The Experts below are selected from a list of 411 Experts worldwide ranked by ideXlab platform
Gemma A. Figtree - One of the best experts on this subject based on the ideXlab platform.
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oxidative modification of the cardiac sodium potassium pump is worsened in the absence of FXYD1 contributing to cardiac dysfunction and fibrosis
Free Radical Biology and Medicine, 2018Co-Authors: Kristen J Bubb, Thomas Hansen, Owen Tang, Gemma A. FigtreeAbstract:Introduction FXYD1 is a small membrane protein that endogenously protects the cardiac Na+-K+ ATPase from oxidative inhibition. Given the importance of the Na+-K+ ATPase in normal cardiac function, we hypothesized that absence of FXYD1 would worsen reactive oxygen species (ROS)-induced cardiac dysfunction. Methods and Results In studies were performed using wild-type (WT) and FXYD1 knockout (KO) mice. FXYD1 KO mice are prone to exacerbated vascular superoxide generation (P Summary This data defines a new role for FXYD1 in preventing cardiac dysfunction and fibrosis characterized by elevated ROS. Impaired oxidative inhibition of the Na+-K+ ATPase β1 subunit plays a likely role in mediating this protective response.
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abstract 20047 FXYD1 protects against reactive oxygen species dependent cardiac remodelling and fibrosis
Circulation, 2017Co-Authors: Kristen J Bubb, Owen Tang, Thomas F Hansen, Carmine Gentile, Gemma A. FigtreeAbstract:Introduction: Fibrosis plays a critical role in cardiac pathophysiology. We have shown FXYD1 to be an endogenous protector of oxidative inhibition of the cardiac membrane Na+-K+ ATPase. However, the effects of FXYD1 on longer term cardiac signalling, and particularly cardiac fibrosis have not been examined. We hypothesized that absence of FXYD1 would worsen Angiotensin II-induced cardiac fibrosis. Methods and Results: In vivo studies were performed using wild-type (WT) and FXYD1 knockout (KO) mice. Under baseline conditions, cardiac perivascular fibrosis was ~3-fold higher in KO vs. WT mice (P<0.01), however interstitial fibrosis was absent. To stimulate cardiac interstitial fibrosis, Ang II (0.72 or 2.1 mg/kg/day) was infused via subcutaneous osmotic mini pump for 2 weeks. Ang II infusion resulted in elevated blood pressure (11 mmHg higher in FXYD1 KO mice vs. WT mice; P=0.01). This was associated with dose-dependent cardiac hypertrophy in FXYD1 KO mice (heart:body weight [mg/kg] sham: 4.8 +/- 0.3; AngII...
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Abstract 20047: FXYD1 Protects Against Reactive Oxygen Species-Dependent Cardiac Remodelling and Fibrosis
Circulation, 2017Co-Authors: Kristen J Bubb, Owen Tang, Thomas F Hansen, Carmine Gentile, Gemma A. FigtreeAbstract:Introduction: Fibrosis plays a critical role in cardiac pathophysiology. We have shown FXYD1 to be an endogenous protector of oxidative inhibition of the cardiac membrane Na+-K+ ATPase. However, the effects of FXYD1 on longer term cardiac signalling, and particularly cardiac fibrosis have not been examined. We hypothesized that absence of FXYD1 would worsen Angiotensin II-induced cardiac fibrosis. Methods and Results: In vivo studies were performed using wild-type (WT) and FXYD1 knockout (KO) mice. Under baseline conditions, cardiac perivascular fibrosis was ~3-fold higher in KO vs. WT mice (P
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abstract 15521 FXYD1 protects against redox dependent uncoupling of endothelial nitric oxide synthase
Circulation, 2016Co-Authors: Kristen J Bubb, Keyvan Karimi Galougahi, Owen Tang, Thomas F Hansen, Gemma A. FigtreeAbstract:Background: Vascular health is dependent on the vasoprotective molecule, nitric oxide (NO), produced by endothelial NO synthase (eNOS). Under conditions of oxidative stress such as diabetes and hypertension, eNOS becomes “uncoupled” via glutathionylation, preferentially producing the damaging free radical, superoxide (O2 .- ). Discovery of protective mechanisms against this will have critical implications for vascular function in health and disease. We hypothesised that caveolar co-localisation of FXYD1 and eNOS may result in functional interaction and redox signalling in the vasculature. Methods and results: FXYD1-eNOS co-localisation was demonstrated by both proximity ligation assay and co-immunoprecipitation in human umbilical vein endothelial cells (HUVECs). eNOS glutathionylation, assessed by co-immunoprecipitation of eNOS and glutathione, was significantly increased (~1.5 fold, p=0.04, n=3) after silencing of FXYD1 using siRNA and this was associated with reduced NO bioavailability, as assessed by diaminofluorescein stain after acetylcholine stimulation (~60% reduction, p .- production, determined by lucigenin enhanced chemiluminescence (n = 3, P .- production in FXYD1 knockout (KO) mice (n = 5, P Conclusions: Our findings demonstrated a novel functional partnership of FXYD1 with eNOS, protecting this vital enzyme from glutathionylation-mediated uncoupling. This has important implications for our understanding of ROS-signalling in the vasculature and could lead to novel treatment options with recombinant FXYD1 for redox-dependent vascular disease.
