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

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.

Sporadic Inclusion Body Myositis at the Crossroads between Muscle Degeneration, Inflammation, and Aging

“…Considering the lack of appropriate pre-clinical models, alternative technologies need to be exploited. Omics approaches have been recently contributing to improving our understanding of the disease [ 67 , 258 , 259 , 260 , 261 , 262 , 263 , 264 ]. Proteomics analysis performed on skeletal muscle biopsies of patients with sIBM has revealed alterations of pathways related to oxidative stress and regulation of apoptosis [ 261 ].…”

“…Metabolomic and transcriptomic analyses have been used in combination to uncover alterations in histamine biosynthesis, certain glycosaminoglycan biosynthesis, carnitine, and creatine metabolism, providing the rationale for the identification of mast cells in sIBM muscle biopsy [ 259 ]. A more systemic approach has been adopted in a recent study where metabolomic and transcriptomic analyses were performed on a set of tissues, cells, and biological fluids obtained from patients with sIBM [ 258 ]. This strategy uncovered systemic metabolic alterations occurring in sIBM and identified L-pyroglutamic and orotic acids in urine as a highly specific and selective biomarker signature for sIBM [ 258 ].…”

“…A more systemic approach has been adopted in a recent study where metabolomic and transcriptomic analyses were performed on a set of tissues, cells, and biological fluids obtained from patients with sIBM [ 258 ]. This strategy uncovered systemic metabolic alterations occurring in sIBM and identified L-pyroglutamic and orotic acids in urine as a highly specific and selective biomarker signature for sIBM [ 258 ]. Single-cell RNA sequencing (scRNAseq) has been recently applied to characterize the muscle-infiltrating T cells and peripheral blood memory T cells in patients with IIM, including subjects with sIBM [ 266 ].…”