Excessive Secretion of IL-8 by Skeletal Muscle in Type 2 Diabetes Impairs Tube Growth: Potential Role of PI3K and the Tie2 Receptor

Reduced capillary density is a feature of skeletal muscle (SkM) in type 2 diabetes (T2D), which is associated with multiple metabolic and functional abnormalities. SkM has been identified as a secretory tissue, releasing myokines that regulate multiple processes, including vascularization. We sought to determine how myokines secreted from T2D myotubes might influence SkM angiogenesis. Conditioned media (CM) were generated by myotubes from T2D and nondiabetic (ND) subjects. Primary human endothelial cells (HUVEC) and SkM explants were exposed to CM or recombinant myokines, and tube number or capillary outgrowth was determined as well as measurement of protein expression and phosphorylation. CM from ND myotubes stimulated tube formation of HUVEC to a greater extent than T2D myotubes (T2D-CM = 100%, ND-CM = 288 ± 90% after 48 h, P < 0.05). The effects of T2D myotube CM were mediated by IL-8, not IL-15 or GROα, and were due not to cell damage but rather through regulating tube production and maintenance (response to T2D-IL-8 = 100%, response to ND-IL-8 = 263 ± 46% after 48 h, P < 0.05). A similar effect was seen in SkM explants with exposure to IL-8. The dose-dependent effect of IL-8 on tube formation was also observable in the PI3K and FAK signaling pathways and mediated at least in part by PI3K, leading to regulation of Tie2 expression. These results suggest that elevated levels of IL-8 secreted from T2D myotubes create a muscle microenvironment that supports reduced capillarization in T2D. Impaired vascularization of SkM limits the availability of substrates, including glucose and contributes to the T2D phenotype.