scholarly journals Induction of autophagy through the activating transcription factor 4 (ATF4)-dependent amino acid response pathway in maternal skeletal muscle may function as the molecular memory in response to gestational protein restriction to alert offspring to maternal nutrition

2015 ◽  
Vol 114 (4) ◽  
pp. 519-532 ◽  
Author(s):  
Huan Wang ◽  
Gabriel J. Wilson ◽  
Dan Zhou ◽  
Stéphane Lezmi ◽  
Xiuwen Chen ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Amino Acid ◽  
Protein Expression ◽  
Mrna Expression ◽  
Protein Restriction ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Transcription Factor 4

The aim of the present study was to investigate the mechanistic basis of protein deficiency during pregnancy in mother that is transduced to offspring. To this end, timed-pregnant Sprague–Dawley rats were fed either a control (20 % of energy from protein) or low-protein (LP, 8 % of energy from protein) diet during gestation. Tissues were collected after delivery from rat dams, and skeletal muscle was collected at postnatal day 38 from the offspring. Quantitative RT-PCR and Western blot analyses were performed to determine mRNA and protein levels. Histological analysis was performed to evaluate myofibre size. LP dams gained significantly less weight during pregnancy, developed muscle atrophy, and had significantly lower circulating threonine and histidine levels than control dams. The mRNA expression of the well-known amino acid response (AAR) pathway-related target genes was increased only in the skeletal muscle of LP dams, as well as the protein expression levels of activating transcription factor 4 (ATF4) and phosphorylated eukaryotic translation initiation factor 2α (p-eIF2α). The mRNA expression of autophagy-related genes was significantly increased in the skeletal muscle of LP dams. Moreover, the mRNA expression of genes involved in both AAR and autophagy pathways remained elevated and was memorised in the muscle of LP offspring that consumed a post-weaning control diet. Additionally, the LP diet increased an autophagy marker, microtubule-associated proteins 1A/1B light chain 3B (LC3B) protein expression in the skeletal muscle of rat dams, consistent with the initiation of autophagy. The LP diet further increased ATF4 binding at the predicted regions of AAR and autophagy pathway-related genes. Increased binding of ATF4 unveils the crucial role of ATF4 in the activation of autophagy in response to protein restriction. Our data suggest that molecular changes in maternal muscle are memorised in the offspring long after gestational protein restriction, reinforcing the role of maternal signalling in programming offspring health.

scholarly journals Role of activating transcription factor 4 in the hepatic response to amino acid depletion by asparaginase

2017 ◽  
Vol 7 (1) ◽  
Author(s):  
Rana J. T. Al-Baghdadi ◽  
Inna A. Nikonorova ◽  
Emily T. Mirek ◽  
Yongping Wang ◽  
Jinhee Park ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Amino Acid ◽  
Activating Transcription Factor 4 ◽  
Amino Acid Depletion ◽  
Activating Transcription Factor ◽  
Transcription Factor 4

Activating transcription factor 4-dependent induction of FGF21 during amino acid deprivation

2012 ◽  
Vol 443 (1) ◽  
pp. 165-171 ◽  
Author(s):  
Ana Luísa De Sousa-Coelho ◽  
Pedro F. Marrero ◽  
Diego Haro
Keyword(s):  
Transcription Factor ◽  
Amino Acid ◽  
Initiation Factor ◽  
Nutrient Deprivation ◽  
Fibroblast Growth Factor 21 ◽  
Amino Acid Deprivation ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Transcription Factor 4 ◽  
Human Fgf21

Nutrient deprivation or starvation frequently correlates with amino acid limitation. Amino acid starvation initiates a signal transduction cascade starting with the activation of the kinase GCN2 (general control non-derepressible 2) phosphorylation of eIF2 (eukaryotic initiation factor 2), global protein synthesis reduction and increased ATF4 (activating transcription factor 4). ATF4 modulates a wide spectrum of genes involved in the adaptation to dietary stress. The hormone FGF21 (fibroblast growth factor 21) is induced during fasting in liver and its expression induces a metabolic state that mimics long-term fasting. Thus FGF21 is critical for the induction of hepatic fat oxidation, ketogenesis and gluconeogenesis, metabolic processes which are essential for the adaptive metabolic response to starvation. In the present study, we have shown that FGF21 is induced by amino acid deprivation in both mouse liver and cultured HepG2 cells. We have identified the human FGF21 gene as a target gene for ATF4 and we have localized two conserved ATF4-binding sequences in the 5′ regulatory region of the human FGF21 gene, which are responsible for the ATF4-dependent transcriptional activation of this gene. These results add FGF21 gene induction to the transcriptional programme initiated by increased levels of ATF4 and offer a new mechanism for the induction of the FGF21 gene expression under nutrient deprivation.

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

2020 ◽  
Vol 295 (9) ◽  
pp. 2787-2803 ◽  
Author(s):  
Scott M. Ebert ◽  
Steven A. Bullard ◽  
Nathan Basisty ◽  
George R. Marcotte ◽  
Zachary P. Skopec ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Transcription Factor ◽  
Muscle Atrophy ◽  
Molecular Level ◽  
Muscle Fibers ◽  
Skeletal Muscle Atrophy ◽  
Skeletal Muscle Fibers ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Transcription Factor 4

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 β (C/EBPβ), mediates muscle atrophy. Within skeletal muscle fibers, the ATF4–C/EBPβ 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/EBPβ, 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.

Role of Activating Transcription Factor-4 in 24-Hour Rhythm of Serotonin Transporter Expression in the Mouse Midbrain

2012 ◽  
Vol 82 (2) ◽  
pp. 264-270 ◽  
Author(s):  
Kentarou Ushijima ◽  
Satoru Koyanagi ◽  
Yuuki Sato ◽  
Takamitsu Ogata ◽  
Naoya Matsunaga ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Serotonin Transporter ◽  
Activating Transcription Factor 4 ◽  
Activating Transcription Factor ◽  
Transcription Factor 4 ◽  
Transporter Expression
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