RANKL Mediates Muscle Atrophy and Dysfunction in a Cigarette Smoke–induced Model of Chronic Obstructive Pulmonary Disease
| Autor: | Yuhan Hu, Yanqing Le, Yongchang Sun, Jing Xiong, Yafei Rao, Suliang Guo, Lu Zhou |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
musculoskeletal diseases
0301 basic medicine Pulmonary and Respiratory Medicine medicine.medical_specialty Clinical Biochemistry Myostatin 03 medical and health sciences 0302 clinical medicine Atrophy Osteoclast Internal medicine medicine Molecular Biology Myogenin biology Myogenesis business.industry Skeletal muscle Cell Biology medicine.disease Muscle atrophy 030104 developmental biology Endocrinology medicine.anatomical_structure 030228 respiratory system RANKL biology.protein medicine.symptom business |
| Zdroj: | American Journal of Respiratory Cell and Molecular Biology. 64:617-628 |
| ISSN: | 1535-4989 1044-1549 |
| DOI: | 10.1165/rcmb.2020-0449oc |
| Popis: | Skeletal muscle dysfunction is one of the important comorbidities of chronic obstructive pulmonary disease (COPD); however, the underlying mechanisms remain largely unknown. RANKL (receptor activator of nuclear factor κB ligand), 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 as-of-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 and atrogin-1), and the NF-κb inflammatory pathway were also evaluated in skeletal muscles. The effect of CS extract on RANKL/RANK expression and that of exogenous RANKL on the 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 expression 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 the NF-κb pathway in skeletal muscles from CS-exposed mice. In in vitro experiments with C2C12 myotubes, CS extract induced expression of RANKL/RANK, and exogenous RANKL induced activation of the 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. |
| Databáze: | OpenAIRE |
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