COPD is been increasingly recognised as a systemic disease, where comorbidities play a major role. Among them, conditions affecting the musculoskeletal system such as sarcopenia and osteoporosis, are associated with decreased quality of life and higher mortality [1Zhang L., Sun Y. Muscle-bone crosstalk in chronic obstructive pulmonary disease Front Endocrinol (Lausanne) 2021 ;  12 : 724911

Cliccare qui per andare alla sezione Riferimenti]. Although the histological abnormalities of sarcopenia are well-characterized, including myofibers atrophy, decreased capillarization and metabolic switch from oxidative phosphorylation to glycolysis, the relative contribution of these processes, as well as the molecular determinants are not fully understood. The expression of both the chemokine receptor CXCR4 and its ligand CXCL12 has been shown to be altered in COPD patients, potentially affecting immune cells recruitment such as neutrophils and fibrocytes [2Henrot P., Prevel R., Berger P., Dupin I. Chemokines in COPD: from implication to therapeutic use Int J Mol Sci 2019 ;  20 : 2785 [cross-ref]

Cliccare qui per andare alla sezione Riferimenti]. Our goal was to study the implication of the CXCR4/CXCL12 axis in sarcopenia and osteoporosis in a previously validated murine model of COPD.

C57BL/6 mice were exposed for ten weeks to cigarette smoke (CS) and intranasal instillations of poly-IC to mimick exacerbations. Airway obstruction and peribronchial remodelling was confirmed as previously shown (unpublished data). A conditional inactivation of CXCR4 (CXCR4-/- mice) 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. Bone density was evaluated with micro-CT of the proximal region of the tibia in harvested bone samples.

CS-exposed mice displayed no evidence of decreased force or muscular atrophy compared to control mice, but their endurance, assessed by the hanging test, was significantly decreased. CXCR4 deletion attenuated CS-induced muscle dysfunction (Fig. 1A). Histological and proteomic analysis in the quadriceps muscle, composed of both oxidative and glycolytic fibres, showed no difference in the metabolic profile of myofibres between the three groups; however, there was a decreased capillarization in the exposed group, which was reversed in the CXCR4-/- exposed mice. Moreover, analysis of the soleus muscle, exclusively composed of oxidative fibers, showed a metabolic switch from oxidative phosphorylation to glycolysis in the exposed group (Fig. 1B), as well as a tendency to decreased capillarization, which were both reversed in the CXCR4-/- exposed mice. There was no significant difference in bone density between the three groups.

We observed a decreased endurance in an early COPD mouse model, attributed to a metabolic switch of myofibres, and prevented by inactivation of the CXCR4 chemokine receptor. These results provide a framework to study the CXCR4/CXCL12 axis and implicated cells in COPD sarcopenia.