Biology of Activating Transcription Factor 4 (ATF4) and Its Role in Skeletal Muscle Atrophy

Abstract

Activating Transcription Factor 4 (ATF4) is a multifunctional transcription regulatory protein in the basic leucine zipper (bZIP) superfamily. ATF4 can be expressed in most if not all mammalian cell types, and it can participate in a variety of cellular responses to specific environmental stresses, intracellular derangements, or growth factors. Because ATF4 is involved in a wide range of biological processes, its roles in human health and disease are not yet fully understood. Much of our current knowledge about ATF4 comes from investigations in cultured cell models, where ATF4 was originally characterized and where further investigations continue to provide new insights. ATF4 is also an increasingly prominent topic of in vivo investigations in fully differentiated mammalian cell types, where our current understanding of ATF4 is less complete. Here, we review some important high-level concepts and questions concerning the basic biology of ATF4. We then discuss current knowledge and emerging questions about the in vivo role of ATF4 in one fully differentiated cell type, mammalian skeletal muscle fibers.

Metabolic changes in aging humans: current evidence and therapeutic strategies

“…A number of pathways have been implicated in the muscle atrophy of aging using rodent models. These include activation of activating transcription factor 4 (ATF4), which, through a complex pathway ( 94 ), appears necessary for muscle atrophy to occur with aging (mice that lack ATF4 in skeletal muscle fibers maintain muscle strength and mass into old age; ref. 95 ); and 15-hydroxyprostaglandin dehydrogenase, the prostaglandin E 2 –degrading enzyme, which, when inhibited, increased aged muscle mass, strength, and exercise performance in mice ( 96 ).…”

Activating transcription factor 4 aggravates angiotensin II-induced cell dysfunction in human vascular aortic smooth muscle cells via transcriptionally activating fibroblast growth factor 21

“…Activating transcription factor 4 (ATF4) is a multifunctional transcription regulatory protein involved in diverse biological processes in response to various stimuli [ 8 ]. It has been illustrated that metformin can induce FGF21 upregulation in an ATF4-dependent manner [ 9 ].…”

The transcription regulator ATF4 is a mediator of skeletal muscle aging

“…ATF4 is an essential subunit of at least seven different heterodimeric bZIP transcription factors that regulate gene expression in skeletal muscle fibers [ 6 , 8 , 33 ]. Thus, to begin to understand the preventive effects of ATF4 gene deletion on age-related muscle atrophy and weakness, we used RNA sequencing (RNA-seq) to assess mRNA levels in skeletal muscle from both younger (6 months old) and older (22 months old) control and ATF4 mKO mice (Table S1 ).…”

“…Although skeletal muscle aging has a significant impact on health and quality of life, its molecular mechanisms are complex, challenging, and not well understood [ 3 – 5 ]. In previous studies, we investigated the potential role of ATF4, a stress-inducible transcription regulator in the basic leucine zipper (bZIP) superfamily [ 6 , 7 ]. In skeletal muscle fibers of young adult mice (3 months old), forced expression of ATF4 is sufficient to induce skeletal muscle atrophy within one week [ 8 ].…”