Cited by 130Muscle Physiology and DisordersEndoplasmic Reticulum Stress and DiseaseMuscle metabolism and nutrition

The Transcription Factor ATF4 Promotes Skeletal Myofiber Atrophy during Fasting

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Ebert, Scott M., Monteys, Alex Mas, Fox, Daniel K., Bongers, Kale S., Shields, Bridget E., Malmberg, Sharon E., Davidson, Beverly L., Suneja, Manish +1 more·2010·Molecular Endocrinology

Abstract

Prolonged fasting alters skeletal muscle gene expression in a manner that promotes myofiber atrophy, but the underlying mechanisms are not fully understood. Here, we examined the potential role of activating transcription factor 4 (ATF4), a transcription factor with an evolutionarily ancient role in the cellular response to starvation. In mouse skeletal muscle, fasting increases the level of ATF4 mRNA. To determine whether increased ATF4 expression was required for myofiber atrophy, we reduced ATF4 expression with an inhibitory RNA targeting ATF4 and found that it reduced myofiber atrophy during fasting. Likewise, reducing the fasting level of ATF4 mRNA with a phosphorylation-resistant form of eukaryotic initiation factor 2alpha decreased myofiber atrophy. To determine whether ATF4 was sufficient to reduce myofiber size, we overexpressed ATF4 and found that it reduced myofiber size in the absence of fasting. In contrast, a transcriptionally inactive ATF4 construct did not reduce myofiber size, suggesting a requirement for ATF4-mediated transcriptional regulation. To begin to determine the mechanism of ATF4-mediated myofiber atrophy, we compared the effects of fasting and ATF4 overexpression on global skeletal muscle mRNA expression. Interestingly, expression of ATF4 increased a small subset of five fasting-responsive mRNAs, including four of the 15 mRNAs most highly induced by fasting. These five mRNAs encode proteins previously implicated in growth suppression (p21(Cip1/Waf1), GADD45alpha, and PW1/Peg3) or titin-based stress signaling [muscle LIM protein (MLP) and cardiac ankyrin repeat protein (CARP)]. Taken together, these data identify ATF4 as a novel mediator of skeletal myofiber atrophy during starvation.

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Crossref · 10.1210/me.2009-0345

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Authors
Ebert, S. M., Monteys, A. M., Fox, D. K., Bongers, K. S., Shields, B. E., Malmberg, S. E., Davidson, B. L., Suneja, M., & Adams, C. M.
Affiliations
  • University of Iowa (US)
  • Iowa City VA Medical Center (US)
Corresponding author
  • Suneja, Manish
  • Adams, Christopher M.
Venue
Molecular Endocrinology
Published
2010-04
Volume
24
Issue
4
Pages
790-799
ISSN
  • 0888-8809 (ISSN-L)
  • 1944-9917
OpenAlex
W1965629756
Cited by
130
References
53
Citations by year
2026: 3 · 2025: 8 · 2024: 10 · 2023: 5 · 2022: 13 · 2021: 8 · 2020: 13 · 2019: 8 · 2018: 8 · 2017: 9 · 2016: 8 · 2015: 12 · 2014: 6 · 2013: 6 · 2012: 8
FWCI
2.34
Type
journal article
Language
en
Open access
Locations
  • Molecular Endocrinology (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • U.S. Department of Veterans Affairs (I01 BX000976)
  • National Institute of General Medical Sciences (T32GM073610, T32GM007337)
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R01AR059115)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Endoplasmic Reticulum Stress and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
Keywords
ATF4, muscle fiber atrophy, skeletal muscle, fasting, starvation response, eIF2α phosphorylation, transcriptional regulation, muscle gene expression, p21, GADD45A, muscle LIM protein, cardiac ankyrin repeat protein, growth inhibition
MeSH terms
Animals, Fasting, Male, Mice, Inbred C57BL, Muscular Atrophy, RNA, Messenger, Polymerase Chain Reaction, Muscle, Skeletal, Oligonucleotide Array Sequence Analysis, Mice, Activating Transcription Factor 4

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