title: 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.
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Amy E
authors.initials: AE
authors.lastname: Knapp
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Daniel
authors.initials: D
authors.lastname: Goldberg
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Hamid
authors.initials: H
authors.lastname: Delavar
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Breanna M
authors.initials: BM
authors.lastname: Trisko
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Kechun
authors.initials: K
authors.lastname: Tang
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Michael C
authors.initials: MC
authors.lastname: Hogan
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Wagner
authors.affiliation: Department of Medicine, University of California, San Diego, La Jolla, California ebreen@ucsd.edu.
authors.forename: Ellen C
authors.initials: EC
authors.lastname: Breen
mesh_terms: D000375:Aging; D000818:Animals; D001835:Body Weight / Q000502:physiology; D002196:Capillaries / Q000502:physiology*; D005080:Exercise Test; D005221:Fatigue; D051379:Mice; D018345:Mice, Knockout; D009119:Muscle Contraction / Q000502:physiology*; D018485:Muscle Fibers, Skeletal / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000098:blood supply*; D009929:Organ Size / Q000502:physiology; D010805:Physical Conditioning, Animal; D005082:Physical Exertion / Q000502:physiology*; D012039:Regional Blood Flow / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*
chemical_list: D042461:Vascular Endothelial Growth Factor A; C467480:vascular endothelial growth factor A, mouse
keywords: exercise; fatigue; perfusion; skeletal myofiber; vascular endothelial growth factor