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FXYD1 protects against redox dependent endothelial dysfunction and angiotensin ii induced hypertension
Free Radical Biology and Medicine, 2016Co-Authors: Kristen J Bubb, Gemma A. Figtree, Keyvan Karimi Galougahi, Thomas Hansen, Owen TangAbstract:Background Protein S-glutathionylation (GSS) can increase the generation of reactive oxygen species and cause eNOS uncoupling, thereby reducing nitric oxide (NO) bioavailability. Thus, mechanisms that protect against eNOS-GSS could improve vascular function and cardiovascular health. We hypothesised that caveolar co-localisation of FXYD1 with eNOS may result in functional interaction and ‘protective’ redox signalling in the vasculature. Methods and results: Blood pressure (MABP), measured by arterial cannulation was not different between anaesthetised FXYD1 wildtype (WT) and knockout (KO) mice (MABP (mmHg): WT 88.7±1.3 vs. KO 91.1 ± 2.2, n=7); confirmed by telemetry in conscious mice. Endothelium-dependent vasodilation, determined by MABP changes after increasing bolus doses of bradykinin acetate, was impaired in KO mice (max ΔmmHg at 10 µg/kg: KO -9.6±1.4 vs. WT -16.6±1.7, P Conclusions We have identified a functional partnership of FXYD1 with eNOS, protecting this vital enzyme from GSS-mediated eNOS uncoupling. This could lead to novel treatment options with recombinant FXYD1 for redox-dependent vascular disease.
Jens Bangsbo - One of the best experts on this subject based on the ideXlab platform.
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Cycling with blood flow restriction improves performance and muscle K+ regulation and blunts the effect of antioxidant infusion in humans
bioRxiv, 2018Co-Authors: Danny Christiansen, Jens BangsboAbstract:We examined if blood flow restriction (BFR) would augment training-induced improvements in muscle K + handling and performance during intense exercise in men, and if these adaptations would be associated with an effect of muscle antioxidant function on thigh K + release and with fibre type-dependent modulation of Na + ,K + -ATPase-isoform abundance and FXYD1 phosphorylation. Ten recreationally-active men (25 ± 4 y, 49.7 ± 5.3 mL/kg/min) performed 6 weeks of interval cycling, where one leg trained without (control; CON-leg) and the other leg with BFR (BFR-leg, pressure: 178 mmHg). Before and after training, catheters were inserted into the femoral artery and vein, and blood flow was assessed during single-leg knee-extensions at 25% (Ex1) and 90% of leg peak aerobic power (Ex2) with intravenous infusion of N-acetylcysteine (NAC) or saline (placebo), and a resting muscle biopsy was collected. After training, performance during exhaustive exercise increased to a greater extent in BFR-leg (23%) than in CON-leg (12%, p + release during Ex2 was attenuated in BFR-leg only (p + release during Ex1 (p 0.05). After training, this effect was blunted in BFR-leg (p + ,K + -ATPase-isoform α 1 in type-II (51%), β 1 in type-I (33%), and FXYD1 in type-I (108%) and type-II (60%) fibres was higher in BFR-leg (p + release during intense exercise, which may be caused by elevated ROS scavenging and fibre type-dependent increases in Na + ,K + -ATPase-isoform abundance.
