator for some of such trials. The other authors report no disclosures.

Author information

Authors and Affiliations

  1. Istituto di Neurologia, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli”, Largo A. Gemelli, 8, 00168, Rome, Italy

    Giorgio Tasca, Mauro Monforte, Giuseppe Granata & Enzo Ricci

  2. Istituto di Patologia Generale, Università Cattolica del Sacro Cuore, Rome, Italy

    Maddalena Corbi, Donatella Lucchetti & Alessandro Sgambato

Authors
  1. Giorgio Tasca
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Mauro Monforte
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maddalena Corbi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Giuseppe Granata
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Donatella Lucchetti
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Alessandro Sgambato
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Enzo Ricci
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Giorgio Tasca.

Additional information

Alessandro Sgambato and Enzo Ricci shared senior authorship.

Electronic Supplementary Materials

ESM. 1

(PDF 1021 kb)

ESM. 2

(PDF 338 kb)

ESM. 3

(PDF 360 kb)

ESM. 4

(WMV 10033 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tasca, G., Monforte, M., Corbi, M. et al. Muscle Microdialysis to Investigate Inflammatory Biomarkers in Facioscapulohumeral Muscular Dystrophy. Mol Neurobiol 55, 2959–2966 (2018). https://doi.org/10.1007/s12035-017-0563-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12035-017-0563-x

Keywords

Search

Navigation