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 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

Increased susceptibility to exacerbated liver injury in hypercholesterolemic ApoE-deficient mice: potential involvement of oxysterols

2009 ◽  
Vol 296 (3) ◽  
pp. G553-G562 ◽  
Author(s):  
Natàlia Ferré ◽  
Marcos Martínez-Clemente ◽  
Marta López-Parra ◽  
Ana González-Périz ◽  
Raquel Horrillo ◽  
...  
Keyword(s):  
Liver Injury ◽  
Smooth Muscle Actin ◽  
Cell Types ◽  
Dependent Manner ◽  
Wild Type ◽  
Sod Activity ◽  
Concentration Dependent Manner ◽  
Oil Red O Staining ◽  
Cytochrome P 450 ◽  
Oxidized Products

The contribution of metabolic factors to the severity of liver disease is not completely understood. In this study, apolipoprotein E-deficient (ApoE−/−) mice were evaluated to define potential effects of hypercholesterolemia on the severity of carbon tetrachloride (CCl4)-induced liver injury. Under baseline conditions, hypercholesterolemic ApoE−/− mice showed increased hepatic oxidative stress (SOD activity/4-hydroxy-2-nonenal immunostaining) and higher hepatic TGF-β1, MCP-1, and TIMP-1 expression than wild-type control mice. After CCl4 challenge, ApoE−/− mice exhibited exacerbated steatosis (Oil Red O staining), necroinflammation (hematoxylin-eosin staining), macrophage infiltration (F4/80 immunohistochemistry), and fibrosis (Sirius red staining and α-smooth muscle actin immunohistochemistry) and more severe liver injury [alanine aminotransferase (ALT) and aspartate aminotransferase] than wild-type controls. Direct correlations were identified between serum cholesterol and hepatic steatosis, fibrosis, and ALT levels. These changes did not reflect the usual progression of the disease in ApoE−/− mice, since exacerbated liver injury was not present in untreated age-paired ApoE−/− mice. Moreover, hepatic cytochrome P-450 expression was unchanged in ApoE−/− mice. To explore potential mechanisms, cell types relevant to liver pathophysiology were exposed to selected cholesterol-oxidized products. Incubation of hepatocytes with a mixture of oxysterols representative of those detected by GC-MS in livers from ApoE−/− mice resulted in a concentration-dependent increase in total lipoperoxides and SOD activity. In hepatic stellate cells, oxysterols increased IL-8 secretion through a NF-κB-independent mechanism and upregulated TIMP-1 expression. In macrophages, oxysterols increased TGF-β1 secretion and MCP-1 expression in a concentration-dependent manner. Oxysterols did not compromise cell viability. Taken together, these findings demonstrate that hypercholesterolemic mice are sensitized to liver injury and that cholesterol-derived products (i.e., oxysterols) are able to induce proinflammatory and profibrogenic mechanisms in liver cells.

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.

Exercise training increases the Ca2+sensitivity of tension in rat cardiac myocytes

2001 ◽  
Vol 91 (1) ◽  
pp. 309-315 ◽  
Author(s):  
Gary M. Diffee ◽  
Eric A. Seversen ◽  
Marci M. Titus
Keyword(s):  
Steady State ◽  
Exercise Training ◽  
Cardiac Myocytes ◽  
Citrate Synthase ◽  
Contractile Function ◽  
Weight Ratio ◽  
Force Transducer ◽  
Heart Weight ◽  
Sprague Dawley ◽  
Cellular Mechanisms

