To clarify the preventive effects of low-current electrical stimulation (ES) under blood flow restriction (Bfr) on diabetes-associated capillary regression in skeletal muscles, we assessed the changes in three-dimensional capillary architecture and angiogenic factors. Twenty-four Goto-Kakizaki rats were randomly divided into four groups: the sedentary diabetes mellitus (DM), Bfr (DM + Bfr), electrical stimulation (DM + ES), and Bfr plus ES (DM + Bfr + ES) groups. Six healthy Wistar rats were used as age-matched controls. Bfr was performed using pressure cuffs (80 mmHg) around the thighs of the rats, and low-current ES was applied to the calf muscles of the rats. The current intensity was set at 30% of the maximal isometric contraction (24-30 mA). The treatments were delivered three times a week for 8 wk. In the DM group, the capillary diameter and volume of the soleus muscle decreased, and, the antiangiogenic factor level increased. Furthermore, DM caused an increase in the hypoxia-inducible factor. Individually, Bfr or ES treatments failed to inhibit the DM-associated capillary regression and increase in antiangiogenic factor. However, combined treatment with Bfr and ES prevented DM-associated capillary regression via inhibition of the increased antiangiogenic factor and enhancement of interleukin-15 expression, mitochondrial biogenesis factors, and a proangiogenic factor. Therefore, DM-associated capillary regression inhibited by the combined treatment may prevent the effects of the increased antiangiogenic factor and enhance the proangiogenic factor.NEW & NOTEWORTHY The combined treatment of blood flow restriction and low intensity electrical stimulation attenuated type 2 diabetes (T2D)-associated capillary regression in the skeletal muscles. The treatment inhibits the T2D-associated increase in antiangiogenic factors via inhibition of intramuscular chronic hypoxia; it can inhibit intramuscular chronic hypoxia by enhancing proangiogenic factors. These results suggest that the combined treatment may be an effective therapeutic intervention for the prevention of T2D-associated capillary regression in the skeletal muscles.
Keywords: blood flow restriction; capillary regression; diabetes; electrical stimulation; myokine.