Integrated Multi-Omics Analysis for Inferring Molecular Players in Inclusion Body Myositis

Author:

Cantó-Santos Judith123ORCID,Valls-Roca Laura123,Tobías Ester123,Oliva Clara4,García-García Francesc Josep123,Guitart-Mampel Mariona123,Andújar-Sánchez Félix123,Esteve-Codina Anna56ORCID,Martín-Mur Beatriz5,Padrosa Joan123ORCID,Aránega Raquel123,Moreno-Lozano Pedro J.123ORCID,Milisenda José César123,Artuch Rafael4,Grau-Junyent Josep M.123,Garrabou Glòria123ORCID

Affiliation:

1. Inherited Metabolic Disorders and Muscular Diseases Research Group, Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) and Faculty of Medicine and Health Sciences, University of Barcelona, 08036 Barcelona, Spain

2. Department of Internal Medicine, Hospital Clinic of Barcelona, 08036 Barcelona, Spain

3. CIBERER—Spanish Biomedical Research Centre in Rare Diseases, 28029 Madrid, Spain

4. Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain

5. CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, 08028 Barcelona, Spain

6. Department of Medicine and Health Sciences, Universitat Pompeu Fabra (UPF), 08003 Barcelona, Spain

Abstract

Inclusion body myositis (IBM) is an acquired inflammatory myopathy affecting proximal and distal muscles that leads to weakness in patients over 50. It is diagnosed based on clinical and histological findings in muscle related to inflammation, degeneration, and mitochondria. In relation to IBM, a shortage of validated disease models and a lack of biomarkers and effective treatments constitute an unmet medical need. To overcome these hurdles, we performed an omics analysis of multiple samples from IBM patients (saliva, fibroblasts, urine, plasma, and muscle) to gain insight into the pathophysiology of IBM. Degeneration was evident due to the presence of amyloid β peptide 1–42 (Aβ1–42) in the saliva of the analyzed IBM patients. The presence of metabolic disarrangements in IBM was indicated by an imbalanced organic acid profile in fibroblasts and urine. Specifically, abnormal levels of L-pyroglutamic and orotic acid were supported by the abnormal expression of related metabolites in plasma and urine (glutathione and pyrimidines) and the aberrant expression of upstream gene regulators (L2HGDH, IDH2, OPLAH, and ASL) in muscle. Combined levels of L-pyroglutamic and orotic acid displayed an outstanding biomarker signature in urine with 100% sensitivity and specificity. The confirmation of systemic metabolic disarrangements in IBM and the identification of novel biomarkers reported herein unveil novel insights that require validation in larger cohorts.

Funder

Instituto de Salud de Carlos Ill

European Union

CIBERER

Torrons Vicens

IRSJD

ISCIII-FSE+

Publisher

MDPI AG

Subject

Cell Biology,Clinical Biochemistry,Molecular Biology,Biochemistry,Physiology

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