The heart is known to respond to a program of chronic exercise in ways that enhance cardiac function. However, the cellular mechanisms involved in training-induced improvements in the contractile function of the myocardium are not known. In this study we tested the hypothesis that increased contractility of the myocardium associated with exercise training is due, in part, to increases in the Ca2+ sensitivity of steady-state tension. Female Sprague-Dawley rats were randomly divided into sedentary control (C) and exercise-trained (T) groups. The T rats underwent 11 wk of progressive treadmill exercise (1 h/day, 5 days/wk, 26 m/min, 20% grade). Evidence of training effect included a 5.9% increase in heart mass, increases in heart weight-to-body weight ratio, and a 60% increase in skeletal muscle citrate synthase activity in T rats compared with C rats. After the training program, cardiac myocytes were isolated from T and C hearts. Myocytes were chemically skinned (i.e., the sarcolemma was removed) and attached to a force transducer, and steady-state tension was determined in solutions of various Ca2+ concentrations ([Ca2+]). Myocytes isolated from the hearts of T rats showed a significantly ( P < 0.01) increased sensitivity of tension to [Ca2+]. The [Ca2+] giving 50% of maximal tension (pCa50) was 5.90 ± 0.033 and 5.82 ± 0.023 (SD) in T and C myocytes, respectively ( n = 70 myocytes/group). This result suggests that exercise training affects the myofibrillar proteins, such that Ca2+ sensitivity is increased, and that this may be the mechanism that underlies, at least in part, the effect of training to increase myocardial contractility.

Porcine cardiac myocyte power output is increased after chronic exercise training

2006 ◽  
Vol 101 (1) ◽  
pp. 40-46 ◽  
Author(s):  
Aaron C. Hinken ◽  
F. Steven Korte ◽  
Kerry S. McDonald
Keyword(s):  
Exercise Training ◽  
Power Output ◽  
Cardiac Myocyte ◽  
Troponin I ◽  
Citrate Synthase ◽  
Contractile Function ◽  
Heart Weight ◽  
Peak Power Output ◽  
Chronic Exercise ◽  
Miniature Swine

Chronic exercise training increases the functional capacity of the heart, perhaps by increased myocyte contractile function, as has been observed in rodent exercise models. We examined whether cardiac myocyte function is enhanced after chronic exercise training in Yucatan miniature swine, whose heart characteristics are similar to humans. Animals were designated as either sedentary (Sed), i.e., cage confined, or exercise trained (Ex), i.e., underwent 16–20 wk of progressive treadmill training. Exercise training efficacy was shown with significantly increased heart weight-to-body weight ratios, skeletal muscle citrate synthase activity, and exercise tolerance. Force-velocity properties were measured by attaching skinned cardiac myocytes between a force transducer and position motor, and shortening velocities were measured over a range of loads during maximal Ca2+ activation. Myocytes ( n = 9) from nine Ex pigs had comparable force production but a ∼30% increase in peak power output compared with myocytes ( n = 8) from eight Sed. Interestingly, Ex myofibrillar samples also had higher baseline PKA-induced phosphorylation levels of cardiac troponin I, which may contribute to the increase in power. Overall, these results suggest that enhanced power-generating capacity of porcine cardiac myofibrils contributes to improved cardiac function after chronic exercise training.

COX-2 is not required for the development of murine chronic pancreatitis

2011 ◽  
Vol 300 (6) ◽  
pp. G968-G975 ◽  
Author(s):  
Alberto Silva ◽  
Achim Weber ◽  
Martha Bain ◽  
Theresia Reding ◽  
Mathias Heikenwalder ◽  
...  
Keyword(s):  
Chronic Pancreatitis ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Transforming Growth Factor Β ◽  
Collagen Deposition ◽  
Wild Type ◽  
Therapeutic Implications ◽  
Adult Mice ◽  
Cox 2 ◽  
Species Specific