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increased FXYD1 and pgc 1α mrna after blood flow restricted running is related to fibre type specific ampk signalling and oxidative stress in human muscle
Acta Physiologica, 2018Co-Authors: Danny Christiansen, Jens Bangsbo, Robyn M Murphy, Christos G Stathis, David BishopAbstract:AIM: This study explored the effects of blood flow restriction (BFR) on mRNA responses of PGC-1α (total, 1α1, and 1α4) and Na+ ,K+ -ATPase isoforms (NKA; α1-3 , β1-3 , and FXYD1) to an interval running session and determined whether these effects were related to increased oxidative stress, hypoxia, and fibre type-specific AMPK and CaMKII signalling, in human skeletal muscle. METHODS: In a randomized, crossover fashion, 8 healthy men (26 ± 5 year and 57.4 ± 6.3 mL kg-1 min-1 ) completed 3 exercise sessions: without (CON) or with blood flow restriction (BFR), or in systemic hypoxia (HYP, ~3250 m). A muscle sample was collected before (Pre) and after exercise (+0 hour, +3 hours) to quantify mRNA, indicators of oxidative stress (HSP27 protein in type I and II fibres, and catalase and HSP70 mRNA), metabolites, and α-AMPK Thr172 /α-AMPK, ACC Ser221 /ACC, CaMKII Thr287 /CaMKII, and PLBSer16 /PLB ratios in type I and II fibres. RESULTS: Muscle hypoxia (assessed by near-infrared spectroscopy) was matched between BFR and HYP, which was higher than CON (~90% vs ~70%; P < .05). The mRNA levels of FXYD1 and PGC-1α isoforms (1α1 and 1α4) increased in BFR only (P < .05) and were associated with increases in indicators of oxidative stress and type I fibre ACC Ser221 /ACC ratio, but dissociated from muscle hypoxia, lactate, and CaMKII signalling. CONCLUSION: Blood flow restriction augmented exercise-induced increases in muscle FXYD1 and PGC-1α mRNA in men. This effect was related to increased oxidative stress and fibre type-dependent AMPK signalling, but unrelated to the severity of muscle hypoxia, lactate accumulation, and modulation of fibre type-specific CaMKII signalling.
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Increased FXYD1 and PGC-1α mRNA after blood flow-restricted running is related to fibre type-specific AMPK signalling and oxidative stress in human muscle.
Acta Physiologica, 2018Co-Authors: Danny Christiansen, Jens Bangsbo, Robyn M Murphy, Christos G Stathis, David BishopAbstract:AIM: This study explored the effects of blood flow restriction (BFR) on mRNA responses of PGC-1α (total, 1α1, and 1α4) and Na+ ,K+ -ATPase isoforms (NKA; α1-3 , β1-3 , and FXYD1) to an interval running session and determined whether these effects were related to increased oxidative stress, hypoxia, and fibre type-specific AMPK and CaMKII signalling, in human skeletal muscle. METHODS: In a randomized, crossover fashion, 8 healthy men (26 ± 5 year and 57.4 ± 6.3 mL kg-1 min-1 ) completed 3 exercise sessions: without (CON) or with blood flow restriction (BFR), or in systemic hypoxia (HYP, ~3250 m). A muscle sample was collected before (Pre) and after exercise (+0 hour, +3 hours) to quantify mRNA, indicators of oxidative stress (HSP27 protein in type I and II fibres, and catalase and HSP70 mRNA), metabolites, and α-AMPK Thr172 /α-AMPK, ACC Ser221 /ACC, CaMKII Thr287 /CaMKII, and PLBSer16 /PLB ratios in type I and II fibres. RESULTS: Muscle hypoxia (assessed by near-infrared spectroscopy) was matched between BFR and HYP, which was higher than CON (~90% vs ~70%; P
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Repeated-ischaemic exercise enhances mitochondrial and ion transport gene adaptations in human skeletal muscle: Role of muscle redox state and AMPK
bioRxiv, 2017Co-Authors: Danny Christiansen, Jens Bangsbo, Robyn M Murphy, Christos G Stathis, David BishopAbstract:This study assessed the effect of repeated-ischaemic exercise on the mRNA content of PGC-1α (total, 1α1, and 1α4) and Na+,K+-ATPase (NKA; α1-3, β1-3, and FXYD1) isoforms in human skeletal muscle, and studied some of the potential molecular mechanisms involved. Eight trained men (26 y and 57.4 mL·kg-1·min-1) completed three interval running sessions with (ISC) or without ischaemia (CON), or in hypoxia (HYP, ~3250 m), in a randomised, crossover fashion separated by 1 week. A muscle sample was collected from the dominant leg before (Pre) and after exercise (+0h, +3h) in all sessions to measure the mRNA content of PGC-1α and NKA isoforms, oxidative stress markers (i.e. catalase and HSP70 mRNA), muscle lactate, and phosphorylation of AMPK, ACC, CaMKII, and PLB protein in type I and II fibres. Muscle hypoxia (i.e. deoxygenated haemoglobin) was matched between ISC and HYP, which was higher than in CON (~90% vs. ~70%; p
