Histone Deacetylase 6 Is a FoxO Transcription Factor-dependent Effector in Skeletal Muscle Atrophy

Ratti, Francesca; Ramond, Francis; Moncollin, Vincent; Simonet, Thomas; Milan, Giulia; Méjat, Alexandre; Thomas, Jean; Streichenberger, Nathalie; Gilquin, Benoît; Matthias, Patrick; Khochbin, Saadi; Sandri, Marco; Schaeffer, Laurent

doi:10.1074/jbc.m114.600916

Cited by 39 publications

(33 citation statements)

References 37 publications

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“…Furthermore, it has been reported that HDAC6 is not a traditional deacetylation enzyme, and it is directly involved in the protein ubiquitin-proteasome degradation pathway though via its ubiquitin connecting region. HDAC6 is able to interact with atrogin-1 and regulate FOXO protein ubiquitination (117). This finding further demonstrates that FOXO proteins are regulated by acetylation and ubiquitination.…”

Section: Ubiquitination Of Foxo Proteinsmentioning

confidence: 55%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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Abstract. The Forkhead box O (FOXO) protein family is predominantly involved in apoptosis, oxidative stress, DNA damage/repair, tumor angiogenesis, glycometabolism, regulating life span and other important biological processes. Its activity is affected by a variety of posttranslational modifications (PTMs), including phosphorylation, acetylation, ubiquitination, methylation and glycosylation. When cells are subjected to different environments, the corresponding PTMs act on the FOXO protein family, to change transcriptional activity or subcellular localization, and the expression of downstream target genes, will ultimately affect the biological behavior of the cells. In this review, we will discuss the biological characteristics of FOXO protein PTMs.

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Section: Ubiquitination Of Foxo Proteinsmentioning

confidence: 55%

Post-translational modifications of FOXO family proteins

Wang

Huang

2016

Molecular Medicine Reports

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“…Given the role of increased protein turnover in the regulation of skeletal muscle atrophy, it is perhaps not surprising that several HDAC proteins were recently identified to regulate the muscle atrophy process. Indeed, HDACs 1, 4, 5 and 6 are independently required for skeletal muscle atrophy in response to cast immobilization, denervation and /or chronic angiotensin II signaling [ 9 – 12 , 16 ]. However, despite this knowledge, our understanding of the skeletal muscle proteins modified through lysine acetylation/deacetylation during atrophying conditions remains extremely limited.…”

Section: Introductionmentioning

confidence: 99%

Identification of the Acetylation and Ubiquitin-Modified Proteome during the Progression of Skeletal Muscle Atrophy

et al. 2015

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Skeletal muscle atrophy is a consequence of several physiological and pathophysiological conditions including muscle disuse, aging and diseases such as cancer and heart failure. In each of these conditions, the predominant mechanism contributing to the loss of skeletal muscle mass is increased protein turnover. Two important mechanisms which regulate protein stability and degradation are lysine acetylation and ubiquitination, respectively. However our understanding of the skeletal muscle proteins regulated through acetylation and ubiquitination during muscle atrophy is limited. Therefore, the purpose of the current study was to conduct an unbiased assessment of the acetylation and ubiquitin-modified proteome in skeletal muscle during a physiological condition of muscle atrophy. To induce progressive, physiologically relevant, muscle atrophy, rats were cast immobilized for 0, 2, 4 or 6 days and muscles harvested. Acetylated and ubiquitinated peptides were identified via a peptide IP proteomic approach using an anti-acetyl lysine antibody or a ubiquitin remnant motif antibody followed by mass spectrometry. In control skeletal muscle we identified and mapped the acetylation of 1,326 lysine residues to 425 different proteins and the ubiquitination of 4,948 lysine residues to 1,131 different proteins. Of these proteins 43, 47 and 50 proteins were differentially acetylated and 183, 227 and 172 were differentially ubiquitinated following 2, 4 and 6 days of disuse, respectively. Bioinformatics analysis identified contractile proteins as being enriched among proteins decreased in acetylation and increased in ubiquitination, whereas histone proteins were enriched among proteins increased in acetylation and decreased in ubiquitination. These findings provide the first proteome-wide identification of skeletal muscle proteins exhibiting changes in lysine acetylation and ubiquitination during any atrophy condition, and provide a basis for future mechanistic studies into how the acetylation and ubiquitination status of these identified proteins regulates the muscle atrophy phenotype.

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“…These observations are in agreement with previous reports showing that HDAC4 and HDAC6 contribute to the regulation of skeletal muscle mass. Overexpression of the former, in particular, has been shown to result in reduced myofiber cross sectional area [37], while its ablation improves phenotype in denervated muscles [37] [38].Similarly, HDAC6 is overexpressed during muscle atrophy and its inactivation has been shown to protect against denervation-induced muscle atrophy [39]. HDACs have also been proposed to play a role in the regulation of atrogene expression, such as the muscle-specific ubiquitin ligases MurF1 and atrogin1/MAFbx, acting on two transcription factors that are relevant to muscle atrophy, namely myogenin and FoxOs.…”

Section: Hdacs In the Skeletal Musclementioning

confidence: 99%

“…Indeed, while acetylated FoxO3 is translocated from the nucleus to the cytoplasm and subsequently degraded, its deacetylation results in increased transcriptional activity [40]. Another feed-forward mechanism also occurs, HDAC6 expression in atrophic muscles being regulated by FoxO3 [39]. Myogenin, one of the muscle regulatory factors overexpressed in late myogenesis, also participates to the induction of atrogin1/MAFbx during denervation, with a mechanism that requires HDAC4 [38].…”

Section: Hdacs In the Skeletal Musclementioning

confidence: 99%

New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia

Penna

Costelli

2018

Expert Opinion on Investigational Drugs

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Introduction: Cachexia is a frequent feature of chronic diseases. This syndrome includes loss of body weight, depletion of skeletal muscle mass and altered metabolic homeostasis. Acceleration of protein and energy metabolism, impaired myogenesis and systemic inflammation contribute to cachexia. Its occurrence impinges on treatment tolerance as well as on patient quality of life, however, no effective therapy is still available. Areas covered in this review: This review will focus on the use of histone deacetylase inhibitors as pharmacological tools to prevent/delay cachexia, with particular reference to muscle wasting. Expert opinion: Besides their interference with histone acetylation, novel histone deacetylase inhibitors could be considered as exercise mimetics, supporting their use to treat muscle wastingassociated diseases such as cachexia. In addition, the ability displayed by some of these inhibitors in modulating the release of extracellular vesicles from tumor cells might be an interesting tool to interfere with the development of cancer-induced muscle protein depletion. At present there are few clinical trials testing histone deacetylase inhibitors to treat cachexia, reflecting the lack of robust experimental evidence of effectiveness. Further investigation uncovering the pathogenic mechanisms of muscle wasting coupled with the identification of suitable histone deacetylase inhibitors targeting such alterations is needed.

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Histone Deacetylase 6 Is a FoxO Transcription Factor-dependent Effector in Skeletal Muscle Atrophy

Cited by 39 publications

References 37 publications

Post-translational modifications of FOXO family proteins

Post-translational modifications of FOXO family proteins

Identification of the Acetylation and Ubiquitin-Modified Proteome during the Progression of Skeletal Muscle Atrophy

New developments in investigational HDAC inhibitors for the potential multimodal treatment of cachexia

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