The HDAC3 enzymatic activity regulates skeletal muscle fuel metabolism.

Abstract

Histone deacetylase 3 (HDAC3) is a major HDAC, whose enzymatic activity is targeted by small molecule inhibitors for treating a variety of conditions. However, its enzymatic activity is largely dispensable for its function in embryonic development and hepatic lipid metabolism. HDAC3 plays a pivotal role in regulating muscle fuel metabolism and contractile function. Here, we address whether these muscular functions of HDAC3 require its enzymatic activity. By mutating the NCoR/SMRT corepressors in a knock-in mouse model named NS-DADm, we ablated the enzymatic activity of HDAC3 without affecting its protein levels. Compared to the control mice, skeletal muscles from NS-DADm mice showed lower force generation, enhanced fatigue resistance, enhanced fatty acid oxidation, reduced glucose uptake during exercise, upregulated expression of metabolic genes involved in branched-chain amino acids catabolism, and reduced muscle mass during aging, without changes in the muscle fiber-type composition or mitochondrial protein content. These muscular phenotypes are similar to those observed in the HDAC3-depleted skeletal muscles, which demonstrates that, unlike that in the liver or embryonic development, the metabolic function of HDAC3 in skeletal muscles requires its enzymatic activity. These results suggest that drugs specifically targeting HDAC3 enzyme activity could be developed and tested to modulate muscle energy metabolism and exercise performance.

• Authors: Shiyang Song, Yefei Wen, Hui Tong, Emanuele Loro, Yingyun Gong, Jidong Liu, Sungguan Hong, Lei Li, Tejvir S Khurana, Maoping Chu, Zheng Sun
• Journal: Journal of molecular cell biology (J Mol Cell Biol) Vol. 11 Issue 2 Pg. 133-143 (02 01 2019) ISSN: 1759-4685 [Electronic] United States
• PMID: 30428023 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © The Author(s) (2019). Published by Oxford University Press on behalf of Journal of Molecular Cell Biology, IBCB, SIBS, CAS.

Chemical References

• Nuclear Receptor Co-Repressor 2
• Histone Deacetylases
• histone deacetylase 3

Topics

• Animals
• Energy Metabolism
• Gene Expression Regulation
• Histone Deacetylases (metabolism)
• Mice
• Muscle, Skeletal (metabolism, physiology)
• Nuclear Receptor Co-Repressor 2 (genetics, metabolism)