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Post-exercise cold-water immersion increases Na+,K+-ATPase α2-isoform mRNA content in parallel with elevated Sp1 expression in human skeletal muscle
bioRxiv, 2017Co-Authors: Danny Christiansen, Jens Bangsbo, Robyn M Murphy, James R. Broatch, Michael J. Mckenna, Jujiao Kuang, David BishopAbstract:We investigated the effect of a session of sprint-interval exercise on the mRNA content of NKA isoforms (a1-3, b1-3) and FXYD1 in human skeletal muscle. To explore some of the cellular stressors involved in this regulation, we evaluated the association between these mRNA responses and those of the transcription factors Sp1, Sp3 and HIF-1a. Given cold exposure perturbs muscle redox homeostasis, which may be one mechanism important for increases in NKA-isoform mRNA, we also explored the effect of post-exercise cold-water immersion (CWI) on the mRNA responses. Muscle was sampled from nineteen men before (Pre) and after (+0h, +3h) exercise plus passive rest (CON, n=10) or CWI (10 degrees C; COLD, n=9). In COLD, exercise increased NKAa2 and Sp1 mRNA (+0h, p 0.05). In both conditions, exercise increased NKAa1, NKAb3 and HIF-1a mRNA (+3h; p 0.05). These human findings highlight 1) sprint-interval exercise increases the mRNA content of NKAa1 and b3, and decreases that of NKA b2, which may relate, in part, to exercise-induced muscle hypoxia, and 2) post-exercise CWI augments NKAa2 mRNA, which may be associated with promoted Sp1 activation.
Owen Tang - One of the best experts on this subject based on the ideXlab platform.
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oxidative modification of the cardiac sodium potassium pump is worsened in the absence of FXYD1 contributing to cardiac dysfunction and fibrosis
Free Radical Biology and Medicine, 2018Co-Authors: Kristen J Bubb, Thomas Hansen, Owen Tang, Gemma A. FigtreeAbstract:Introduction FXYD1 is a small membrane protein that endogenously protects the cardiac Na+-K+ ATPase from oxidative inhibition. Given the importance of the Na+-K+ ATPase in normal cardiac function, we hypothesized that absence of FXYD1 would worsen reactive oxygen species (ROS)-induced cardiac dysfunction. Methods and Results In studies were performed using wild-type (WT) and FXYD1 knockout (KO) mice. FXYD1 KO mice are prone to exacerbated vascular superoxide generation (P Summary This data defines a new role for FXYD1 in preventing cardiac dysfunction and fibrosis characterized by elevated ROS. Impaired oxidative inhibition of the Na+-K+ ATPase β1 subunit plays a likely role in mediating this protective response.
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abstract 20047 FXYD1 protects against reactive oxygen species dependent cardiac remodelling and fibrosis
Circulation, 2017Co-Authors: Kristen J Bubb, Owen Tang, Thomas F Hansen, Carmine Gentile, Gemma A. FigtreeAbstract:Introduction: Fibrosis plays a critical role in cardiac pathophysiology. We have shown FXYD1 to be an endogenous protector of oxidative inhibition of the cardiac membrane Na+-K+ ATPase. However, the effects of FXYD1 on longer term cardiac signalling, and particularly cardiac fibrosis have not been examined. We hypothesized that absence of FXYD1 would worsen Angiotensin II-induced cardiac fibrosis. Methods and Results: In vivo studies were performed using wild-type (WT) and FXYD1 knockout (KO) mice. Under baseline conditions, cardiac perivascular fibrosis was ~3-fold higher in KO vs. WT mice (P<0.01), however interstitial fibrosis was absent. To stimulate cardiac interstitial fibrosis, Ang II (0.72 or 2.1 mg/kg/day) was infused via subcutaneous osmotic mini pump for 2 weeks. Ang II infusion resulted in elevated blood pressure (11 mmHg higher in FXYD1 KO mice vs. WT mice; P=0.01). This was associated with dose-dependent cardiac hypertrophy in FXYD1 KO mice (heart:body weight [mg/kg] sham: 4.8 +/- 0.3; AngII...
