Cannon 2019 J Appl Physiol (1985)

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Cannon DT, Rodewohl L, Adams V, Breen EC, Bowen TS (2019) Skeletal myofiber VEGF deficiency leads to mitochondrial, structural and contractile alterations in mouse diaphragm. J Appl Physiol (1985) 127:1360-69.

» PMID: 31487223 Open Access

Cannon DT, Rodewohl L, Adams V, Breen EC, Bowen TS (2019) J Appl Physiol (1985)

Abstract: Diaphragm dysfunction accompanies cardiopulmonary disease and impaired oxygen delivery. Vascular endothelial growth factor (VEGF) regulates oxygen delivery through angiogenesis, capillary maintenance, and contraction-induced perfusion. We hypothesized that myofiber-specific VEGF deficiency contributes to diaphragm weakness and fatigability. Diaphragm protein expression, capillarity and fiber morphology, mitochondrial respiration and hydrogen peroxide (H2O2) generation, and contractile function were compared between adult mice with conditional gene ablation of skeletal myofiber VEGF (SkmVEGF-/-; n=12) and littermate controls (n=13). Diaphragm VEGF protein was ~50 % lower in SkmVEGF-/- than littermate controls (1.45±0.65 vs. 3.04±1.41 pg/total protein; P=0.001). This was accompanied by an ~15% impairment in maximal isometric specific force (F[1,23] = 15.01, P=0.001) and a trend for improved fatigue resistance (P=0.053). Mean fiber cross-sectional area and type I fiber cross-sectional area were lower in SkmVEGF-/- by ~40 % and ~25% (P<0.05). Capillary-to-fiber ratio was also lower in SkmVEGF-/- by ~40% (P<0.05), thus capillary density was not different. Sarcomeric actin expression was ~30% lower in SkmVEGF-/- (P<0.05), while myosin heavy chain and MAFbx were similar (measured via immunoblot). Mitochondrial respiration, citrate synthase activity, PGC-1α, and HIF-1α were not different in SkmVEGF-/- (P>0.05). However mitochondrial-derived reactive oxygen species (ROS) flux was lower in SkmVEGF-/- (P=0.0003). In conclusion, myofiber-specific VEGF gene deletion resulted in a lower capillary-to-fiber ratio, type I fiber atrophy, actin loss, and contractile dysfunction in the diaphragm. In contrast, mitochondrial respiratory function was preserved alongside lower ROS generation, which may play a compensatory role to preserve fatigue resistance in the diaphragm.

Keywords: Diaphragm, VEGF, Angiogenesis, Exercise intolerance, Skeletal muscle Bioblast editor: Plangger M O2k-Network Lab: US CA San Diego Cannon DT, US CA La Jolla Hogan MC

Labels: MiParea: Respiration, Genetic knockout;overexpression 

Organism: Mouse  Tissue;cell: Skeletal muscle  Preparation: Permeabilized tissue 

Coupling state: LEAK, OXPHOS, ET  Pathway: N, S, NS  HRR: Oxygraph-2k, O2k-Fluorometer 

Labels, 2019-11, AmR