Pyruvate kinase M2 and the mitochondrial ATPase Inhibitory Factor 1 provide novel biomarkers of dermatomyositis: a metabolic link to oncogenesis.
Metabolic 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.



A 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).



When 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.



Expression 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.
Departamento de Biología Molecular, Centro de Biología Molecular Severo, Ochoa, CSIC-UAM, Universidad Autónoma de Madrid, c/Nicolás Cabrera 1, 28049, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Instituto de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
Fulvio
F
Santacatterina
Departamento de Biología Molecular, Centro de Biología Molecular Severo, Ochoa, CSIC-UAM, Universidad Autónoma de Madrid, c/Nicolás Cabrera 1, 28049, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Instituto de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
María
M
Sánchez-Aragó
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Muscle Research and Mitochondrial Function Laboratory, CELLEX-IDIBAPS, Faculty of Medicine-University of Barcelona, Internal Medicine Department-Hospital Clinic of Barcelona, Barcelona, Spain.
Marc
M
Catalán-García
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Muscle Research and Mitochondrial Function Laboratory, CELLEX-IDIBAPS, Faculty of Medicine-University of Barcelona, Internal Medicine Department-Hospital Clinic of Barcelona, Barcelona, Spain.
Glòria
G
Garrabou
Departamento de Biología Molecular, Centro de Biología Molecular Severo, Ochoa, CSIC-UAM, Universidad Autónoma de Madrid, c/Nicolás Cabrera 1, 28049, Madrid, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Instituto de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain.
Cristina Nuñez
CN
de Arenas
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Muscle Research and Mitochondrial Function Laboratory, CELLEX-IDIBAPS, Faculty of Medicine-University of Barcelona, Internal Medicine Department-Hospital Clinic of Barcelona, Barcelona, Spain.
Josep M
JM
Grau
Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain.|Muscle Research and Mitochondrial Function Laboratory, CELLEX-IDIBAPS, Faculty of Medicine-University of Barcelona, Internal Medicine Department-Hospital Clinic of Barcelona, Barcelona, Spain.
Francesc
F
Cardellach
Departamento de Biología Molecular, Centro de Biología Molecular Severo, Ochoa, CSIC-UAM, Universidad Autónoma de Madrid, c/Nicolás Cabrera 1, 28049, Madrid, Spain. jmcuezva@cbm.csic.es.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain. jmcuezva@cbm.csic.es.|Instituto de Investigación Hospital 12 de Octubre, ISCIII, Madrid, Spain. jmcuezva@cbm.csic.es.
José M
JM
Cuezva
D000906:Antibodies / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D001706:Biopsy; D063646:Carcinogenesis / Q000378:metabolism*; D016000:Cluster Analysis; D003882:Dermatomyositis / Q000378:metabolism*; D004734:Energy Metabolism; D006801:Humans; D007249:Inflammation / Q000175:diagnosis / Q000473:pathology; D008928:Mitochondria / Q000378:metabolism*; D009132:Muscles / Q000378:metabolism / Q000473:pathology; D040081:Protein Array Analysis; D011506:Proteins / Q000378:metabolism*; D011770:Pyruvate Kinase / Q000378:metabolism*; D015203:Reproducibility of Results; D013347:Subcellular Fractions / Q000378:metabolism; D000097795:ATPase Inhibitory Protein
D000906:Antibodies; D015415:Biomarkers; D011506:Proteins; D011770:Pyruvate Kinase; D000097795:ATPase Inhibitory Protein
ATPase Inhibitory Factor 1; Biomarkers; Dermatomyositis; Energy metabolism; Inflammatory myopathies; Mitochondria; Pyruvate kinase M2