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Abstract 20047: FXYD1 Protects Against Reactive Oxygen Species-Dependent Cardiac Remodelling and Fibrosis
Circulation, 2017Co-Authors: Kristen J Bubb, Owen Tang, Thomas F Hansen, Carmine Gentile, Gemma A. FigtreeAbstract:Introduction: Fibrosis plays a critical role in cardiac pathophysiology. We have shown FXYD1 to be an endogenous protector of oxidative inhibition of the cardiac membrane Na+-K+ ATPase. However, the effects of FXYD1 on longer term cardiac signalling, and particularly cardiac fibrosis have not been examined. We hypothesized that absence of FXYD1 would worsen Angiotensin II-induced cardiac fibrosis. Methods and Results: In vivo studies were performed using wild-type (WT) and FXYD1 knockout (KO) mice. Under baseline conditions, cardiac perivascular fibrosis was ~3-fold higher in KO vs. WT mice (P
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abstract 15521 FXYD1 protects against redox dependent uncoupling of endothelial nitric oxide synthase
Circulation, 2016Co-Authors: Kristen J Bubb, Keyvan Karimi Galougahi, Owen Tang, Thomas F Hansen, Gemma A. FigtreeAbstract:Background: Vascular health is dependent on the vasoprotective molecule, nitric oxide (NO), produced by endothelial NO synthase (eNOS). Under conditions of oxidative stress such as diabetes and hypertension, eNOS becomes “uncoupled” via glutathionylation, preferentially producing the damaging free radical, superoxide (O2 .- ). Discovery of protective mechanisms against this will have critical implications for vascular function in health and disease. We hypothesised that caveolar co-localisation of FXYD1 and eNOS may result in functional interaction and redox signalling in the vasculature. Methods and results: FXYD1-eNOS co-localisation was demonstrated by both proximity ligation assay and co-immunoprecipitation in human umbilical vein endothelial cells (HUVECs). eNOS glutathionylation, assessed by co-immunoprecipitation of eNOS and glutathione, was significantly increased (~1.5 fold, p=0.04, n=3) after silencing of FXYD1 using siRNA and this was associated with reduced NO bioavailability, as assessed by diaminofluorescein stain after acetylcholine stimulation (~60% reduction, p .- production, determined by lucigenin enhanced chemiluminescence (n = 3, P .- production in FXYD1 knockout (KO) mice (n = 5, P Conclusions: Our findings demonstrated a novel functional partnership of FXYD1 with eNOS, protecting this vital enzyme from glutathionylation-mediated uncoupling. This has important implications for our understanding of ROS-signalling in the vasculature and could lead to novel treatment options with recombinant FXYD1 for redox-dependent vascular disease.
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FXYD1 protects against redox dependent endothelial dysfunction and angiotensin ii induced hypertension
Free Radical Biology and Medicine, 2016Co-Authors: Kristen J Bubb, Gemma A. Figtree, Keyvan Karimi Galougahi, Thomas Hansen, Owen TangAbstract:Background Protein S-glutathionylation (GSS) can increase the generation of reactive oxygen species and cause eNOS uncoupling, thereby reducing nitric oxide (NO) bioavailability. Thus, mechanisms that protect against eNOS-GSS could improve vascular function and cardiovascular health. We hypothesised that caveolar co-localisation of FXYD1 with eNOS may result in functional interaction and ‘protective’ redox signalling in the vasculature. Methods and results: Blood pressure (MABP), measured by arterial cannulation was not different between anaesthetised FXYD1 wildtype (WT) and knockout (KO) mice (MABP (mmHg): WT 88.7±1.3 vs. KO 91.1 ± 2.2, n=7); confirmed by telemetry in conscious mice. Endothelium-dependent vasodilation, determined by MABP changes after increasing bolus doses of bradykinin acetate, was impaired in KO mice (max ΔmmHg at 10 µg/kg: KO -9.6±1.4 vs. WT -16.6±1.7, P Conclusions We have identified a functional partnership of FXYD1 with eNOS, protecting this vital enzyme from GSS-mediated eNOS uncoupling. This could lead to novel treatment options with recombinant FXYD1 for redox-dependent vascular disease.
David Bishop - One of the best experts on this subject based on the ideXlab platform.
