HDAC9 inhibition reduces skeletal muscle atrophy and enhances regeneration in mice with cigarette smoke-induced COPD.

Abstract

Cigarette smoke (CS) is the major risk factor for chronic obstructive pulmonary disease (COPD), and sarcopenia is one of the significant comorbidities of COPD. However, the pathogenesis of CS-related deficient skeletal muscle regeneration has yet to be clarified. The impact of CS on myoblast differentiation was examined, and then we determined which HDAC influenced the myogenic process and muscle atrophy in vitro and in vivo. Finally, we further investigated the potential mechanisms via RNA sequencing. Long-term CS exposure activated skeletal muscle primary satellite cells (SCs) while inhibiting differentiation, and defective myogenesis was also observed in C2C12 cells treated with CS extract (CSE). The level of HDAC9 changed in vitro and in vivo in CS exposure models as well as COPD patients, as detected by bioinformatics analysis. Our data showed that CSE impaired myogenic capacity and myotube formation in C2C12 cells via HDAC9. Moreover, inhibition of HDAC9 in mice exposed to CS prevented skeletal muscle dysfunction and promoted SC differentiation. The results of RNA-Seq analysis and verification indicated that HDAC9 knockout improved muscle differentiation in CS-exposed mice, probably by acting on the AKT/mTOR pathway and inhibiting the P53/P21 pathway. More importantly, the serum of HDAC9 KO mice exposed to CS alleviated the differentiation impairment of C2C12 cells caused by serum intervention in CS-exposed mice, and this effect was inhibited by LY294002 (an AKT/mTOR pathway inhibitor). These results suggest that HDAC9 plays an essential role in the defective regeneration induced by chronic exposure to CS.

• Authors: Guixian Zheng, Chao Li, Xiaoli Chen, Zhaohui Deng, Ting Xie, Zengyu Huo, Xinyan Wei, Yanbing Huang, Xia Zeng, Yu Luo, Jing Bai
• Journal: Biochimica et biophysica acta. Molecular basis of disease (Biochim Biophys Acta Mol Basis Dis) Vol. 1870 Issue 3 Pg. 167023 (03 2024) ISSN: 1879-260X [Electronic] Netherlands
• PMID: 38218381 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2024. Published by Elsevier B.V.

Chemical References

• Proto-Oncogene Proteins c-akt
• TOR Serine-Threonine Kinases
• HDAC9 protein, human
• Histone Deacetylases
• Repressor Proteins

Topics

• Humans
• Animals
• Mice
• Proto-Oncogene Proteins c-akt (metabolism)
• Cigarette Smoking
• Pulmonary Disease, Chronic Obstructive (chemically induced, genetics)
• Muscular Atrophy (pathology)
• Muscle, Skeletal (metabolism)
• TOR Serine-Threonine Kinases (metabolism)
• Histone Deacetylases (genetics, metabolism)
• Repressor Proteins (metabolism)