Abstract

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.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049022-03
Application #
6925439
Study Section
Special Emphasis Panel (ZRG1-SMB (01))
Program Officer
Nuckolls, Glen H
Project Start
2003-07-01
Project End
2008-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
3
Fiscal Year
2005
Total Cost
$318,308
Indirect Cost

  Institution

Name
Baylor College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
051113330
City
Houston
State
TX
Country
United States
Zip Code
77030

  Publications

Niu, Airu; Wang, Bin; Li, Yi-Ping (2015) TNF? shedding in mechanically stressed cardiomyocytes is mediated by Src activation of TACE. J Cell Biochem 116:559-65
Ennequin, Gaël; Boisseau, Nathalie; Caillaud, Kevin et al. (2015) Exercise training and return to a well-balanced diet activate the neuregulin 1/ErbB pathway in skeletal muscle of obese rats. J Physiol 593:2665-77
Li, Yi-Ping; Niu, Airu; Wen, Yefei (2014) Regulation of myogenic activation of p38 MAPK by TACE-mediated TNF? release. Front Cell Dev Biol 2:21
Niu, Airu; Wen, Yefei; Liu, Huijie et al. (2013) Src mediates the mechanical activation of myogenesis by activating TNF*-converting enzyme. J Cell Sci 126:4349-57
Liu, Huijie; Niu, Airu; Chen, Shuen-Ei et al. (2011) Beta3-integrin mediates satellite cell differentiation in regenerating mouse muscle. FASEB J 25:1914-21
Liu, Huijie; Chen, Shuen-Ei; Jin, Bingwen et al. (2010) TIMP3: a physiological regulator of adult myogenesis. J Cell Sci 123:2914-21
Zhan, Mei; Jin, Bingwen; Chen, Shuen-Ei et al. (2007) TACE release of TNF-alpha mediates mechanotransduction-induced activation of p38 MAPK and myogenesis. J Cell Sci 120:692-701
Chen, Shuen-Ei; Jin, Bingwen; Li, Yi-Ping (2007) TNF-alpha regulates myogenesis and muscle regeneration by activating p38 MAPK. Am J Physiol Cell Physiol 292:C1660-71
Jin, Bingwen; Li, Yi-Ping (2007) Curcumin prevents lipopolysaccharide-induced atrogin-1/MAFbx upregulation and muscle mass loss. J Cell Biochem 100:960-9
Ottenheijm, Coen A C; Heunks, Leo M A; Li, Yi-Ping et al. (2006) Activation of the ubiquitin-proteasome pathway in the diaphragm in chronic obstructive pulmonary disease. Am J Respir Crit Care Med 174:997-1002

Showing the most recent 10 out of 13 publications