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The transcription factor ATF4 promotes skeletal muscle fiber atrophy during fasting
Abstract   Open access   Peer reviewed

The transcription factor ATF4 promotes skeletal muscle fiber atrophy during fasting

Scott Matthew Ebert, Daniel K Fox, Kale S Bongers, Sharon E Malmberg and Christopher M Adams
The FASEB journal, Vol.25(S1), pp.1113.2-1113.2
04/2011
DOI: 10.1096/fasebj.25.1_supplement.1113.2
url
https://doi.org/10.1096/fasebj.25.1_supplement.1113.2View
Published (Version of record) Open Access

Abstract

Abstract only Prolonged fasting alters skeletal muscle gene expression in a manner that promotes skeletal muscle atrophy, but the underlying mechanisms are not fully understood. Here, we examined the potential role of ATF4, a transcription factor whose expression is increased in atrophying muscle. To determine if increased ATF4 expression was required for muscle fiber atrophy, we reduced ATF4 expression with an inhibitory RNA targeting ATF4, and found that it decreased fasting-induced atrophy in vivo. To determine if ATF4 was sufficient to reduce muscle fiber size, we overexpressed ATF4, and found that it reduced muscle fiber size in the absence of fasting. In contrast, a transcriptionally inactive ATF4 construct did not reduce muscle fiber size, suggesting a requirement for ATF4-mediated transcriptional regulation. To begin to determine the mechanism of ATF4-mediated atrophy, we compared the effects of fasting and ATF4 overexpression on global skeletal muscle mRNA expression. Interestingly, ATF4 increased 5 fasting-responsive mRNAs, including 4 of the 15 mRNAs most highly induced by fasting. These 5 mRNAs encode proteins previously implicated in muscle fiber atrophy including p21(Cip1/Waf1), GADD45a, PW1/Peg3, MLP, and CARP. Taken together, these data identify ATF4 as a novel mediator of skeletal muscle fiber atrophy during starvation.

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