Celecoxib alleviates denervation-induced muscle atrophy by suppressing inflammation and oxidative stress and improving microcirculation
Lilei Zhang, Ming Li, Wei Wang, Weiran Yu, Hua Liu, Kexin Wang, Mengyuan Chang, Chunyan Deng, Yanan Ji, Yuntian Shen, Lei Qi, Hualin Sun
Abstract
The molecular mechanism underlying denervation-induced muscle atrophy is complex and incompletely understood. Our previous results suggested that inflammation may play an important role in the early stages of muscle atrophy. Celecoxib is reported to exert anti-inflammatory effects. Here, we explored the effect of celecoxib on denervation-induced muscle atrophy and sought to identify the mechanism involved. We found that celecoxib treatment significantly increased the wet weight ratio and CSA of the tibialisanteriormuscle. Additionally, celecoxib downregulated the levels of COX-2, inflammatory factors and reduced inflammatory cell infiltration. GO and KEGG pathway enrichment analysis indicated that after 3 days of celecoxib treatment in vivo, the differentially expressed genes (DEGs) were mainly associated with the regulation of immune responses related to complement activation; after 14 days, the DEGs were mainly involved in the regulation of oxidative stress and inflammation-related responses. Celecoxib administration reduced the levels of ROS and oxidative stress-related proteins. Furthermore, we found that celecoxib treatment inhibited the denervation-induced up-regulation of the ubiquitin-proteasome and autophagy-lysosomal systems related proteins; decreased mitophagy in target muscles; and increased levels of MHC. Finally, celecoxib also attenuated microvascular damage in denervated skeletal muscle. Combined, our findings demonstrated that celecoxib inhibits inflammation and oxidative stress in denervated skeletal muscle, thereby suppressing mitophagy and proteolysis, improving blood flow in target muscles, and, ultimately, alleviating denervation-induced muscle atrophy. Our results confirmed that inflammatory responses play a key role in denervation-induced muscle atrophy and highlight a novel strategy for the prevention and treatment of this condition.