Activation of the wnt/β-Catenin Signaling Pathway in Polymyositis, Dermatomyositis and Duchenne Muscular Dystrophy

Abstract

Background and PurposeThe wnt/β-catenin signaling pathway plays a critical role in embryonic development and adult-tissue homeostasis. Recent investigations implicate the importance of wnt/β-catenin signaling in normal wound healing and its sustained activation being associated with fibrogenesis. We investigated the immunolocalization and activation of wnt/β-catenin in polymyositis (PM), dermatomyositis (DM), and Duchenne muscular dystrophy (DMD).MethodsImmunofluorescence staining and Western blot analysis of β-catenin were performed in muscle specimens from 6 PM, 8 DM, and 6 DMD subjects. The β-catenin/Tcf4 DNA-binding activity in muscle was studied using an electrophoretic mobility shift assay (EMSA), and serum wnt/β-catenin/Tcf transcriptional activity was measured using a luciferase reporter gene assay.ResultsImmunoreactivity for β-catenin was found in the cytoplasm and nuclei of muscle fibers in PM, DM, and DMD. The protein level of β-catenin was elevated, and EMSA analysis confirmed the activation of wnt/β-catenin signaling. The transcriptional activities of β-catenin/Tcf in the circulation were increased in patients with PM, DM, and DMD, especially in those with interstitial lung disease, and these transcriptional activities decreased when PM or DM patients exhibited obvious clinical improvements.ConclusionsOur findings indicate that wnt/β-catenin signaling is activated in PM, DM, and DMD. Its activation in muscle tissue and the circulation may play a role in modulating muscle regeneration and be at least partly involved in the process of muscle and pulmonary fibrosis.

Plasma-Derived Exosomal hsa-miR-4488 and hsa-miR-1228-5p: Novel Biomarkers for Dermatomyositis-Associated Interstitial Lung Disease with Anti-Melanoma Differentiation-Associated Protein 5 Antibody-Positive Subset

“…Several differentially regulated KEGG pathways were identified. The Wnt signaling pathway, which was indicated to be upregulated in patients with DM-associated ILD [ 39 ], and the cyclic adenosine monophosphate signaling pathway, which has been known to antagonize pulmonary fibrosis activated by phosphodiesterase 4 [ 40 ], were involved in DM-ILD-MDA5 Ab(+) exosomes when compared to both HC and DM-nonILD-MSA16(-) exosomes, suggesting that these signaling pathways may be unique to ILD, particularly in the DM-ILD-MDA5 Ab(+) subset. Transforming growth factor- β signaling, which was reported to be upregulated in muscle samples with sporadic inclusion body myositis [ 41 ], and mTOR signaling may be potential pathways of autoimmune diseases [ 42 ] and were included in the CTGs of DE miRNAs in the DM-nonILD-MSA16(-) exosomes, suggesting that these pathways may contribute to the pathogenesis of DM.…”

Genetic Analysis of HIBM Myopathy-Specific GNE V727M Hotspot Mutation Identifies a Novel COL6A3 Allied Gene Signature That Is Also Deregulated in Multiple Neuromuscular Diseases and Myopathies

“…To identify the key genes with an important role, we next used panther analysis to find key pathways in which the lincRNA target genes were involved. Our study showed targets of the lincRNAs were part of essential processes of WNT signaling, TGF-β, and Apoptotic inducing pathways ( Figure 2 c,d); some of these pathways are well known to be important in various myopathies and dystrophies [ 29 , 30 , 31 , 32 , 33 , 34 , 35 ].…”

Role of the Renin–Angiotensin–Aldosterone System in Dystrophin-Deficient Cardiomyopathy

“…Major characteristics of muscle biopsies of the dystrophic hearts include necrotic muscle fibres surrounded by macrophages, lymphocytes, mast cells and myofibroblasts [ 31 , 42 , 50 , 51 ], supporting that DDC results from imbalance between muscle fibre necrosis, inflammatory response and myofibroblasts regeneration [ 30 , 52 , 53 , 54 , 55 , 56 , 57 , 58 ]. At the molecular level, the fibrotic process is regulated by a complex network of signalling pathways that includes inflammatory cells (lymphocytes, macrophages, mast cells), inflammatory factors (IL, TNF-a, NF-kB) peptides (ANG2, endothelin 1 (ET-1), aldosterone), growth factors (Transforming growth factor (TGF-β), connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF)), ions (Ca2+), oxidative stress molecules (NADPH, NOX, LOX…), adhesion molecules (integrins, osteopontin), matrix metalloproteinases (MMP), and immunoproteasome ( Figure 2 ) [ 59 , 60 , 61 , 62 , 63 , 64 , 65 ]. These interdependent factors favour the activation and proliferation of myofibroblasts [ 66 , 67 , 68 ].…”