Histone deacetylase 6 is a FoxO transcription factor-dependent effector in skeletal muscle atrophy.

Abstract

Skeletal muscle atrophy is a severe condition of muscle mass loss. Muscle atrophy is caused by a down-regulation of protein synthesis and by an increase of protein breakdown due to the ubiquitin-proteasome system and autophagy activation. Up-regulation of specific genes, such as the muscle-specific E3 ubiquitin ligase MAFbx, by FoxO transcription factors is essential to initiate muscle protein ubiquitination and degradation during atrophy. HDAC6 is a particular HDAC, which is functionally related to the ubiquitin proteasome system via its ubiquitin binding domain. We show that HDAC6 is up-regulated during muscle atrophy. HDAC6 activation is dependent on the transcription factor FoxO3a, and the inactivation of HDAC6 in mice protects against muscle wasting. HDAC6 is able to interact with MAFbx, a key ubiquitin ligase involved in muscle atrophy. Our findings demonstrate the implication of HDAC6 in skeletal muscle wasting and identify HDAC6 as a new downstream target of FoxO3a in stress response. This work provides new insights in skeletal muscle atrophy development and opens interesting perspectives on HDAC6 as a valuable marker of muscle atrophy and a potential target for pharmacological treatments.

• Authors: Francesca Ratti, Francis Ramond, Vincent Moncollin, Thomas Simonet, Giulia Milan, Alexandre Méjat, Jean-Luc Thomas, Nathalie Streichenberger, Benoit Gilquin, Patrick Matthias, Saadi Khochbin, Marco Sandri, Laurent Schaeffer
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 290 Issue 7 Pg. 4215-24 (Feb 13 2015) ISSN: 1083-351X [Electronic] United States
• PMID: 25516595 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

Chemical References

• FOXO3 protein, human
• Forkhead Box Protein O3
• Forkhead Transcription Factors
• FoxO3 protein, mouse
• RNA, Messenger
• RNA, Small Interfering
• Cre recombinase
• Integrases
• HDAC6 protein, human
• Histone Deacetylase 6
• Histone Deacetylases

Topics

• Animals
• Blotting, Western
• Cells, Cultured
• Chromatin Immunoprecipitation
• Electrophoretic Mobility Shift Assay
• Forkhead Box Protein O3
• Forkhead Transcription Factors (genetics, metabolism)
• Gene Expression Regulation
• Histone Deacetylase 6
• Histone Deacetylases (chemistry, genetics, metabolism)
• Humans
• Immunoprecipitation
• Integrases (metabolism)
• Mice
• Mice, Knockout
• Muscle Denervation
• Muscle, Skeletal (metabolism, pathology)
• Muscular Atrophy (genetics, metabolism, pathology)
• RNA, Messenger (genetics)
• RNA, Small Interfering (genetics)
• Real-Time Polymerase Chain Reaction
• Reverse Transcriptase Polymerase Chain Reaction