title: Serum proteomic profiling reveals fragments of MYOM3 as potential biomarkers for monitoring the outcome of therapeutic interventions in muscular dystrophies.
abstract: Therapy-responsive biomarkers are an important and unmet need in the muscular dystrophy field where new treatments are currently in clinical trials. By using a comprehensive high-resolution mass spectrometry approach and western blot validation, we found that two fragments of the myofibrillar structural protein myomesin-3 (MYOM3) are abnormally present in sera of Duchenne muscular dystrophy (DMD) patients, limb-girdle muscular dystrophy type 2D (LGMD2D) and their respective animal models. Levels of MYOM3 fragments were assayed in therapeutic model systems: (1) restoration of dystrophin expression by antisense oligonucleotide-mediated exon-skipping in mdx mice and (2) stable restoration of α-sarcoglycan expression in KO-SGCA mice by systemic injection of a viral vector. Following administration of the therapeutic agents MYOM3 was restored toward wild-type levels. In the LGMD model, where different doses of vector were used, MYOM3 restoration was dose-dependent. MYOM3 fragments showed lower inter-individual variability compared with the commonly used creatine kinase assay, and correlated better with the restoration of the dystrophin-associated protein complex and muscle force. These data suggest that the MYOM3 fragments hold promise for minimally invasive assessment of experimental therapies for DMD and other neuromuscular disorders.
authors.affiliation: Généthon, Evry, France.
authors.forename: Jérémy
authors.initials: J
authors.lastname: Rouillon
authors.affiliation: Généthon, Evry, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Poupiot
authors.affiliation: Généthon, Evry, France.
authors.forename: Aleksandar
authors.initials: A
authors.lastname: Zocevic
authors.affiliation: Généthon, Evry, France.
authors.forename: Fatima
authors.initials: F
authors.lastname: Amor
authors.affiliation: Mass spectrometry Laboratory, Institut Jacques Monod, UMR 7592, University Paris Diderot, CNRS, Sorbonne Paris Cité, F-75205 Paris, France.
authors.forename: Thibaut
authors.initials: T
authors.lastname: Léger
authors.affiliation: Mass spectrometry Laboratory, Institut Jacques Monod, UMR 7592, University Paris Diderot, CNRS, Sorbonne Paris Cité, F-75205 Paris, France.
authors.forename: Camille
authors.initials: C
authors.lastname: Garcia
authors.affiliation: Mass spectrometry Laboratory, Institut Jacques Monod, UMR 7592, University Paris Diderot, CNRS, Sorbonne Paris Cité, F-75205 Paris, France.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Camadro
authors.affiliation: Division of Pediatric Neurology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.
authors.forename: Brenda
authors.initials: B
authors.lastname: Wong
authors.affiliation: Généthon, Evry, France.
authors.forename: Robin
authors.initials: R
authors.lastname: Pinilla
authors.affiliation: Généthon, Evry, France.
authors.forename: Jérémie
authors.initials: J
authors.lastname: Cosette
authors.affiliation: Department of Physiology, Anatomy and Genetics Oxford, Oxford, OX1 3QX, UK.
authors.forename: Anna M L
authors.initials: AM
authors.lastname: Coenen-Stass
authors.affiliation: Department of Physiology, Anatomy and Genetics Oxford, Oxford, OX1 3QX, UK.
authors.forename: Graham
authors.initials: G
authors.lastname: Mcclorey
authors.affiliation: Department of Physiology, Anatomy and Genetics Oxford, Oxford, OX1 3QX, UK, Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA, USA.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Roberts
authors.affiliation: Department of Physiology, Anatomy and Genetics Oxford, Oxford, OX1 3QX, UK.
authors.forename: Matthew J A
authors.initials: MJ
authors.lastname: Wood
authors.affiliation: Service of Clinical Trials and Databases, Institut de Myologie, Paris, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Servais
authors.affiliation: Folkhälsan Institute of Genetics and Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Bjarne
authors.initials: B
authors.lastname: Udd
authors.affiliation: UPMC Inserm, UMRS 974, CNRS FRE 3617, Paris, France, Université Pierre et Marie Curie- Paris 6, Institut de Myologie, GH Pitié-Salpêtrière, Paris, France and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Voit
authors.affiliation: Genethon, CNRS UMR 8587, Evry, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Richard
authors.affiliation: Généthon, Evry, France, svinart@genethon.fr.
authors.forename: Fedor
authors.initials: F
authors.lastname: Svinartchouk
mesh_terms: D000293:Adolescent; D000328:Adult; D000818:Animals; D015415:Biomarkers; D001798:Blood Proteins / Q000378:metabolism*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D064211:Connectin / Q000097:blood / Q000378:metabolism*; D003402:Creatine Kinase; D004195:Disease Models, Animal; D006801:Humans; D013058:Mass Spectrometry; D051379:Mice; D018101:Mice, Inbred mdx; D009136:Muscular Dystrophies / Q000097:blood / Q000378:metabolism* / Q000628:therapy; D020388:Muscular Dystrophy, Duchenne / Q000097:blood / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D064211:Connectin; C000607429:MYOM3 protein, human; D003402:Creatine Kinase