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increased FXYD1 and pgc 1α mrna after blood flow restricted running is related to fibre type specific ampk signalling and oxidative stress in human muscle
Acta Physiologica, 2018Co-Authors: Danny Christiansen, Jens Bangsbo, Robyn M Murphy, Christos G Stathis, David BishopAbstract:AIM: This study explored the effects of blood flow restriction (BFR) on mRNA responses of PGC-1α (total, 1α1, and 1α4) and Na+ ,K+ -ATPase isoforms (NKA; α1-3 , β1-3 , and FXYD1) to an interval running session and determined whether these effects were related to increased oxidative stress, hypoxia, and fibre type-specific AMPK and CaMKII signalling, in human skeletal muscle. METHODS: In a randomized, crossover fashion, 8 healthy men (26 ± 5 year and 57.4 ± 6.3 mL kg-1 min-1 ) completed 3 exercise sessions: without (CON) or with blood flow restriction (BFR), or in systemic hypoxia (HYP, ~3250 m). A muscle sample was collected before (Pre) and after exercise (+0 hour, +3 hours) to quantify mRNA, indicators of oxidative stress (HSP27 protein in type I and II fibres, and catalase and HSP70 mRNA), metabolites, and α-AMPK Thr172 /α-AMPK, ACC Ser221 /ACC, CaMKII Thr287 /CaMKII, and PLBSer16 /PLB ratios in type I and II fibres. RESULTS: Muscle hypoxia (assessed by near-infrared spectroscopy) was matched between BFR and HYP, which was higher than CON (~90% vs ~70%; P < .05). The mRNA levels of FXYD1 and PGC-1α isoforms (1α1 and 1α4) increased in BFR only (P < .05) and were associated with increases in indicators of oxidative stress and type I fibre ACC Ser221 /ACC ratio, but dissociated from muscle hypoxia, lactate, and CaMKII signalling. CONCLUSION: Blood flow restriction augmented exercise-induced increases in muscle FXYD1 and PGC-1α mRNA in men. This effect was related to increased oxidative stress and fibre type-dependent AMPK signalling, but unrelated to the severity of muscle hypoxia, lactate accumulation, and modulation of fibre type-specific CaMKII signalling.
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Increased FXYD1 and PGC-1α mRNA after blood flow-restricted running is related to fibre type-specific AMPK signalling and oxidative stress in human muscle.
Acta Physiologica, 2018Co-Authors: Danny Christiansen, Jens Bangsbo, Robyn M Murphy, Christos G Stathis, David BishopAbstract:AIM: This study explored the effects of blood flow restriction (BFR) on mRNA responses of PGC-1α (total, 1α1, and 1α4) and Na+ ,K+ -ATPase isoforms (NKA; α1-3 , β1-3 , and FXYD1) to an interval running session and determined whether these effects were related to increased oxidative stress, hypoxia, and fibre type-specific AMPK and CaMKII signalling, in human skeletal muscle. METHODS: In a randomized, crossover fashion, 8 healthy men (26 ± 5 year and 57.4 ± 6.3 mL kg-1 min-1 ) completed 3 exercise sessions: without (CON) or with blood flow restriction (BFR), or in systemic hypoxia (HYP, ~3250 m). A muscle sample was collected before (Pre) and after exercise (+0 hour, +3 hours) to quantify mRNA, indicators of oxidative stress (HSP27 protein in type I and II fibres, and catalase and HSP70 mRNA), metabolites, and α-AMPK Thr172 /α-AMPK, ACC Ser221 /ACC, CaMKII Thr287 /CaMKII, and PLBSer16 /PLB ratios in type I and II fibres. RESULTS: Muscle hypoxia (assessed by near-infrared spectroscopy) was matched between BFR and HYP, which was higher than CON (~90% vs ~70%; P
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Repeated-ischaemic exercise enhances mitochondrial and ion transport gene adaptations in human skeletal muscle: Role of muscle redox state and AMPK
bioRxiv, 2017Co-Authors: Danny Christiansen, Jens Bangsbo, Robyn M Murphy, Christos G Stathis, David BishopAbstract:This study assessed the effect of repeated-ischaemic exercise on the mRNA content of PGC-1α (total, 1α1, and 1α4) and Na+,K+-ATPase (NKA; α1-3, β1-3, and FXYD1) isoforms in human skeletal muscle, and studied some of the potential molecular mechanisms involved. Eight trained men (26 y and 57.4 mL·kg-1·min-1) completed three interval running sessions with (ISC) or without ischaemia (CON), or in hypoxia (HYP, ~3250 m), in a randomised, crossover fashion separated by 1 week. A muscle sample was collected from the dominant leg before (Pre) and after exercise (+0h, +3h) in all sessions to measure the mRNA content of PGC-1α and NKA isoforms, oxidative stress markers (i.e. catalase and HSP70 mRNA), muscle lactate, and phosphorylation of AMPK, ACC, CaMKII, and PLB protein in type I and II fibres. Muscle hypoxia (i.e. deoxygenated haemoglobin) was matched between ISC and HYP, which was higher than in CON (~90% vs. ~70%; p
