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Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBP?.

ABSTRACT: Skeletal muscle atrophy is a highly-prevalent and debilitating condition that remains poorly understood at the molecular level. Previous work found that aging, fasting, and immobilization promote skeletal muscle atrophy via expression of activating transcription factor 4 (ATF4) in skeletal muscle fibers. However, the direct biochemical mechanism by which ATF4 promotes muscle atrophy is unknown. ATF4 is a member of the basic leucine zipper transcription factor (bZIP) superfamily. Because bZIP transcription factors are obligate dimers, and because ATF4 is unable to form highly-stable homodimers, we hypothesized that ATF4 may promote muscle atrophy by forming a heterodimer with another bZIP family member. To test this hypothesis, we biochemically isolated skeletal muscle proteins that associate with the dimerization- and DNA-binding domain of ATF4 (the bZIP domain) in mouse skeletal muscle fibers in vivo Interestingly, we found that ATF4 forms at least five distinct heterodimeric bZIP transcription factors in skeletal muscle fibers. Furthermore, one of these heterodimers, composed of ATF4 and CCAAT enhancer-binding protein ? (C/EBP?), mediates muscle atrophy. Within skeletal muscle fibers, the ATF4-C/EBP? heterodimer interacts with a previously unrecognized and evolutionarily conserved ATF-C/EBP composite site in exon 4 of the Gadd45a gene. This three-way interaction between ATF4, C/EBP?, and the ATF-C/EBP composite site activates the Gadd45a gene, which encodes a critical mediator of muscle atrophy. Together, these results identify a biochemical mechanism by which ATF4 induces skeletal muscle atrophy, providing molecular-level insights into the etiology of skeletal muscle atrophy.

SUBMITTER: Ebert SM

PROVIDER: S-EPMC7049960 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ.

Ebert Scott M SM Bullard Steven A SA Basisty Nathan N Marcotte George R GR Skopec Zachary P ZP Dierdorff Jason M JM Al-Zougbi Asma A Tomcheck Kristin C KC DeLau Austin D AD Rathmacher Jacob A JA Bodine Sue C SC Schilling Birgit B Adams Christopher M CM

The Journal of biological chemistry 20200117 9

Skeletal muscle atrophy is a highly-prevalent and debilitating condition that remains poorly understood at the molecular level. Previous work found that aging, fasting, and immobilization promote skeletal muscle atrophy via expression of activating transcription factor 4 (ATF4) in skeletal muscle fibers. However, the direct biochemical mechanism by which ATF4 promotes muscle atrophy is unknown. ATF4 is a member of the basic leucine zipper transcription factor (bZIP) superfamily. Because bZIP tra ...[more]

PMID: 31953319

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Project description:Age-related skeletal muscle atrophy is a debilitating condition that has significant negative impacts on health and quality of life. Despite broad clinical impact, the molecular basis of age-related skeletal muscle atrophy is not well understood. Here, we determined protein turnover rates in skeletal muscle of 22-month-old control mice and 22-month-old muscle-specific ATF4 knockout (ATF4 mKO) mice, which are partially resistant to age-related muscle atrophy. All samples were analyzed by DDA TripleTOF 6600 mass spectrometer for downstream analysis of protein turnover. Quantitative MS1 peak areas were extracted from DDA raw files in the Skyline-Daily software platform. ProteinPilot search results were imported into the Skyline software to build a spectral library, followed by import of raw MS files for extraction of chromatographic peak areas. A custom skyline report containing all peptide and protein characteristics, annotations, and quantitative information including isotopologue peak areas was exported and used for downstream analysis and calculation of protein turnover rates in R using in-house R scripts (TurnoveR tool). Precursor-pool corrected protein turnover rates were calculated using the same approach employed in previous studies using the Topograph software platform. For calculation of protein abundance changes, DIA acquisitions from six samples (3 ATF4 KO and 3 WT samples) were quantitatively processed using Spectronaut v14. Analysis of protein turnover indicates that most proteins with altered turnover rates in ATF4 mKO muscles have decreased half-lives and are components of the mitochondrion. These proteins include subunits of the ATP Synthase (Atp5b, Atp5o), Ubiquinol-Cytochrome C Reductase (Uqcrc1, Uqcrh) and Cytochrome C Oxidase (Cox6b1) complexes, among others. These findings implicate increased rates of mitochondrial protein turnover as a mechanism that underlies, at least in part, the protection from age-induced muscle atrophy in ATF4 mKO mice.

Dataset Information

Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBP?.

Publications

Activating transcription factor 4 (ATF4) promotes skeletal muscle atrophy by forming a heterodimer with the transcriptional regulator C/EBPβ.

Similar Datasets

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