title: Effects of HMGB1 on in vitro responses of isolated muscle fibers and functional aspects in skeletal muscles of idiopathic inflammatory myopathies.
abstract: Idiopathic inflammatory myopathies (IIMs) are heterogeneous rheumatic disorders of unknown cause characterized by muscle weakness, inflammatory cell infiltrates, and major histocompatibility complex (MHC) class I expression on muscle fibers. The nonhistone nuclear protein alarmin high-mobility group box 1 protein (HMGB1) has been detected extranuclearly in muscle biopsies from patients with IIMs. We hypothesize that HMGB1 has a central role in the cause of muscle weakness, particularly in the early phases of IIMs. Experiments were performed on skeletal muscle fibers isolated from adult mice, which were exposed to recombinant interferon (IFN)-gamma or HMGB1. The myoplasmic free [Ca(2+)] was measured. Stimulation with IFN-gamma resulted in increased HMGB1 expression in muscle nuclei and the myoplasm. Exposure to HMGB1 induced a reversible up-regulation of MHC class I in the muscle fibers. However, HMGB1 exposure caused an irreversible decrease in Ca(2+) release from the sarcoplasmic reticulum during fatigue, induced by repeated tetanic contractions. HMGB1 and MHC class I were frequently colocalized in the myoplasm of muscle fibers in muscle biopsies from patients with early IIMs. However, HMGB1-expressing fibers outnumbered fibers expressing MHC class I. Our data indicate that HMGB1 could be an early inducer of skeletal muscle dysfunction in IIMs.
authors.affiliation: Rheumatology Unit, Department of Medicine, Karolinska University Hospital-Solna, Stockholm, Sweden. cecilia.grundtman@i-med.ac.at
authors.forename: Cecilia
authors.initials: C
authors.lastname: Grundtman
authors.forename: Joseph
authors.initials: J
authors.lastname: Bruton
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamada
authors.forename: Therese
authors.initials: T
authors.lastname: Ostberg
authors.forename: David S
authors.initials: DS
authors.lastname: Pisetsky
authors.forename: Helena Erlandsson
authors.initials: HE
authors.lastname: Harris
authors.forename: Ulf
authors.initials: U
authors.lastname: Andersson
authors.forename: Ingrid E
authors.initials: IE
authors.lastname: Lundberg
authors.forename: Håkan
authors.initials: H
authors.lastname: Westerblad
mesh_terms: D000328:Adult; D000818:Animals; D002118:Calcium / Q000378:metabolism; D003882:Dermatomyositis / Q000503:physiopathology; D005260:Female; D024243:HMGB1 Protein / Q000096:biosynthesis / Q000494:pharmacology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D008931:Mitochondria, Muscle / Q000378:metabolism; D018763:Muscle Fatigue / Q000502:physiology; D018485:Muscle Fibers, Skeletal / Q000187:drug effects / Q000502:physiology*; D009220:Myositis / Q000503:physiopathology*; D017285:Polymyositis / Q000503:physiopathology; D017382:Reactive Oxygen Species; D012519:Sarcoplasmic Reticulum / Q000378:metabolism
chemical_list: D024243:HMGB1 Protein; D015395:Histocompatibility Antigens Class I; D017382:Reactive Oxygen Species; D007371:Interferon-gamma; D002118:Calcium