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Post-exercise cold-water immersion increases Na+,K+-ATPase α2-isoform mRNA content in parallel with elevated Sp1 expression in human skeletal muscle
bioRxiv, 2017Co-Authors: Danny Christiansen, Jens Bangsbo, Robyn M Murphy, James R. Broatch, Michael J. Mckenna, Jujiao Kuang, David BishopAbstract:We investigated the effect of a session of sprint-interval exercise on the mRNA content of NKA isoforms (a1-3, b1-3) and FXYD1 in human skeletal muscle. To explore some of the cellular stressors involved in this regulation, we evaluated the association between these mRNA responses and those of the transcription factors Sp1, Sp3 and HIF-1a. Given cold exposure perturbs muscle redox homeostasis, which may be one mechanism important for increases in NKA-isoform mRNA, we also explored the effect of post-exercise cold-water immersion (CWI) on the mRNA responses. Muscle was sampled from nineteen men before (Pre) and after (+0h, +3h) exercise plus passive rest (CON, n=10) or CWI (10 degrees C; COLD, n=9). In COLD, exercise increased NKAa2 and Sp1 mRNA (+0h, p 0.05). In both conditions, exercise increased NKAa1, NKAb3 and HIF-1a mRNA (+3h; p 0.05). These human findings highlight 1) sprint-interval exercise increases the mRNA content of NKAa1 and b3, and decreases that of NKA b2, which may relate, in part, to exercise-induced muscle hypoxia, and 2) post-exercise CWI augments NKAa2 mRNA, which may be associated with promoted Sp1 activation.
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regulation of na k atpase isoforms and phospholemman FXYD1 in skeletal muscle fibre types by exercise training and cold water immersion in men
bioRxiv, 2017Co-Authors: Danny Christiansen, Jens Bangsbo, Robyn M Murphy, James R. Broatch, Michael J. Mckenna, David BishopAbstract:Little is understood about the fibre type-dependent regulation of Na+,K+-ATPase (NKA) isoforms by exercise training in humans. The main aim of this study was therefore to assess the impact of a period of repeated exercise sessions on NKA-isoform protein abundance in different skeletal muscle fibre types in men. Post-exercise cold-water immersion (CWI) has been reported to increase oxidative stress, which may be one mechanism underlying increases in NKA-isoform expression. Thus, a second aim was to evaluate the effect of CWI on training-induced modulation of NKA-isoform abundance. Vastus lateralis muscle biopsies were obtained from nineteen men at rest before (Pre) and after (Post) six weeks of intense interval cycling, with training sessions followed by passive rest (CON, n=7) or CWI (10 degrees C; COLD, n=5). Training increased (p 0.05). Furthermore, training decreased FXYD1 protein content in type I fibres, which abolished its fibre type-specific expression detected at Pre (p 0.05). These results highlight that NKA isoforms are regulated in a fibre type-dependent fashion in response to intense training in humans. This may partly explain the improvement in muscle Na+/K+ handling after a period of intense training. CWI may be performed without adversely or favourably affecting training-induced changes in NKA-isoform abundance.
Kristen J Bubb - One of the best experts on this subject based on the ideXlab platform.
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oxidative modification of the cardiac sodium potassium pump is worsened in the absence of FXYD1 contributing to cardiac dysfunction and fibrosis
Free Radical Biology and Medicine, 2018Co-Authors: Kristen J Bubb, Thomas Hansen, Owen Tang, Gemma A. FigtreeAbstract:Introduction FXYD1 is a small membrane protein that endogenously protects the cardiac Na+-K+ ATPase from oxidative inhibition. Given the importance of the Na+-K+ ATPase in normal cardiac function, we hypothesized that absence of FXYD1 would worsen reactive oxygen species (ROS)-induced cardiac dysfunction. Methods and Results In studies were performed using wild-type (WT) and FXYD1 knockout (KO) mice. FXYD1 KO mice are prone to exacerbated vascular superoxide generation (P Summary This data defines a new role for FXYD1 in preventing cardiac dysfunction and fibrosis characterized by elevated ROS. Impaired oxidative inhibition of the Na+-K+ ATPase β1 subunit plays a likely role in mediating this protective response.
