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Molecular Medicine

, Volume 21, Issue 1, pp 817–823 | Cite as

BACE-1, PS-1 and sAPPβ Levels Are Increased in Plasma from Sporadic Inclusion Body Myositis Patients: Surrogate Biomarkers among Inflammatory Myopathies

  • Marc Catalán-García
  • Glòria Garrabou
  • Constanza Morén
  • Mariona Guitart-Mampel
  • Ingrid Gonzalez-Casacuberta
  • Adriana Hernando
  • Jose Miquel Gallego-Escuredo
  • Dèlia Yubero
  • Francesc Villarroya
  • Raquel Montero
  • Albert Selva O-Callaghan
  • Francesc Cardellach
  • Josep Maria Grau
Research Article

Abstract

Sporadic inclusion body myositis (sIBM) is a rare disease that is difficult to diagnose. Muscle biopsy provides three prominent pathological findings: inflammation, mitochondrial abnormalities and fibber degeneration, represented by the accumulation of protein depots constituted by β-amyloid peptide, among others. We aim to perform a screening in plasma of circulating molecules related to the putative etiopathogenesis of sIBM to determine potential surrogate biomarkers for diagnosis. Plasma from 21 sIBM patients and 20 age- and gender-paired healthy controls were collected and stored at −80°C. An additional population of patients with non-sIBM inflammatory myopathies was also included (nine patients with dermatomyositis and five with polymyositis). Circulating levels of inflammatory cytokines (interleukin [IL]-6 and tumor necrosis factor (TNF)-α), mitochondrial-related molecules (free plasmatic mitochondrial DNA [mtDNA], fibroblast growth factor-21 [FGF-21] and coenzyme-Q10 [CoQ]) and amyloidogenic-related molecules (beta-secretase-1 [BACE-1], presenilin-1 [PS-1], and soluble Aβ precursor protein [sAPPβ]) were assessed with magnetic bead-based assays, real-time polymerase chain reaction, enzyme-linked immunosorbent assay (ELISA) and high-pressure liquid chromatography (HPLC). Despite remarkable trends toward altered plasmatic expression of inflammatory and mitochondrial molecules (increased IL-6, TNF-α, circulating mtDNA and FGF-21 levels and decreased content in CoQ), only amyloidogenic degenerative markers including BACE-1, PS-1 and sAPPβ levels were significantly increased in plasma from sIBM patients compared with controls and other patients with non-sIBM inflammatory myopathies (p < 0.05). Inflammatory, mitochondrial and amyloidogenic degeneration markers are altered in plasma of sIBM patients confirming their etiopathological implication in the disease. Sensitivity and specificity analysis show that BACE-1, PS-1 and sAPPβ represent a good predictive noninvasive tool for the diagnosis of sIBM, especially in distinguishing this disease from polymyositis.

Notes

Acknowledgments

This study has been funded by Fondo de Investigación Sanitaria (FIS 0229/08, 00462/11 and 01199/12) granted by ISCIII and Fondo Europeo de Desarrollo Regional (FEDER), Fundació Cellex, Fundación para la Investigación y la Prevención del SIDA en España (FIPSE 360745/09 and 360982/10), Suports a Grups de Recerca de la Generalitat de Catalunya (SGR 09/1158 and 09/1385) and CIBER de Enfermedades Raras (CIBERER, an initiative of ISCIII).

