Exercise-induced skeletal muscle remodeling is influenced by immune signaling, but this mechanism is altered in type 2 diabetes. The European Association for the Study of Diabetes (EASD) 2025 study investigated how the hypoxia-responsive chemokine CXCL12 (SDF-1) regulates muscle adaptation post-exercise in people with type 2 diabetes and healthy controls.

Twenty-seven individuals with type 2 diabetes and 20 with normal glucose tolerance performed 30 minutes of high-intensity cycling. Plasma CXCL12 levels were measured before, immediately after, and three hours post-exercise. In parallel, mice were exposed to hindlimb hypoxia, with or without CXCR4 (CXCL12 receptor) inhibition, and cultured muscle cells were treated with recombinant CXCL12 or CXCR4 silencing to evaluate myogenic gene expression.

Results showed that individuals with normal glucose tolerance had higher baseline and post-exercise CXCL12 levels, while those with type 2 diabetes displayed a blunted response. CXCL12 positively correlated with lean mass and negatively with insulin resistance. In vivo and in vitro models demonstrated that CXCL12/CXCR4 signaling influenced vascular growth and muscle differentiation under hypoxic conditions.

These findings suggest that targeting the CXCL12/CXCR4 axis may enhance exercise-induced skeletal muscle remodeling in type 2 diabetes, potentially improving metabolic and functional outcomes.