scholarly journals Selective Life-Long Skeletal Myofiber-Targeted VEGF Gene Ablation Impairs Exercise Capacity in Adult Mice

2015 ◽  
Vol 231 (2) ◽  
pp. 505-511 ◽  
Author(s):  
Kechun Tang ◽  
Yusu Gu ◽  
Nancy D. Dalton ◽  
Harrieth Wagner ◽  
Kirk L. Peterson ◽  
...  
Keyword(s):  
Exercise Capacity ◽  
Vegf Gene ◽  
Adult Mice ◽  
Gene Ablation ◽  
Skeletal Myofiber

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

2016 ◽  
Vol 311 (1) ◽  
pp. R192-R199 ◽  
Author(s):  
Amy E. Knapp ◽  
Daniel Goldberg ◽  
Hamid Delavar ◽  
Breanna M. Trisko ◽  
Kechun Tang ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Muscle Contraction ◽  
Exercise Capacity ◽  
Fatigue Resistance ◽  
Gene Deletion ◽  
Endurance Capacity ◽  
Force Frequency ◽  
Vegf Gene ◽  
Adult Mice ◽  
Skeletal Myofiber

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.

scholarly journals Skeletal myofiber VEGF is essential for the exercise training response in adult mice

2014 ◽  
Vol 306 (8) ◽  
pp. R586-R595 ◽  
Author(s):  
Hamid Delavar ◽  
Leonardo Nogueira ◽  
Peter D. Wagner ◽  
Michael C. Hogan ◽  
Daniel Metzger ◽  
...  
Keyword(s):  
Exercise Training ◽  
Citrate Synthase ◽  
Contractile Function ◽  
Smooth Muscle Actin ◽  
Cell Types ◽  
Wild Type ◽  
Vegf Gene ◽  
Adult Mice ◽  
Training Response ◽  
Skeletal Myofiber

Vascular endothelial growth factor (VEGF) is exercise responsive, pro-angiogenic, and expressed in several muscle cell types. We hypothesized that in adult mice, VEGF generated within skeletal myofibers (and not other cells within muscle) is necessary for the angiogenic response to exercise training. This was tested in adult conditional, skeletal myofiber-specific VEGF gene-deleted mice (skmVEGF−/−), with VEGF levels reduced by >80%. After 8 wk of daily treadmill training, speed and endurance were unaltered in skmVEGF−/− mice, but increased by 18% and 99% ( P < 0.01), respectively, in controls trained at identical absolute speed, incline, and duration. In vitro, isolated soleus and extensor digitorum longus contractile function was not impaired in skmVEGF−/− mice. However, training-induced angiogenesis was inhibited in plantaris (wild type, 38%, skmVEGF−/− 18%, P < 0.01), and gastrocnemius (wild type, 43%, P < 0.01; skmVEGF−/−, 7%, not significant). Capillarity was maintained (different from VEGF gene deletion targeted to multiple cell types) in untrained skmVEGF−/− mice. Arteriogenesis (smooth muscle actin+, artery number, and diameter) and remodeling [vimentin+, 5′-bromodeoxycytidine (BrdU)+, and F4/80+ cells] occurred in skmVEGF−/− mice, even in the absence of training. skmVEGF−/− mice also displayed a limited oxidative enzyme [citrate synthase and β-hydroxyacyl CoA dehydrogenase (β-HAD)] training response; β-HAD activity levels were elevated in the untrained state. These data suggest that myofiber expressed VEGF is necessary for training responses in capillarity and oxidative capacity and for improved running speed and endurance.

scholarly journals Wnt/β-Catenin Is Essential for Intestinal Homeostasis and Maintenance of Intestinal Stem Cells

2007 ◽  
Vol 27 (21) ◽  
pp. 7551-7559 ◽  
Author(s):  
Tea Fevr ◽  
Sylvie Robine ◽  
Daniel Louvard ◽  
Joerg Huelsken
Keyword(s):  
Stem Cells ◽  
Wnt Signaling ◽  
Intestinal Epithelium ◽  
Transcriptional Profiling ◽  
Wnt Signaling Pathway ◽  
Intestinal Stem Cells ◽  
Intestinal Homeostasis ◽  
Adult Mice ◽  
Gene Ablation ◽  
Functional Preservation

