In the current study, by using a well-established model of COPD with skeletal muscle dysfunction, we found that the expression of Fndc5 was downregulated, with reduced PGC-1α but increased p-Smad3 expression, in skeletal muscles from CS-exposed mice and in CSE-stimulated C2C12 myotubes, accompanied by enhanced expression of Mstn. This evidence concerns the gene SMAD3 and chronic obstructive pulmonary disease.