Skeletal myofiber VEGF regulates contraction-induced perfusion and exercise capacity but not muscle capillarity in adult mice

Abstract

A single bout of exhaustive exercise signals expression of vascular endothelial growth factor (VEGF) in the exercising muscle. Previous studies have reported that mice with life-long deletion of skeletal myofiber VEGF have fewer capillaries and a severe reduction in endurance exercise. However, in adult mice, VEGF gene deletion conditionally targeted to skeletal myofibers limits exercise capacity without evidence of capillary regression. To explain this, we hypothesized that adult skeletal myofiber VEGF acutely regulates skeletal muscle perfusion during muscle contraction. A tamoxifen-inducible skeletal myofiber-specific VEGF gene deletion mouse (skmVEGF-/-) was used to reduce skeletal muscle VEGF protein by 90% in adult mice. Three weeks after inducing deletion of the skeletal myofiber VEGF gene, skmVEGF-/- mice exhibited diminished maximum running speed (-10%, P < 0.05) and endurance capacity (-47%; P < 0.05), which did not persist after 8 wk. In skmVEGF-/- mice, gastrocnemius complex time to fatigue measured in situ was 71% lower than control mice. Contraction-induced perfusion measured by optical imaging during a period of electrically stimulated muscle contraction was 85% lower in skmVEGF-/- than control mice. No evidence of capillary rarefication was detected in the soleus, gastrocnemius, and extensor digitorum longus (EDL) up to 8 wk after tamoxifen-induced VEGF ablation, and contractility and fatigue resistance of the soleus measured ex vivo were also unchanged. The force-frequency of the EDL showed a small right shift, but fatigue resistance did not differ between EDL from control and skmVEGF-/- mice. These data suggest myofiber VEGF is required for regulating perfusion during periods of contraction and may in this manner affect endurance capacity.

Skeletal myofiber vascular endothelial growth factor is required for the exercise training‐induced increase in dentate gyrus neuronal precursor cells

“…In the present study VEGF‐dependent control of perfusion through capillary beds appears to extend beyond locomotor skeletal muscles (Knapp et al . ) and influence or regulate perfusion of the hippocampus. Blood flow through the hippocampal region at rest under normoxic conditions was 36% and 40% lower in untrained and trained myofiber VEGF null mice, respectively, relative to untrained VEGF f/f mice.…”

“…Most (60-90%) of the VEGF content in adult skeletal muscle is produced by skeletal myofibers (Delavar et al 2014;Knapp et al 2016). Therefore, we hypothesized that skeletal myofiber VEGF may either be a source of VEGF for the brain or may indirectly modify other exercise signals that regulate the fate of neuronal stem cells in the dentate gyrus.…”

Cigarette smoke directly impairs skeletal muscle function through capillary regression and altered myofibre calcium kinetics in mice

“…2017). VEGF LoxP mice were from Genentech (Oceanside, CA, USA) and HSA‐Cre‐ER T2 mice were generated and kindly provided by Dr Daniel Metzger (Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch‐Graffenstaden, France) as previously described (Knapp et al . 2016).…”

“…Nestin-green fluorescent protein (GFP) mice were generated and kindly provided by Dr M. Yamaguchi (Rich et al 2017). VEGFLoxP mice were from Genentech (Oceanside, CA, USA) and HSA-Cre-ER T2 mice were generated and kindly provided by Dr Daniel Metzger (Institut de Génétique et de Biologie Moléculaire et Cellulaire, Illkirch-Graffenstaden, France) as previously described (Knapp et al 2016). After all functional assessments were completed mice were killed by surgical removal of the heart while under anaesthesia (ketamine:xylazine, 10:1 mg kg −1 , I.P.…”

“…The protocol to stimulate the gastrocnemiusplantaris-soleus (GPS) complex via the sciatic nerve to evaluate the fatigue resistance of the vascular myofibre system has been previously described (Knapp et al 2016). Mice were anaesthetized with ketamine and xylazine (10:1 mg kg −1 , I.P.).…”