Chronic pancreatitis is a severe inflammation of the pancreas associated with destruction of the parenchyma, fibrosis, and persistent abdominal pain. Cyclooxygenase-2 (COX-2) and COX-2-derived prostaglandins, key mediators of the inflammatory response, are elevated in patients with chronic pancreatitis. Previous studies investigated COX-2 as a therapeutic target. These reports showed a reduced pathology in COX-2-deficient mice with a better outcome. Here we compared the role of COX-2 in acute and chronic pancreatic inflammation using the same COX-2−/− mouse model of cerulein-induced pancreatitis. In a setting of acute pancreatitis, juvenile COX-2−/− mice exhibited a reduced histopathological score compared with wild-type littermates; on the contrary, adult mice did not show any difference in the development of the disease. Similarly, in a setting of chronic pancreatitis induced over a period of 4 wk, adult mice of the two strains showed comparable histological score and collagen deposition. However, the abundance of mRNAs coding for profibrotic genes, such as collagen, α-smooth muscle actin, and transforming growth factor-β was consistently lower in COX-2−/− mice. In addition, comparable histological scores and collagen deposition were observed in wild-type mice treated with a COX-2 inhibitor. We conclude that, in contrast to what was observed in the rat pancreatitis models, COX-2 has a limited and age-dependent effect on inflammatory processes in the mouse pancreas. These results suggest that COX-2 modulates the inflammatory process during the development of pancreatitis in a species-specific manner. Thus the pathophysiological roles of COX-2 and its therapeutic implications in patients with pancreatitis should be reexamined.

Targeted disruption of the Dictyostelium myosin essential light chain gene produces cells defective in cytokinesis and morphogenesis

1995 ◽  
Vol 108 (10) ◽  
pp. 3207-3218 ◽  
Author(s):  
T.L. Chen ◽  
P.A. Kowalczyk ◽  
G. Ho ◽  
R.L. Chisholm
Keyword(s):  
Atpase Activity ◽  
Cell Line ◽  
Light Chain ◽  
Contractile Function ◽  
Cell Types ◽  
Chain Gene ◽  
Dictyostelium Cell ◽  
Wild Type ◽  
Light Chain Gene ◽  
Essential Light Chain

We have previously demonstrated that the myosin essential light chain (ELC) is required for myosin function in a Dictyostelium cell line, 7–11, in which the expression of ELC was inhibited by antisense RNA overexpression. We have now disrupted the gene encoding the ELC (mlcE) in Dictyostelium by gene targeting. The mlcE- mutants provide a clean genetic background for phenotypic analysis and biochemical characterization by removing complications arising from the residual ELC present in 7–11 cells, as well as the possibility of mutations due to insertion of the antisense construct at multiple sites in the genome. The mlcE- mutants, when grown in suspension, exhibited the typical multinucleate phenotype observed in both myosin heavy chain mutants and 7–11 cells. This phenotype was rescued by introducing a construct that expressed the wild-type Dictyostelium ELC cDNA. Myosin purified from the mlcE- cells exhibited significant calcium ATPase activity, but the actin-activated ATPase activity was greatly reduced. The results obtained from the mlcE- mutants strengthen our previous conclusion based on the antisense cell line 7–11 that ELC is critical for myosin function. The proper localization of myosin in mlcE- cells suggests that its phenotypic defects primarily arise from defective contractile function of myosin rather than its mislocalization. The enzymatic defect of myosin in mlcE- cells also suggests a possible mechanism for the observed chemotactic defect of mlcE- cells. We have shown that while mlcE- cells were able to respond to chemoattractant with proper directionality, their rate of movement was reduced. During chemotaxis, proper directionality toward chemoattractant may depend primarily on proper localization of myosin, while efficient motility requires contractile function. In addition, we have analyzed the morphogenetic events during the development of mlcE- cells using lacZ reporter constructs expressed from cell type specific promoters. By analyzing the morphogenetic patterns of the two major cell types arising during Dictyostelium development, prespore and prestalk cells, we have shown that the localization of prespore cells is more susceptible to the loss of ELC than prestalk cells, although localization of both cell types is abnormal when developed in chimeras formed by mixing equal numbers of wild-type and mutant cells. These results suggest that the morphogenetic events during Dictyostelium development have different requirements for myosin.

