Regulation of autophagy and the ubiquitin–proteasome system by the FoxO transcriptional network during muscle atrophy

Abstract

Stresses like low nutrients, systemic inflammation, cancer or infections provoke a catabolic state characterized by enhanced muscle proteolysis and amino acid release to sustain liver gluconeogenesis and tissue protein synthesis. These conditions activate the family of Forkhead Box (Fox) O transcription factors. Here we report that muscle-specific deletion of FoxO members protects from muscle loss as a result of the role of FoxOs in the induction of autophagy–lysosome and ubiquitin–proteasome systems. Notably, in the setting of low nutrient signalling, we demonstrate that FoxOs are required for Akt activity but not for mTOR signalling. FoxOs control several stress–response pathways such as the unfolded protein response, ROS detoxification, DNA repair and translation. Finally, we identify FoxO-dependent ubiquitin ligases including MUSA1 and a previously uncharacterised ligase termed SMART (Specific of Muscle Atrophy and Regulated by Transcription). Our findings underscore the central function of FoxOs in coordinating a variety of stress-response genes during catabolic conditions.

Muscle Wasting in Fasting Requires Activation of NF-κB and Inhibition of AKT/Mechanistic Target of Rapamycin (mTOR) by the Protein Acetylase, GCN5

“…Interestingly, in knock-out mice lacking all three FoxOs (1, 3, and 4) in their muscles, the activities of AKT and mTOR were reduced in both fed and fasted conditions, whereas AMPK activity was stimulated (36). In light of our findings upon inhibition of NF-B (Figs.…”

Preventive Effects of the Dietary Intake of Medium-chain Triacylglycerols on Immobilization-induced Muscle Atrophy in Rats

“…These results suggest that the preventive effects of MCTs on muscle atrophy are mediated, at least in part, by inhibition of the ubiquitin-proteasome pathway. The FoxO and NF-κB transcription factors are reported to be involved in the regulation of MuRF-1 gene expression in disuse-induced muscle atrophy 21,22 . To further elucidate the mechanism underlying the suppression of MuRF-1 expression by MCTs, we determined FoxO3a and p50 NF-κB1 protein levels in the soleus muscle.…”

“…tor-kappa B NF-κB are important signaling pathways that are involved in the regulation of MuRF-1 expression and muscle atrophy 21,22 . To elucidate the underlying mechanisms by which MCTs suppressed MuRF-1 content in immobilized soleus muscle, we determined the protein levels of the transcription factors FoxO3a and p50 NF-κB1 , which are upregulated during skeletal muscle atrophy 10,23 .…”

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

“…The tools for such discovery are largely at hand, so we can expect more refined models of the mechanisms of muscle wasting in the near future. Some genes such as the ligases Fbxo21/SMART (70) and Fbxo30/MUSA (91) are clearly involved based on loss-of-function studies, but their mechanisms of action remain to be reported. Although some signaling pathways, such as that activated by glucocorticoids, can regulate several UPS genes, there is no apparent pathway that coordinately regulates all or most of the currently known essential genes involved in this process.…”

“…Importantly, Akt also phosphorylates FoxO transcription factors, resulting in their cytoplasmic sequestration and thereby inhibiting the transcription of their target genes. Prominent examples of these target genes are the ubiquitin ligases MuRF1, atrogin-1, Fbxo30/MUSA1, Fbxo21/ SMART, Fbxo31, Ube4b, USP14, and the ubiquitin gene UBC, some proteasome subunits, as well as many autophagy genes (70). This pathway can also modulate myogenesis in a GSK3b-dependent mechanism (109) and regulate the expression of myogenin (26,121).…”