Introduction: Skeletal muscle dysfunction (SKD) is a common comorbidity of COPD, and significantly affects disease severity, hospitalization and fatality. However, the underlying mechanisms linking COPD and SKD remain obscure. As skeletal muscle secretes lots of myokines to exert physiological and pathological effects, we delineated the profile of myokines related to COPD to identify potentially key molecules for further study.

Methods: We performed RNA-seq of muscles from mice model of COPD and COPD patients. Immunofluorescence staining was performed on myokines in muscles from our COPD mice. In vitro, we induced C2C12 myoblasts to myotubes, stimulated them with cigarette smoke extract (CSE), and evaluated the expression of myokines by RT-PCR.

Results: RNA-seq analysis revealed that fibronectin type III domain-containing 5 (Fndc5), Metrnl, and decorin (Dcn) were downregulated, and Fndc5 was correlated negatively with insulin-like growth factor (Igf)-1, transforming growth factor-?1, interleukin (Il)-7, and leukemia inhibitory factor, but positively with Il-15, Metrnl, Dcn, and brain-derived neurotrophic factor (Bdnf) in COPD mouse models. FNDC5 was decreased in COPD patients, while MSTN was increased and correlated positively with IL-6 and IL-7, but negatively with IGF-1, BDNF, and follistatin-like protein-1. In addition, MSTN was decreased in exercise-trained COPD patients, and low BMI was associated with lower MSTN and higher DCN in COPD patients both with and without exercise training. In vitro, the changes of myokines in myotubes treated with CSE were similar to those in vivo.

Discussion: Myokines are dysregulated in muscles from COPD, while exercise may improve muscle function by affecting MSTN expression.