TY - JOUR TI - RANKL Mediates Muscle Atrophy and Dysfunction in a Cigarette Smoke-induced Model of COPD AU - Xiong, Jing AU - Le, Yanqing AU - Rao, Yafei AU - Zhou, Lu AU - Hu, Yuhan AU - Guo, Suliang AU - Sun, Yongchang T2 - American Journal of Respiratory Cell and Molecular Biology AB - Skeletal muscle dysfunction is one of the important comorbidities of COPD, however the underlying mechanisms remain largely unknown. RANKL, a key mediator in osteoclast differentiation, was also found to play a role in skeletal muscle pathogenesis. Whether RANKL is involved in COPD-related skeletal muscle dysfunction is yet unknown. We examined the expression of RANKL/RANK in skeletal muscles from mice exposed to cigarette smoke (CS) for 24 weeks. Grip strength and exercise capacity as well as muscular morphology were evaluated in CS-exposed mice with or without anti-RANKL treatment. The expressions of protein-synthesis or muscle-growth related molecules (IGF-1, myogenin, and myostatin), muscle specific ubiquitin E3 ligases (MuRF1, Atrogin1), and NF-κb inflammatory pathway were also evaluated in skeletal muscles. The effect of CS extract (CSE) on RANKL/RANK expression and that of exogenous RANKL on ubiquitin-proteasome pathway in C2C12 myotubes were investigated in vitro. Long-term CS exposure induced skeletal muscle dysfunction and atrophy, together with upregulation of RANKL/RANK expressions in a well-established mouse model of COPD. RANKL neutralization prevented skeletal muscle dysfunction and atrophy. RANKL inhibition decreased expressions of myostatin and MuRF1/Atrogin1, and suppressed NF-κb pathway in skeletal muscles from CS-exposed mice. In in vitro experiments with C2C12 myotubes, CSE induced expression of RANKL/RANK, and exogenous RANKL induced activation of ubiquitin-proteasome pathway and NF-κb pathway via RANK. Our results revealed an important role of the RANKL/RANK pathway in muscle atrophy induced by CS exposure, suggesting that RANKL may be a potential therapeutic target in COPD-related skeletal muscle dysfunction. DA - 2021/03/09/ PY - 2021 DO - 10.1165/rcmb.2020-0449OC DP - atsjournals.org (Atypon) J2 - Am J Respir Cell Mol Biol SN - 1044-1549 UR - https://www.atsjournals.org/doi/10.1165/rcmb.2020-0449OC Y2 - 2021/03/12/05:56:25 ER -