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TNF promotes muscle catabolism via a p38/PGC‐1/Foxo cascade
Author(s) -
Moylan Jennifer Stevenson,
Walters Andrew,
Smith Jacqueline L,
Smith Jeffrey D,
Walker Scott A,
Barger Phillip M,
Reid Michael B
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a801-d
Subject(s) - myogenesis , wortmannin , downregulation and upregulation , protein kinase b , p38 mitogen activated protein kinases , pi3k/akt/mtor pathway , ubiquitin ligase , chemistry , microbiology and biotechnology , ubiquitin , biology , endocrinology , myocyte , mapk/erk pathway , signal transduction , biochemistry , gene
TNF is implicated in chronic disease‐associated muscle wasting. Muscle protein loss results from upregulation of the ubiquitin proteaseome pathway. In this study, we examined the TNF induced events that upregulate an E3 ubiquitin ligase, Atrogin1. TNF‐induced Atrogin expression is dependent on p38 MAPK. During starvation, Atrogin regulation involves inactivation of AKT and subsequent binding of Foxo to the Atrogin promoter. To understand how the p38 MAPK and AKT/Foxo pathways interact, we treated C2C12 myotubes with TNF, TNF and SB202190 (p38 inhibitor), or Wortmannin (PI3K/AKT inhibitor) and measured Foxo DNA binding. TNF and Wortmannin induced Foxo DNA binding (2‐fold); this binding was not inhibited by SB202190. To define the p38‐dependent component of Atrogin regulation, we tested whether peroxisome proliferator‐activated receptor‐gamma co‐activator1 (PGC‐1), a p38‐dependent co‐activator of Foxo during gluconeogenesis, is activated by TNF. TNF induces a 1.4‐fold increase in PGC‐1 protein after 90 minutes; this is abolished by SB202190. Overexpression of PGC‐1 leads to a 2.6 fold increase in Atrogin mRNA and decreases total protein, myosin content and myotube size. These data suggest that TNF activates a p38/PGC‐1/Foxo cascade to drive Atrogin expression and subsequent muscle catabolism. Supported by NIH grant HL59878