References

  1. 1.
    Solorzano GE, Phillips LH 2nd. (2011) Inclusion body myositis: diagnosis, pathogenesis, and treatment options. Rheum. Dis. Clin. North Am. 37:173–83.CrossRefGoogle Scholar
  2. 2.
    Griggs RC, et al. (1995) Inclusion body myositis and myopathies. Ann. Neurol. 38:705–13.CrossRefGoogle Scholar
  3. 3.
    Needham M, Mastaglia FL. (2007) Inclusion body myositis: current pathogenetic concepts and diagnostic and therapeutic approaches. Lancet Neurol. 6:620–31.CrossRefGoogle Scholar
  4. 4.
    Catalan M, Selva-O’Callaghan A, Grau JM. (2014) Diagnosis and classification of sporadic inclusion body myositis (sIBM). Autoimmun. Rev. 13:363–6.CrossRefGoogle Scholar
  5. 5.
    Cox FM, et al. (2011) A 12-year follow-up in sporadic inclusion body myositis: an end stage with major disabilities. Brain. 134:3167–75.CrossRefGoogle Scholar
  6. 6.
    Benveniste O, et al. (2011) Long-term observational study of sporadic inclusion body myositis. Brain. 134:3176–84.CrossRefGoogle Scholar
  7. 7.
    Calabrese LH, Mitsumoto H, Chou SM. (1987) Inclusion body myositis presenting as treatment-resistant polymyositis. Arthritis Rheum. 30:397–403.CrossRefGoogle Scholar
  8. 8.
    Benveniste O, et al. (2015) Amyloid deposits and inflammatory infiltrates in sporadic inclusion body myositis: the inflammatory egg comes before the degenerative chicken. Acta Neuropathol. 129:611–24.CrossRefGoogle Scholar
  9. 9.
    Greenberg SA. (2009) Comment on “Interrelation of inflammation and APP in sIBM: IL-1beta induces accumulation of beta-amyloid in skeletal muscle.” Brain. 132:e106.CrossRefGoogle Scholar
  10. 10.
    Abdo WF, et al. (2009) Increased plasma amyloid-beta42 protein in sporadic inclusion body myositis. Acta Neuropathol. 118:429–31.CrossRefGoogle Scholar
  11. 11.
    Salajegheh M, et al. (2009) Sarcoplasmic redistribution of nuclear TDP-43 in inclusion body myositis. Muscle Nerve. 40:19–31.CrossRefGoogle Scholar
  12. 12.
    Machado P, Brady S, Hanna MG. (2013) Update in inclusion body myositis. Curr. Opin. Rheumatol. 25:763–71.CrossRefGoogle Scholar
  13. 13.
    Larman HB, et al. (2013) Cytosolic 5′-nucleotidase 1A autoimmunity in sporadic inclusion body myositis. Ann. Neurol. 73:408–18.CrossRefGoogle Scholar
  14. 14.
    Salajegheh M, Lam T, Greenberg SA. (2011) Autoantibodies against a 43 KDa muscle protein in inclusion body myositis. PLoS One. 6:e20266.CrossRefGoogle Scholar
  15. 15.
    Lloyd TE, et al. (2015) Cytosolic 5′-nucleotidase 1A is a common target of circulating autoantibodies in several autoimmune diseases. Arthritis Care Res. 68:66–71.CrossRefGoogle Scholar
  16. 16.
    Gallucci S, Provenzano C, Mazzarelli P, Scuderi F, Bartoccioni E. (1998) Myoblasts produce IL-6 in response to inflammatory stimuli. Int. Immunol. 10:267–73.CrossRefGoogle Scholar
  17. 17.
    Loell I, Lundberg IE. (2011) Can muscle regeneration fail in chronic inflammation: a weakness in inflammatory myopathies? J. Intern. Med. 269:243–57.CrossRefGoogle Scholar
  18. 18.
    Zhang Q, et al. (2010) Circulating mitochondrial DAMPs cause inflammatory responses to injury. Nature. 464:104–7.CrossRefGoogle Scholar
  19. 19.
    Cossarizza A, et al. (2011) Increased plasma levels of extracellular mitochondrial DNA during HIV infection: a new role for mitochondrial damage-associated molecular patterns during inflammation. Mitochondrion. 11:750–5.CrossRefGoogle Scholar
  20. 20.
    Davis RL, et al. (2013) Fibroblast growth factor 21 is a sensitive biomarker of mitochondrial disease. Neurology. 81:1819–26.CrossRefGoogle Scholar
  21. 21.
    Littlefield N, Beckstrand RL, Luthy KE. (2013) Statins’ effect on plasma levels of Coenzyme Q10 and improvement in myopathy with supplementation. J. Am. Assoc. Nurse Pract. 26:85–90.PubMedGoogle Scholar
  22. 22.
    Santa-Mara I, et al. (2008) Coenzyme q induces tau aggregation, tau filaments, and Hirano bodies. J. Neuropathol. Exp. Neurol. 67:428–34.CrossRefGoogle Scholar
  23. 23.
    Levacic D, Peddareddygari LR, Nochlin D, Sharer LR, Grewal RP. (2013) Inclusion-body myositis associated with Alzheimer’s disease. Case Rep. Med. 2013:536231.CrossRefGoogle Scholar
  24. 24.
    Murphy MP, Golde TE. (2006) Inclusion-body myositis and Alzheimer disease: two sides of the same coin, or different currencies altogether? Neurology. 66:S65–8.CrossRefGoogle Scholar
  25. 25.
    Roos PM, Vesterberg O, Nordberg M. (2011) Inclusion body myositis in Alzheimer’s disease. Acta Neurol. Scand. 124:215–7.CrossRefGoogle Scholar
  26. 26.
    Wu G, et al. (2012) Characterization of plasma beta-secretase (BACE1) activity and soluble amyloid precursor proteins as potential biomarkers for Alzheimer’s disease. J. Neurosci. Res. 90:2247–58.CrossRefGoogle Scholar
  27. 27.
    Nogalska A, Engel WK, Askanas V. (2010) Increased BACE1 mRNA and noncoding BACE1-antisense transcript in sporadic inclusion-body myositis muscle fibers: possibly caused by endoplasmic reticulum stress. Neurosci. Lett. 474:140–3.CrossRefGoogle Scholar
  28. 28.
    Rosen C, Hansson O, Blennow K, Zetterberg H. (2013) Fluid biomarkers in Alzheimer’s disease-current concepts. Mol. Neurodegener. 8:20.CrossRefGoogle Scholar
  29. 29.
    Hoogendijk JE, et al. (2004) 119th ENMC international workshop: trial design in adult idiopathic inflammatory myopathies, with the exception of inclusion body myositis, 10–12 October 2003, Naarden, The Netherlands. Neuromuscul. Disord. 14:337–45.CrossRefGoogle Scholar
  30. 30.
    Rose MR, Group EIW. (2013) 188th ENMC International Workshop: Inclusion Body Myositis, 2–4 December 2011, Naarden, The Netherlands. Neuromuscul. Disord. 3:1044–55.CrossRefGoogle Scholar
  31. 31.
    Jackson CE, et al. (2008) Inclusion body myositis functional rating scale: a reliable and valid measure of disease severity. Muscle Nerve. 37:473–6.CrossRefGoogle Scholar
  32. 32.
    Moren C, et al. (2015) Mitochondrial disturbances in HIV pregnancies. Aids. 29:5–12.CrossRefGoogle Scholar
  33. 33.
    Hondares E, et al. (2014) Fibroblast growth factor-21 is expressed in neonatal and pheochromocytoma-induced adult human brown adipose tissue. Metabolism. 63:312–7.CrossRefGoogle Scholar
  34. 34.
    Yubero D, et al. (2014) Biochemical diagnosis of coenzyme q10 deficiency. Mol. Syndromol. 5:147–55.CrossRefGoogle Scholar
  35. 35.
    Greenberg SA. (2012) Pathogenesis and therapy of inclusion body myositis. Curr. Opin. Neurol. 25:630–9.CrossRefGoogle Scholar
  36. 36.
    Kharitonenkov A, et al. (2005) FGF-21 as a novel metabolic regulator. J. Clin. Invest. 115:1627–35.CrossRefGoogle Scholar
  37. 37.
    Salehi MH, et al. (2013) Association of fibroblast growth factor (FGF-21) as a biomarker with primary mitochondrial disorders, but not with secondary mitochondrial disorders (Friedreich Ataxia). Mol. Biol Rep. 40:6495–9.CrossRefGoogle Scholar
  38. 38.
    Askanas V, Engel WK. (2008) Inclusion-body myositis: muscle-fiber molecular pathology and possible pathogenic significance of its similarity to Alzheimer’s and Parkinson’s disease brains. Acta Neuropathol. 116:583–95.CrossRefGoogle Scholar
  39. 39.
    Askanas V, Engel WK. (2001) Inclusion-body myositis: newest concepts of pathogenesis and relation to aging and Alzheimer disease. J. Neuropathol. Exp. Neurol. 60:1–14.CrossRefGoogle Scholar

