title: Molecular alterations in skeletal muscle in rheumatoid arthritis are related to disease activity, physical inactivity, and disability.
abstract: BACKGROUND
  To identify molecular alterations in skeletal muscle in rheumatoid arthritis (RA) that may contribute to ongoing disability in RA.
  
  
  METHODS
  Persons with seropositive or erosive RA (n = 51) and control subjects matched for age, gender, race, body mass index (BMI), and physical activity (n = 51) underwent assessment of disease activity, disability, pain, physical activity and thigh muscle biopsies. Muscle tissue was used for measurement of pro-inflammatory markers, transcriptomics, and comprehensive profiling of metabolic intermediates. Groups were compared using mixed models. Bivariate associations were assessed with Spearman correlation.
  
  
  RESULTS
  Compared to controls, patients with RA had 75% greater muscle concentrations of IL-6 protein (p = 0.006). In patients with RA, muscle concentrations of inflammatory markers were positively associated (p < 0.05 for all) with disease activity (IL-1β, IL-8), disability (IL-1β, IL-6), pain (IL-1β, TNF-α, toll-like receptor (TLR)-4), and physical inactivity (IL-1β, IL-6). Muscle cytokines were not related to corresponding systemic cytokines. Prominent among the gene sets differentially expressed in muscles in RA versus controls were those involved in skeletal muscle repair processes and glycolytic metabolism. Metabolic profiling revealed 46% higher concentrations of pyruvate in muscle in RA (p < 0.05), and strong positive correlation between levels of amino acids involved in fibrosis (arginine, ornithine, proline, and glycine) and disability (p < 0.05).
  
  
  CONCLUSIONS
  RA is accompanied by broad-ranging molecular alterations in skeletal muscle. Analysis of inflammatory markers, gene expression, and metabolic intermediates linked disease-related disruptions in muscle inflammatory signaling, remodeling, and metabolic programming to physical inactivity and disability. Thus, skeletal muscle dysfunction might contribute to a viscous cycle of RA disease activity, physical inactivity, and disability.
authors.affiliation: Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA. Huffm007@mc.duke.edu.
authors.forename: Kim M
authors.initials: KM
authors.lastname: Huffman
authors.affiliation: Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Ryan
authors.initials: R
authors.lastname: Jessee
authors.affiliation: Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Andonian
authors.affiliation: Biomedical Engineering, Duke University, Durham, NC, USA.
authors.forename: Brittany N
authors.initials: BN
authors.lastname: Davis
authors.affiliation: Harvard University School of Law, Boston, MA, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Narowski
authors.affiliation: Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Janet L
authors.initials: JL
authors.lastname: Huebner
authors.affiliation: Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Virginia B
authors.initials: VB
authors.lastname: Kraus
authors.affiliation: Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Julie
authors.initials: J
authors.lastname: McCracken
authors.affiliation: Department of Surgery, Duke School of Medicine, Durham, NC, USA.
authors.forename: Brian F
authors.initials: BF
authors.lastname: Gilmore
authors.affiliation: Department of Emergency Medicine, Indiana University, Indianapolis, IN, USA.
authors.forename: K Noelle
authors.initials: KN
authors.lastname: Tune
authors.affiliation: Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Milton
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Timothy R
authors.initials: TR
authors.lastname: Koves
authors.affiliation: Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: Deborah M
authors.initials: DM
authors.lastname: Muoio
authors.affiliation: George Washington University, Washington, DC, USA.
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Hubal
authors.affiliation: Department of Medicine, Duke Molecular Physiology Institute, Duke School of Medicine, Durham, NC, USA.
authors.forename: William E
authors.initials: WE
authors.lastname: Kraus
mesh_terms: D000368:Aged; D001172:Arthritis, Rheumatoid / Q000378:metabolism* / Q000503:physiopathology*; D003430:Cross-Sectional Studies; D004185:Disability Evaluation; D004797:Enzyme-Linked Immunosorbent Assay; D015444:Exercise; D005260:Female; D006801:Humans; D008297:Male; D055432:Metabolomics; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000503:physiopathology*; D020411:Oligonucleotide Array Sequence Analysis; D059467:Transcriptome
keywords: Fibrosis; Gene expression; Inflammation; Metabolomics; Satellite cells