Initiation of the myogenic program in adult muscle is a critical step in skeletal muscle regeneration, which is essential for muscle maintenance and adaptation. Muscle regeneration requires chromatin remodeling in myogenic cells that allows transcriptional activation of myogenic target genes. The activation of p38 MAPK plays a critical role in chromatin remodeling and in the activation of key myogenic transcription factors and, thus, is considered a molecular switch for the activation of myogenesis. However, the signaling mechanism that mediates p38 activation in response to diverse myogenic stimuli in adult muscle remains poorly understood. Supported by R01 AR049022, we have discovered that myogenic activation of p38 is mediated by TNF-1 converting enzyme (TACE) through the release of TNF-1, a cytokine that activates p38, from myogenic cells as an autocrine factor. These discoveries reveal a new paradigm of the regulation of myogenesis. Nevertheless, to fully establish this new paradigm, the mechanism of myogenic activation of TACE must be delineated. In preliminary studies, we obtained initial evidence that two mechanisms mediate myogenic activation of TACE. One involves a down-regulation of tissue inhibitor of metallopreoteinase3 (TIMP3), which removes the suppression on TACE. The other involves tyrosine phosphorylation of TACE that augments TACE activity. Based on our preliminary data, the current project will evaluate the signaling mechanisms that mediate myogenic activation of TACE by pursuing three specific aims.
Aim 1. To determine whether TIMP3 regulates myogenesis via its inhibition of TACE. We will test the conceptual model in cultured myoblasts and adult muscle that as an endogenous inhibitor of TACE, constitutively expressed TIMP3 suppresses myogenic differentiation;when stimulated by myogenic stimuli, TIMP3 undergoes a down-regulation which removes the inhibition on TACE and permits myogenesis to take place. We will also elucidate the mechanisms through which TIMP3 is down-regulated.
Aim 2. To determine whether Src mediates TACE activation by myogenic stimuli. We will test the conceptual model that TACE is activated via phosphorylation by the tyrosine protein kinase Src when stimulated by myogenic stimuli;and this reaction is critical to myogenesis.
Aim 3. To determine whether 23 integrin mediates myogenic activation of Src. We will test the conceptual model that the 23 integrin serves as the membrane receptor that transduces mechanochemical cues of myogenesis into myogenic cells through recruiting and activating Src. Thus, a 23 integrin Src TACE pathway that mediates the myogenic activation of p38 can be established. Our long term goal is to identify means for promoting muscle regeneration via the understanding of the signaling mechanisms that regulate muscle regeneration.

Public Health Relevance

. Muscle regeneration is essential for muscle maintenance and adaptation. The goal of the current grant application is to identify means for promoting muscle regeneration via the understanding of the signaling mechanisms that regulate myogenesis by activating p38 MAPK in adult muscle.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR049022-10
Application #
8291127
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Boyce, Amanda T
Project Start
2002-07-05
Project End
2013-09-30
Budget Start
2012-07-01
Budget End
2013-09-30
Support Year
10
Fiscal Year
2012
Total Cost
$282,269
Indirect Cost
$94,090
Name
University of Texas Health Science Center Houston
Department
Biology
Type
Schools of Medicine
DUNS #
800771594
City
Houston
State
TX
Country
United States
Zip Code
77225
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
Durham, William J; Arbogast, Sandrine; Gerken, Eric et al. (2006) Progressive nuclear factor-kappaB activation resistant to inhibition by contraction and curcumin in mdx mice. Muscle Nerve 34:298-303
Chen, Shuen-Ei; Gerken, Eric; Zhang, Yingmin et al. (2005) Role of TNF-{alpha} signaling in regeneration of cardiotoxin-injured muscle. Am J Physiol Cell Physiol 289:C1179-87

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