Integrated Multi-Omics Analysis for Inferring Molecular Players in Inclusion Body Myositis
Judith Cantó-Santos,
Laura Valls-Roca,
Ester Tobías,
Clara Oliva,
Francesc Josep García-García,
Mariona Guitart-Mampel,
Félix Andújar-Sánchez,
Anna Esteve-Codina,
Beatriz Martín-Mur,
Joan Padrosa,
Raquel Aránega,
Pedro J. Moreno-Lozano,
José César Milisenda,
Rafael Artuch,
Josep M. Grau-Junyent,
Glòria Garrabou
Affiliations
Judith Cantó-Santos
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
Laura Valls-Roca
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
Ester Tobías
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
Clara Oliva
Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
Francesc Josep García-García
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
Mariona Guitart-Mampel
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
Félix Andújar-Sánchez
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
Anna Esteve-Codina
CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Beatriz Martín-Mur
CNAG-CRG, Centre for Genomic Regulation, Barcelona Institute of Science and Technology, 08028 Barcelona, Spain
Joan Padrosa
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
Raquel Aránega
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
Pedro J. Moreno-Lozano
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
José César Milisenda
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
Rafael Artuch
Department of Clinical Biochemistry, Institut de Recerca Sant Joan de Déu, Esplugues de Llobregat, 08950 Barcelona, Spain
Josep M. Grau-Junyent
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
Glòria Garrabou
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
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.