Cannon, DT, Rodewohl, L, Adams, V et al. (2 more authors) (2019) Skeletal myofiber VEGF deficiency leads to mitochondrial, structural and contractile alterations in mouse diaphragm. Journal of Applied Physiology, 127 (5). pp. 1360-1369. ISSN 8750-7587
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.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | Copyright © 2019, Journal of Applied Physiology. This is an author produced version of a paper published in Journal of Applied Physiology Uploaded in accordance with the publisher's self-archiving policy. |
Keywords: | diaphragm; fatigue; mitochondria |
Dates: |
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Institution: | The University of Leeds |
Academic Units: | The University of Leeds > Faculty of Biological Sciences (Leeds) > School of Biomedical Sciences (Leeds) |
Funding Information: | Funder Grant number MRC MR/S025472/1 |
Depositing User: | Symplectic Publications |
Date Deposited: | 19 Sep 2019 09:51 |
Last Modified: | 05 Sep 2020 00:38 |
Status: | Published |
Publisher: | American Physiological Society |
Identification Number: | 10.1152/japplphysiol.00779.2018 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:151029 |