Abstract
BackgroundMetabolic alterations play a role in the development of inflammatory myopathies (IMs). Herein, we have investigated through a multiplex assay whether proteins of energy metabolism could provide biomarkers of IMs.MethodsA cohort of thirty-two muscle biopsies and forty plasma samples comprising polymyositis (PM), dermatomyositis (DM) and sporadic inclusion body myositis (sIBM) and control donors was interrogated with monoclonal antibodies against proteins of energy metabolism using reverse phase protein microarrays (RPPA).ResultsWhen compared to controls the expression of the proteins is not significantly affected in the muscle of PM patients. However, the expression of β-actin is significantly increased in DM and sIBM in consistence with muscle and fiber regeneration. Concurrently, the expression of some proteins involved in glucose metabolism displayed a significant reduction in muscle of sIBM suggesting a repression of glycolytic metabolism in these patients. In contrasts to these findings, the expression of the glycolytic pyruvate kinase isoform M2 (PKM2) and of the mitochondrial ATPase Inhibitor Factor 1 (IF1) and Hsp60 were significantly augmented in DM when compared to other IMs in accordance with a metabolic shift prone to cancer development. PKM2 alone or in combination with other biomarkers allowed the discrimination of control and IMs with very high (>95%) sensitivity and specificity. Unfortunately, plasma levels of PKM2 were not significantly altered in DM patients to recommend its use as a non-invasive biomarker of the disease.ConclusionsExpression of proteins of energy metabolism in muscle enabled discrimination of patients with IMs. RPPA identified the glycolysis promoting PKM2 and IF1 proteins as specific biomarkers of dermatomyositis, providing a biochemical link of this IM with oncogenesis.
Highlights
Metabolic alterations play a role in the development of inflammatory myopathies (IMs)
To explore the potential applicability of a signature of metabolism in the diagnosis of IMs we selected for study representative proteins from glycogenolysis (Glycogen phosphorylase, glycogen phosphorylase (PYGM)), glycolysis, oxidative phosphorylation (β-subunit of the H+-ATP synthase, β-F1-ATPase and ATPase Inhibitory Factor 1, Inhibitor Factor 1 (IF1)), and electron shuttling of glycolytic NADH to mitochondria
The major limitation of quantitative reverse phase protein microarrays (RPPA) is the availability of specific monoclonal antibodies against the proteins being studied
Summary
Metabolic alterations play a role in the development of inflammatory myopathies (IMs). We have investigated through a multiplex assay whether proteins of energy metabolism could provide biomarkers of IMs. Inflammatory myopathies (IMs) is a group of heterogeneous diseases characterized by muscle weakness and inflammatory infiltrates within the skeletal muscle. We have studied the putative relevance of proteins of energy metabolism as diagnostic biomarkers in IMs using RPPA. To this aim, we have studied the expression of enzymes of glucose metabolism and of oxidative phosphorylation in a cohort of thirty-two muscle biopsies including samples from control and PM, DM and sIBM affected patients using validated monoclonal antibodies. The final purpose of the study is to translate the “signature” of energy metabolism to bed-side application of patients affected with IMs
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