Exercise training boosts eNOS-dependent mitochondrial biogenesis in mouse heart: role in adaptation of glucose metabolism

2014 ◽  
Vol 306 (5) ◽  
pp. E519-E528 ◽  
Author(s):  
Roberto Vettor ◽  
Alessandra Valerio ◽  
Maurizio Ragni ◽  
Elisabetta Trevellin ◽  
Marnie Granzotto ◽  
...  
Keyword(s):  
Exercise Training ◽  
Glucose Uptake ◽  
Mitochondrial Biogenesis ◽  
Citrate Synthase ◽  
Mouse Heart ◽  
Wild Type ◽  
No Donor ◽  
Small Interference Rna ◽  
Primary Mouse ◽  
And Function

Endurance exercise training increases cardiac energy metabolism through poorly understood mechanisms. Nitric oxide (NO) produced by endothelial NO synthase (eNOS) in cardiomyocytes contributes to cardiac adaptation. Here we demonstrate that the NO donor diethylenetriamine-NO (DETA-NO) activated mitochondrial biogenesis and function, as assessed by upregulated peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α), nuclear respiratory factor 1, and mitochondrial transcription factor A (Tfam) expression, and by increased mitochondrial DNA content and citrate synthase activity in primary mouse cardiomyocytes. DETA-NO also induced mitochondrial biogenesis and function and enhanced both basal and insulin-stimulated glucose uptake in HL-1 cardiomyocytes. The DETA-NO-mediated effects were suppressed by either PGC-1α or Tfam small-interference RNA in HL-1 cardiomyocytes. Wild-type and eNOS−/− mice were subjected to 6 wk graduated swim training. We found that eNOS expression, mitochondrial biogenesis, mitochondrial volume density and number, and both basal and insulin-stimulated glucose uptake were increased in left ventricles of swim-trained wild-type mice. On the contrary, the genetic deletion of eNOS prevented all these adaptive phenomena. Our findings demonstrate that exercise training promotes eNOS-dependent mitochondrial biogenesis in heart, which behaves as an essential step in cardiac glucose transport.

scholarly journals Role of intrinsic aerobic capacity and ventilator-induced diaphragm dysfunction

2015 ◽  
Vol 118 (7) ◽  
pp. 849-857 ◽  
Author(s):  
Kurt J. Sollanek ◽  
Ashley J. Smuder ◽  
Michael P. Wiggs ◽  
Aaron B. Morton ◽  
Lauren G. Koch ◽  
...  
Keyword(s):  
Exercise Training ◽  
Endurance Exercise ◽  
Aerobic Capacity ◽  
Citrate Synthase ◽  
Contractile Function ◽  
Prolonged Mechanical Ventilation ◽  
Diaphragm Muscle ◽  
Oxidative Enzymes ◽  
Diaphragm Dysfunction ◽  
Endurance Exercise Training

Prolonged mechanical ventilation (MV) leads to rapid diaphragmatic atrophy and contractile dysfunction, which is collectively termed “ventilator-induced diaphragm dysfunction” (VIDD). Interestingly, endurance exercise training prior to MV has been shown to protect against VIDD. Further, recent evidence reveals that sedentary animals selectively bred to possess a high aerobic capacity possess a similar skeletal muscle phenotype to muscles from endurance trained animals. Therefore, we tested the hypothesis that animals with a high intrinsic aerobic capacity would naturally be afforded protection against VIDD. To this end, animals were selectively bred over 33 generations to create two divergent strains, differing in aerobic capacity: high-capacity runners (HCR) and low-capacity runners (LCR). Both groups of animals were subjected to 12 h of MV and compared with nonventilated control animals within the same strains. As expected, contrasted to LCR animals, the diaphragm muscle from the HCR animals contained higher levels of oxidative enzymes (e.g., citrate synthase) and antioxidant enzymes (e.g., superoxide dismutase and catalase). Nonetheless, compared with nonventilated controls, prolonged MV resulted in significant diaphragmatic atrophy and impaired diaphragm contractile function in both the HCR and LCR animals, and the magnitude of VIDD did not differ between strains. In conclusion, these data demonstrate that possession of a high intrinsic aerobic capacity alone does not afford protection against VIDD. Importantly, these results suggest that endurance exercise training differentially alters the diaphragm phenotype to resist VIDD. Interestingly, levels of heat shock protein 72 did not differ between strains, thus potentially representing an important area of difference between animals with intrinsically high aerobic capacity and exercise-trained animals.

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