Tumor necrosis factor-alpha (TNF-alpha) is traditionally recognized as a circulating mediator that stimulates muscle catabolism in inflammatory diseases. However, recent discoveries indicate that TNF-alpha plays a more complex and more fundamental role in skeletal muscle. It is now clear that skeletal myocytes constitutively express TNF-alpha. Biological processes that demand myofiber regeneration - degenerative muscle diseases (inflammatory myopathies and Duchenne muscular dystrophy), injury and exercise -- accelerate TNF-alpha expression by myocytes. Further, it is increasingly evident that TNF-alpha is critical for muscle regeneration because it accelerates myogenic gene expression. Based on growing evidence from our and other laboratories, we propose that TNF-alpha functions as an autocrine/paracrine modulator of muscle regeneration by promoting the expression of adult-type muscle proteins during early differentiation via activating MADS-box myogenic factors, MEF2 and SRF, and a muscle hypertrophy mediator GATA-2.
Three specific aims will be pursued to test this model.
Aim 1. To evaluate upregulation of TNF-alpha as an autocrine modulator of primary myoblast differentiation. TNF-alpha expression during differentiation induced by distinct stimuli (serum restriction, cell confluence and cyclic stretch), and effects of TNF-alpha on adult-type muscle protein expression during differentiation will be determined in rat and mouse primary myoblasts.
Aim 2. To determine whether TNF-alpha promotes muscle regeneration in vivo. Effects of TNF-alpha deficiency on muscle regeneration evoked by cardiotoxin-induced muscle injury will be evaluated in mice with genetic or immunological blockade of TNF-alpha receptors. Muscle histology, contractile force generation, and myogenic gene expression will be determined to evaluate regeneration.
Aim 3. To determine signaling events by which TNF-alpha stimulates myogenic differentiation. TNF-alpha stimulation of MEF2, SRF, and GATA-2, and the underlying signaling mechanisms will be evaluated. Our long-term objectives are to understand the role of cytokines as an emerging group of muscle regeneration modulators, and to improve the treatment of degenerative muscle diseases.

National Institute of Health (NIH)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SMB (01))
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Nuckolls, Glen H
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Baylor College of Medicine
Internal Medicine/Medicine
Schools of Medicine
United States
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