ABSTRACT The Wnt signaling pathway is deregulated in over 90% of human colorectal cancers. β-Catenin, the central signal transducer of the Wnt pathway, can directly modulate gene expression by interacting with transcription factors of the TCF/LEF family. In the present study we investigate the role of Wnt signaling in the homeostasis of intestinal epithelium by using tissue-specific, inducible β-catenin gene ablation in adult mice. Block of Wnt/β-catenin signaling resulted in rapid loss of transient-amplifying cells and crypt structures. Importantly, intestinal stem cells were induced to terminally differentiate upon deletion of β-catenin, resulting in a complete block of intestinal homeostasis and fatal loss of intestinal function. Transcriptional profiling of mutant crypt mRNA isolated by laser capture microdissection confirmed those observations and allowed us to identify genes potentially responsible for the functional preservation of intestinal stem cells. Our data demonstrate an essential requirement of Wnt/β-catenin signaling for the maintenance of the intestinal epithelium in the adult organism. This challenges attempts to target aberrant Wnt signaling as a new therapeutic strategy to treat colorectal cancer.

scholarly journals Combined Endothelial and Skeletal Myofiber VEGF Gene Deletion Leads to Capillary Regression in Adult Mouse Hind Limb Muscle

2013 ◽  
Vol 27 (S1) ◽  
Author(s):  
Alexis Gabriella Sulaeman ◽  
Hamid Delavar ◽  
Janelle Fine ◽  
Peter D Wagner ◽  
Ellen C Breen
Keyword(s):  
Hind Limb ◽  
Gene Deletion ◽  
Adult Mouse ◽  
Limb Muscle ◽  
Vegf Gene ◽  
Skeletal Myofiber ◽  
Hind Limb Muscle

scholarly journals Myostatin is a key mediator between energy metabolism and endurance capacity of skeletal muscle

2014 ◽  
Vol 307 (4) ◽  
pp. R444-R454 ◽  
Author(s):  
Etienne Mouisel ◽  
Karima Relizani ◽  
Laurence Mille-Hamard ◽  
Raphaël Denis ◽  
Christophe Hourdé ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Energy Metabolism ◽  
Exercise Capacity ◽  
Fiber Type ◽  
Muscle Metabolism ◽  
Oxidative Capacity ◽  
Muscle Size ◽  
Endurance Capacity ◽  
Adult Mice ◽  
Exercise Induced

Myostatin (Mstn) participates in the regulation of skeletal muscle size and has emerged as a regulator of muscle metabolism. Here, we hypothesized that lack of myostatin profoundly depresses oxidative phosphorylation-dependent muscle function. Toward this end, we explored Mstn −/− mice as a model for the constitutive absence of myostatin and AAV-mediated overexpression of myostatin propeptide as a model of myostatin blockade in adult wild-type mice. We show that muscles from Mstn −/− mice, although larger and stronger, fatigue extremely rapidly. Myostatin deficiency shifts muscle from aerobic toward anaerobic energy metabolism, as evidenced by decreased mitochondrial respiration, reduced expression of PPAR transcriptional regulators, increased enolase activity, and exercise-induced lactic acidosis. As a consequence, constitutively reduced myostatin signaling diminishes exercise capacity, while the hypermuscular state of Mstn−/− mice increases oxygen consumption and the energy cost of running. We wondered whether these results are the mere consequence of the congenital fiber-type switch toward a glycolytic phenotype of constitutive Mstn −/− mice. Hence, we overexpressed myostatin propeptide in adult mice, which did not affect fiber-type distribution, while nonetheless causing increased muscle fatigability, diminished exercise capacity, and decreased Pparb/d and Pgc1a expression. In conclusion, our results suggest that myostatin endows skeletal muscle with high oxidative capacity and low fatigability, thus regulating the delicate balance between muscle mass, muscle force, energy metabolism, and endurance capacity.

scholarly journals Late-in-life treadmill-training rejuvenates autophagy, protein aggregate clearance, and function in mouse hearts.

