VEGF-Dependent Cell-Cell Interactions between Endothelial Cells and Skeletal Myofibers Regulate Pyruvate Dehydrogenase Enzyme Activity
- Author(s): Sulaeman, Alexis G.;
- et al.
In skeletal muscle, interactions between VEGF-expressing cells are thought to regulate capillary number and exercise performance. We hypothesized that inhibiting VEGF expression in both endothelial cells (EC) and skeletal myofibers would reduce capillarity, limit mitochondrial O2 availability and impair exercise performance. This hypothesis was tested by conditionally deleting the VEGF gene, simultaneously, in EC and skeletal myofibers (Skm/EC -VEGF-/- mice) through the use of VEGFLoxP, HSA-CRE-ERT2 and PDGFb-iCre-ERT2 transgenes. In treadmill endurance tests three weeks after initiating gene deletion, Skm/EC- VEGF-/- mice reached exhaustion 40 minutes sooner than WT mice (p < 0.01). WT, SkmVEGF-/-, and EC-VEGF-/- mice (but not Skm/EC-VEGF mice) gained weight (WT, 27.4 ± 0.35 g, Skm/EC-VEGF-/-, 25.7 ± 0.68 g; p < 0.05). However, muscle mass, capillary and artery structure, fiber area and type in the soleus, plantaris, and gastrocnemius were similar across the four groups. Ex vivo muscle contractility and fatigue resistance did not differ between the soleus of WT and Skm/EC-VEGF-/- mice. However, the EDL from Skm/EC-VEGF -/- showed improved fatigue resistance than WT EDL (Skm/EC -VEGF-/-, 188.4 ± 6.57 s; WT, 157.48 ± 9.52 s, p < 0.0001). Phosphofructokinase and pyruvate dehydrogenase activities were increased in Skm/EC-VEGF-/- muscle homogenates but not in muscle from mice with the gene ablation targeted to single cell types. These data suggest VEGF-related signaling between endothelial cells and skeletal myofibers is important for endurance exercise. Exercise intolerance was not due to skeletal muscle capillary regression, as hypothesized, but potentially a greater reliance on glucose oxidation