Sarcopenia in Chronic Obstructive Pulmonary Disease (COPD) is a prevalent and severe comorbidity, defined as loss of both muscle mass and force, and lacking effective treatment. The implication of both the chemokine receptor CXCR4 and its ligand CXCL12 has been suggested in COPD. Our goal was to study its implication in skeletal muscle dysfunction in a murine model of early COPD. C57BL/6 mice were exposed for ten weeks to cigarette smoke (CS) and intranasal instillations of poly-IC to mimick exacerbations. A conditional inactivation of CXCR4 was also generated via a tamoxifen-inducible Cre/Lox system in CS-exposed mice. Skeletal muscle function was assessed and skeletal muscle tissues were harvested for histological and proteomic analysis. CS-exposed mice displayed no evidence of decreased force or muscular atrophy compared to control mice, but their resistance to fatigue, assessed by the hanging test, was significantly decreased, and this was attenuated in the CXCR4-/- exposed group. Analysis of the soleus muscle showed a metabolic switch from oxidative to glycolytic myofibers in the exposed group, which was reversed in the CXCR4-/- exposed mice. Capillarization in the quadriceps muscle showed a similar tendency. Proteomic and transcriptomic analysis showed a dysregulation in mitochondrial proteins as well as inflammation in the CS group. These results provide a framework to study the CXCL12/CXCR4 axis and implicated cells in COPD skeletal muscle dysfunction.