We also demonstrated that CSE led to an increase in Mstn expression by enhanced p-Erk1/2, and Mstn further inhibited Fndc5/irisin expression by the p-Smad3/PGC-1α pathway, which may play a critical role in accelerating the development of skeletal muscle dysfunction in COPD, revealing a novel regulating mechanism of myokines in the pathogenesis of the skeletal muscle comorbidity of COPD (Figure 6). Here, FNDC5 is linked to chronic obstructive pulmonary disease.