2021 ◽  
Author(s):  
Jae Min Cho ◽  
Kellsey Ly ◽  
Caroline Ramous ◽  
Lauren Thompson ◽  
Michele Hansen ◽  
...  
Keyword(s):  
Exercise Capacity ◽  
Cardiac Dysfunction ◽  
Protein Quality ◽  
Citrate Synthase ◽  
Treadmill Running ◽  
Autophagic Flux ◽  
Control Mechanisms ◽  
Protein Aggregate ◽  
Adult Mice ◽  
And Function

There is evidence for a progressive decline of protein quality control mechanisms during the process of cardiac aging. This enables the accumulation of protein aggregates and damaged organelles that contribute to age-associated cardiac dysfunction. Macroautophagy (referred to as autophagy) is the process by which post-mitotic cells such as cardiomyocytes clear defective proteins and organelles. We hypothesized that late-in-life exercise training improves autophagy, protein aggregate clearance, and function that is otherwise dysregulated in hearts from old vs adult mice. As expected, 24-month old male C57BL/6J mice (old) exhibited : (i) repressed autophagosome formation and protein aggregate accumulation in the heart; (ii) systolic and diastolic dysfunction; and (iii) reduced exercise capacity, vs. 8-month old (adult) mice (all p< .05). Separate cohorts of 21 month old mice completed a 3-month progressive resistance treadmill-running program (old-ETR) that improved (all < .05) : (i) body composition; (ii) exercise capacity; and (iii) soleus muscle citrate synthase activity, vs. age-matched mice that did not train (old-SED). Importantly, (iv) protein expression of autophagy markers indicated trafficking of the autophagosome to the lysosome increased, (v) protein aggregate clearance improved, and (vi) overall function was enhanced (all p<0.05), in hearts from old-ETR vs. old-SED mice. Dietary maneuvers and pharmacological interventions shown to elevate basal autophagy are reported to mitigate / reverse age-associated cardiac dysfunction. Here we show the first evidence that a physiological intervention initiated late-in-life improves autophagic flux, protein aggregate clearance, and overall function in mouse hearts.

scholarly journals Skeletal myofiber VEGF deficiency leads to mitochondrial, structural, and contractile alterations in mouse diaphragm

2019 ◽  
Vol 127 (5) ◽  
pp. 1360-1369
Author(s):  
Daniel T. Cannon ◽  
Lukas Rodewohl ◽  
Volker Adams ◽  
Ellen C. Breen ◽  
T. Scott Bowen
Keyword(s):  
Oxygen Delivery ◽  
Contractile Function ◽  
Type I ◽  
Vascular Endothelial ◽  
Cross Sectional ◽  
Diaphragm Dysfunction ◽  
Gene Ablation ◽  
Skeletal Myofiber ◽  
Fiber Atrophy ◽  
Endothelial Growth Factor

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), and thus capillary density was not different. Sarcomeric actin expression was ~30% lower in SkmVEGF−/− ( P < 0.05), whereas myosin heavy chain and MAFbx were similar (measured via immunoblot). Mitochondrial respiration, citrate synthase activity, PGC-1α, and hypoxia-inducible factor 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. NEW & NOTEWORTHY Diaphragm weakness is a hallmark of diseases in which oxygen delivery is compromised. Vascular endothelial growth factor (VEGF) modulates muscle perfusion; however, it remains unclear whether VEGF deficiency contributes to the onset of diaphragm dysfunction. Conditional skeletal myofiber VEGF gene ablation impaired diaphragm contractile function and resulted in type I fiber atrophy, a lower number of capillaries per fiber, and contractile protein content. Mitochondrial function was similar and reactive oxygen species flux was lower. Diaphragm VEGF deficiency may contribute to the onset of respiratory muscle weakness.

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