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

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 ß (C/EBPß), mediates muscle atrophy. Within skeletal muscle fibers, the ATF4-C/EBPß 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/EBPß, 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.

An investigation of p53 in skeletal muscle aging.

Age-related skeletal muscle atrophy is a very common and serious condition that remains poorly understood at the molecular level. Several lines of evidence have suggested that the tumor suppressor p53 may play a central, causative role in skeletal muscle aging, whereas other, apparently contradictory lines of evidence have suggested that p53 may be critical for normal skeletal muscle function. To help address these issues, we performed an aging study in male muscle-specific p53-knockout mice (p53 mKO mice), which have a lifelong absence of p53 expression in skeletal muscle fibers. We found that the absence of p53 expression in skeletal muscle fibers had no apparent deleterious or beneficial effects on skeletal muscle mass or function under basal conditions up to 6 mo of age, when mice are fully grown and exhibit peak muscle mass and function. Furthermore, at 22 and 25 mo of age, when age-related muscle weakness and atrophy are clearly evident in mice, p53 mKO mice demonstrated no improvement or worsening of skeletal muscle mass or function relative to littermate control mice. At advanced ages, p53 mKO mice began to die prematurely and had an increased incidence of osteosarcoma, precluding analyses of muscle mass and function in very old p53 mKO mice. In light of these results, we conclude that p53 expression in skeletal muscle fibers has minimal if any direct, cell autonomous effect on basal or age-related changes in skeletal muscle mass and function up to at least 22 mo of age.NEW & NOTEWORTHY Previous studies implicated the transcriptional regulator p53 as a potential mediator of age-related skeletal muscle weakness and atrophy. We tested this hypothesis by investigating the effect of aging in muscle-specific p53-knockout mice. Our results strongly suggest that p53 activity within skeletal muscle fibers is not required for age-related skeletal muscle atrophy or weakness.

Skeletal Muscle Atrophy: Discovery of Mechanisms and Potential Therapies.

Skeletal muscle atrophy proceeds through a complex molecular signaling network that is just beginning to be understood. Here, we discuss examples of recently identified molecular mechanisms of muscle atrophy and how they highlight an immense need and opportunity for focused biochemical investigations and further unbiased discovery work.

Use of bone age for evaluating bone density in patients with Duchenne muscular dystrophy: A preliminary report.

INTRODUCTION: Patients with Duchenne muscular dystrophy (DMD) exhibit low bone mineral density and increased fracture risk. Because glucocorticoid therapy results in delayed puberty and short stature, it is important to account for delayed skeletal development when interpreting patients' bone mineral density. METHODS: Twelve glucocorticoid-treated patients with DMD were evaluated by dual x-ray absorptiometry scans and wrist x-rays to estimate bone density and bone age, respectively. Z-scores were determined on the basis of chronological age. Each patient was assigned a "corrected" birth date that was calculated according to bone age, and a bone-age-corrected z-score was determined. RESULTS: Z-scores adjusted for chronological age were lower than those adjusted for bone age. DISCUSSION: We suggest the use of bone age as an alternative to chronological age for analysis of bone mineral density in glucocorticoid-treated patients with DMD. Additional research is required to determine the optimal method to predict fracture risk in this patient group. Muscle Nerve 59:422-425, 2019.