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

Author:

Yarar-Fisher Ceren12,Bickel C. Scott32,Kelly Neil A.42,Stec Michael J.42,Windham Samuel T.52,McLain Amie B.12,Oster Robert A.6,Bamman Marcas M.467

Affiliation:

1. Department of Physical Medicine and Rehabilitation,

2. UAB Center for Exercise Medicine, University of Alabama at Birmingham, Birmingham, Alabama; and

3. Physical Therapy,

4. Departments of Cell, Developmental, and Integrative Biology,

5. Surgery, and

6. Medicine/Division of Preventive Medicine, University of Alabama at Birmingham (UAB), Birmingham, Alabama;

7. Geriatric Research, Education, and Clinical Center, Birmingham Veterans Affairs Medical Center, Birmingham, Alabama

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.

Funder

Nutrition and Obesity Training Grant (NIH)

UAB Center for Clinical and Translational Science

VA Meritt Award

UAB Center for Exercise Medicine

UAB Department of Physical Medicine and Rehabilitation

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology,Endocrinology, Diabetes and Metabolism

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