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Authors and Affiliations

  • Marc Catalán-García
    • 1
  • Glòria Garrabou
    • 1
  • Constanza Morén
    • 1
  • Mariona Guitart-Mampel
    • 1
  • Ingrid Gonzalez-Casacuberta
    • 1
  • Adriana Hernando
    • 1
  • Jose Miquel Gallego-Escuredo
    • 2
  • Dèlia Yubero
    • 3
    • 4
  • Francesc Villarroya
    • 2
  • Raquel Montero
    • 3
    • 4
  • Albert Selva O-Callaghan
    • 5
  • Francesc Cardellach
    • 1
  • Josep Maria Grau
    • 1
  1. 1.Laboratory of Muscle Research and Mitochondrial Function, Cellex-IDIBAPS, Faculty of Medicine, Department of Internal Medicine, Hospital Clinic of BarcelonaUniversity of BarcelonaBarcelonaSpain
  2. 2.Department of Biochemistry and Molecular BiologyInstitute of Biomedicine (University of Barcelona), University of Barcelona, and CIBEROBNBarcelonaSpain
  3. 3.Clinical Biochemistry DepartmentHospital Sant Joan de DéuBarcelonaSpain
  4. 4.CIBERERValenciaSpain
  5. 5.Internal Medicine DepartmentHospital Vall d’HebronBarcelonaSpain

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