title: Heightened TWEAK-NF-κB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury.
abstract: Individuals with long-standing spinal cord injury (SCI) often present with extreme muscle atrophy and impaired glucose metabolism at both the skeletal muscle and whole body level. Persistent inflammation and increased levels of proinflammatory cytokines in the skeletal muscle are potential contributors to dysregulation of glucose metabolism and atrophy; however, to date no study has assessed the effects of long-standing SCI on their expression or intracellular signaling in the paralyzed muscle. In the present study, we assessed the expression of genes (TNFαR, TNFα, IL-6R, IL-6, TWEAK, TWEAK R, atrogin-1, and MuRF1) and abundance of intracellular signaling proteins (TWEAK, TWEAK R, NF-κB, and p-p65/p-50/105) that are known to mediate inflammation and atrophy in skeletal muscle. In addition, based on the effects of muscle inflammation on promotion of skeletal muscle fibrosis, we assessed the degree of fibrosis between myofibers and fascicles in both groups. For further insight into the distribution and variability of muscle fiber size, we also analyzed the frequency distribution of SCI fiber size. Resting vastus lateralis (VL) muscle biopsy samples were taken from 11 men with long-standing SCI (≈22 yr) and compared with VL samples from 11 able-bodied men of similar age. Our results demonstrated that chronic SCI muscle has heightened TNFαR and TWEAK R gene expression and NF-κB signaling (higher TWEAK R and phospho-NF-κB p65) and fibrosis, along with substantial myofiber size heterogeneity, compared with able-bodied individuals. Our data suggest that the TWEAK/TWEAK R/NF-κB signaling pathway may be an important mediator of chronic inflammation and fibrotic adaptation in SCI muscle.
authors.affiliation: Department of Physical Medicine and Rehabilitation, UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Ceren
authors.initials: C
authors.lastname: Yarar-Fisher
authors.affiliation: Physical Therapy, UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: C Scott
authors.initials: CS
authors.lastname: Bickel
authors.affiliation: Departments of Cell, Developmental, and Integrative Biology, UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Neil A
authors.initials: NA
authors.lastname: Kelly
authors.affiliation: Departments of Cell, Developmental, and Integrative Biology, UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Stec
authors.affiliation: Surgery, and UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Samuel T
authors.initials: ST
authors.lastname: Windham
authors.affiliation: Department of Physical Medicine and Rehabilitation, UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and.
authors.forename: Amie B
authors.initials: AB
authors.lastname: McLain
authors.affiliation: Medicine/Division of Preventive Medicine, University of Alabama at Birmingham (UAB), Birmingham, Alabama;
authors.forename: Robert A
authors.initials: RA
authors.lastname: Oster
authors.affiliation: Departments of Cell, Developmental, and Integrative Biology, Medicine/Division of Preventive Medicine, University of Alabama at Birmingham (UAB), Birmingham, Alabama; Geriatric Research, Education, and Clinical Center, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama mbamman@uab.edu.
authors.forename: Marcas M
authors.initials: MM
authors.lastname: Bamman
mesh_terms: D000328:Adult; D002908:Chronic Disease; D000074049:Cytokine TWEAK; D005355:Fibrosis; D006801:Humans; D015151:Immunoblotting; D007249:Inflammation; D015850:Interleukin-6 / Q000235:genetics; D008297:Male; D008875:Middle Aged; D018485:Muscle Fibers, Skeletal / Q000473:pathology; D009124:Muscle Proteins / Q000235:genetics; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D016328:NF-kappa B / Q000378:metabolism*; D052002:NF-kappa B p50 Subunit / Q000378:metabolism; D009929:Organ Size; D010750:Phosphoproteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics; D015398:Signal Transduction; D013119:Spinal Cord Injuries / Q000378:metabolism* / Q000473:pathology; D000074050:TWEAK Receptor; D051996:Transcription Factor RelA / Q000378:metabolism; D059467:Transcriptome; D000070584:Tripartite Motif Proteins / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D048069:Tumor Necrosis Factors / Q000235:genetics* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics
chemical_list: D000074049:Cytokine TWEAK; C508600:IL6 protein, human; C508603:IL6R protein, human; D015850:Interleukin-6; D009124:Muscle Proteins; D016328:NF-kappa B; D052002:NF-kappa B p50 Subunit; C489548:NFKB1 protein, human; D010750:Phosphoproteins; C498143:RELA protein, human; D012333:RNA, Messenger; D019947:Receptors, Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; C439524:TNF protein, human; C109743:TNFSF12 protein, human; D000074050:TWEAK Receptor; D051996:Transcription Factor RelA; D000070584:Tripartite Motif Proteins; D014409:Tumor Necrosis Factor-alpha; D048069:Tumor Necrosis Factors; C440907:FBXO32 protein, human; D044843:SKP Cullin F-Box Protein Ligases; C440908:TRIM63 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: TNF-like weak inducer of apoptosis; nuclear factor κ-light-chain-enhancer of activated B cells