Heightened TWEAK-NF-κB signaling and inflammation-associated fibrosis in paralyzed muscles of men with chronic spinal cord injury

• Published in: American journal of physiology: endocrinology and metabolism 2016-05, Vol.310 (9), p.E754-E761
• Main Authors: Yarar-Fisher, Ceren, Bickel, C Scott, Kelly, Neil A, Stec, Michael J, Windham, Samuel T, McLain, Amie B, Oster, Robert A, Bamman, Marcas M
• Format: Article
• Language: English
• Subjects: Adult; Chronic Disease; Cytokine TWEAK; Fibrosis; Humans; Immunoblotting; Inflammation; Interleukin-6 - genetics; Male; Middle Aged; Muscle Fibers, Skeletal - pathology; Muscle Proteins - genetics; Muscle, Skeletal - metabolism; Muscle, Skeletal - pathology; Muscular Atrophy - metabolism; Muscular Atrophy - pathology; NF-kappa B - metabolism; NF-kappa B p50 Subunit - metabolism; Organ Size; Phosphoproteins - metabolism; Receptors, Interleukin-6 - genetics; Receptors, Tumor Necrosis Factor - genetics; Receptors, Tumor Necrosis Factor - metabolism; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - metabolism; Signal Transduction; SKP Cullin F-Box Protein Ligases - genetics; Spinal Cord Injuries - metabolism; Spinal Cord Injuries - pathology; Transcription Factor RelA - metabolism; Transcriptome; Tripartite Motif Proteins - genetics; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factors - genetics; Tumor Necrosis Factors - metabolism; TWEAK Receptor; Ubiquitin-Protein Ligases - genetics
• ISSN: 0193-1849; 1522-1555
• DOI: 10.1152/ajpendo.00240.2015

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.