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

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 ( 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. Online address: http://www.molmed.org doi: 10.2119/molmed.2015.00168 Marc Catalán-García, Muscle Research and Mitochondrial Function Laboratory, Cellex, IDIBAPS, Faculty of Medicine, University of Barcelona, Department of Internal Medicine-Hospital Clinic of Barcelona, CELLEX 4B, Villarroel 170, 08036 Barcelona, Catalonia, Spain. Phone: +34-93227-5400, Ext. 2907; Fax: +34-93227-9365; E-mail: macatala@clinic.ub.es. Submitted July 8, 2015; Accepted for publication October 27, 2015; Published Online (www.molmed.org) November 3, 2015. Address correspondence to N O V E L P L A S M A T I C B I O M A R K E R S F O R s I B M D I A G N O S I S8 1 8 | C a t a L á n -G a r C í a E t a L . | M O L M E D 2 1 : 8 1 7 -8 2 3 , 2 0 1 5

Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

“…In the clinical setting, CK [ 1 ], amyloidogenic-related molecules (β-secretase 1 [ 20 ], presenilin-1 [ 21 ], and soluble Aβ precursor protein [ 20 ]) and cytosolic 5’-nucleotidase 1A (cN-1A) autoantibodies [ 22 ] are used for the diagnosis of sIBM, but none of these are specific. Recently, GDF15 [ 13 , 23 ] and FGF21 [ 23 ] have been recognized to be more sensitive and specific diagnostic markers for mitochondrial diseases than the lactate to pyruvate (L/P) ratio.…”

Diagnosis and Management of Immune-Mediated Myopathies

“…An increase of amyloid precursor protein b, b-secretase-1 (b-site amyloid precursor proteinecleaving enzyme 1) and g-secretase (both enzymes process amyloid precursor protein), was demonstrated in the plasma from patients with IBM when compared with controls and other inflammatory myopathies. 64 However, the low sensitivity of these amyloidogenic biomarkers (despite the high specificity of w90%) limits their use in clinical practice. 65…”

Mitochondrial dysfunction underlying sporadic inclusion body myositis is ameliorated by the mitochondrial homing drug MA-5

“…In the clinical setting, CK [1], amyloidogenic-related molecules (-secretase 1 [20], presenilin-1 [21], and soluble A precursor protein [20]) and cytosolic 5'-nucleotidase 1A (cN-1A) autoantibodies [22] are used for the diagnosis of sIBM, but none of these are specific. Recently, GDF15 [13,23] and FGF21 [23] have been recognized to be more sensitive and specific diagnostic markers for mitochondrial diseases than the lactate to pyruvate (L/P) ratio.…”