Atrogin-1, a muscle-specific F-box protein highly expressed during muscle atrophy

Abstract

Muscle wasting is a debilitating consequence of fasting, inactivity, cancer, and other systemic diseases that results primarily from accelerated protein degradation by the ubiquitin-proteasome pathway. To identify key factors in this process, we have used cDNA microarrays to compare normal and atrophying muscles and found a unique gene fragment that is induced more than ninefold in muscles of fasted mice. We cloned this gene, which is expressed specifically in striated muscles. Because this mRNA also markedly increases in muscles atrophying because of diabetes, cancer, and renal failure, we named it atrogin-1. It contains a functional F-box domain that binds to Skp1 and thereby to Roc1 and Cul1, the other components of SCF-type Ub-protein ligases (E3s), as well as a nuclear localization sequence and PDZ-binding domain. On fasting, atrogin-1 mRNA levels increase specifically in skeletal muscle and before atrophy occurs. Atrogin-1 is one of the few examples of an F-box protein or Ub-protein ligase (E3) expressed in a tissuespecific manner and appears to be a critical component in the enhanced proteolysis leading to muscle atrophy in diverse diseases.

The Polycomb group (PcG) protein EZH2 supports the survival of PAX3-FOXO1 alveolar rhabdomyosarcoma by repressing FBXO32 (Atrogin1/MAFbx)

“…Of note, FBXO32 derepression is associated with both a reduction in EZH2 recruitment and a decrease in H3K27me3 mark to the FBXO32 gene promoter, indicating that in our cell context EZH2 is recruited at this promoter and is enzymatically active to repress transcription, as already shown. 23,40 FBXO32, also known as Atrogin-1/MAFbx, is a musclespecific E3 ligase involved in the massive protein degradation during muscle atrophy 49 and is a FOXO1 target gene in atrophic muscle. 50 However, there is no evidence for PAX3-FOXO1 directly regulating FBXO32 from analyses of ChIPseq data.…”

Myostatin up-regulation is associated with the skeletal muscle response to hypoxic stimuli

“…In addition, at the molecular level this effect is associated with a significant induction of the MAFbx, suggesting an activation of proteasomal degradation which could contribute to a reduction in skeletal muscle mass (Gomes et al, 2001). Thus these data are in agreement with previous studies suggesting a direct effect of hypoxia per se in the induction of skeletal muscle atrophy independent of energy intake status (Bigard et al, 1996;Favier et al, 2010;Pison et al, 1998).…”

High‐Intensity Resistance Training with Insufficient Recovery Time Between Bouts Induce Atrophy and Alterations in Myosin Heavy Chain Content in Rat Skeletal Muscle

“…Although the molecular events that underlie our findings remain unknown, we think that the stimulation of a transcriptional pathway, for example, the ubiquitin-proteasomal, which promotes muscle proteolysis (Bodine et al, 2001;Gomes et al, 2001), might occur as a result of overtraining. Alternatively, the decrease in number of satellite cells during overtraining (Seene et al, 1999) could also be a determinant factor in preventing muscle fiber regeneration.…”

“…Although the mechanisms responsible for muscle atrophy are not completely defined, several factors seem to be involved; these include reduced neuromuscular activity, systemic activation of neurohormones and inflammatory cytokines (Dalla Libera et al, 2001;Filippatos et al, 2005), myostatin/follistatin imbalance (Lima et al, 2010), and ubiquitin-proteasome pathway activation (Schulze and Upä te, 2005). The ubiquitin-proteasomal pathway, which includes the muscle-specific E3 ligases, atrogin-1/muscle atrophy F-box (MAFbx), and muscle RING Finger 1 (MuRF1), is known to be a powerful contributor to muscle proteolysis (Bodine et al, 2001;Gomes et al, 2001). We did not evaluate the ubiquitin-proteasomal pathway in our study, but it is possible that this molecular pathway may be involved in the control of gene expression related to skeletal muscle atrophy that occurred in our high-intensity resistance training and insufficient recovery time model.…”