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abstract 20047 FXYD1 protects against reactive oxygen species dependent cardiac remodelling and fibrosis
Circulation, 2017Co-Authors: Kristen J Bubb, Owen Tang, Thomas F Hansen, Carmine Gentile, Gemma A. FigtreeAbstract:Introduction: Fibrosis plays a critical role in cardiac pathophysiology. We have shown FXYD1 to be an endogenous protector of oxidative inhibition of the cardiac membrane Na+-K+ ATPase. However, the effects of FXYD1 on longer term cardiac signalling, and particularly cardiac fibrosis have not been examined. We hypothesized that absence of FXYD1 would worsen Angiotensin II-induced cardiac fibrosis. Methods and Results: In vivo studies were performed using wild-type (WT) and FXYD1 knockout (KO) mice. Under baseline conditions, cardiac perivascular fibrosis was ~3-fold higher in KO vs. WT mice (P<0.01), however interstitial fibrosis was absent. To stimulate cardiac interstitial fibrosis, Ang II (0.72 or 2.1 mg/kg/day) was infused via subcutaneous osmotic mini pump for 2 weeks. Ang II infusion resulted in elevated blood pressure (11 mmHg higher in FXYD1 KO mice vs. WT mice; P=0.01). This was associated with dose-dependent cardiac hypertrophy in FXYD1 KO mice (heart:body weight [mg/kg] sham: 4.8 +/- 0.3; AngII...
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Abstract 20047: FXYD1 Protects Against Reactive Oxygen Species-Dependent Cardiac Remodelling and Fibrosis
Circulation, 2017Co-Authors: Kristen J Bubb, Owen Tang, Thomas F Hansen, Carmine Gentile, Gemma A. FigtreeAbstract:Introduction: Fibrosis plays a critical role in cardiac pathophysiology. We have shown FXYD1 to be an endogenous protector of oxidative inhibition of the cardiac membrane Na+-K+ ATPase. However, the effects of FXYD1 on longer term cardiac signalling, and particularly cardiac fibrosis have not been examined. We hypothesized that absence of FXYD1 would worsen Angiotensin II-induced cardiac fibrosis. Methods and Results: In vivo studies were performed using wild-type (WT) and FXYD1 knockout (KO) mice. Under baseline conditions, cardiac perivascular fibrosis was ~3-fold higher in KO vs. WT mice (P
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abstract 15521 FXYD1 protects against redox dependent uncoupling of endothelial nitric oxide synthase
Circulation, 2016Co-Authors: Kristen J Bubb, Keyvan Karimi Galougahi, Owen Tang, Thomas F Hansen, Gemma A. FigtreeAbstract:Background: Vascular health is dependent on the vasoprotective molecule, nitric oxide (NO), produced by endothelial NO synthase (eNOS). Under conditions of oxidative stress such as diabetes and hypertension, eNOS becomes “uncoupled” via glutathionylation, preferentially producing the damaging free radical, superoxide (O2 .- ). Discovery of protective mechanisms against this will have critical implications for vascular function in health and disease. We hypothesised that caveolar co-localisation of FXYD1 and eNOS may result in functional interaction and redox signalling in the vasculature. Methods and results: FXYD1-eNOS co-localisation was demonstrated by both proximity ligation assay and co-immunoprecipitation in human umbilical vein endothelial cells (HUVECs). eNOS glutathionylation, assessed by co-immunoprecipitation of eNOS and glutathione, was significantly increased (~1.5 fold, p=0.04, n=3) after silencing of FXYD1 using siRNA and this was associated with reduced NO bioavailability, as assessed by diaminofluorescein stain after acetylcholine stimulation (~60% reduction, p .- production, determined by lucigenin enhanced chemiluminescence (n = 3, P .- production in FXYD1 knockout (KO) mice (n = 5, P Conclusions: Our findings demonstrated a novel functional partnership of FXYD1 with eNOS, protecting this vital enzyme from glutathionylation-mediated uncoupling. This has important implications for our understanding of ROS-signalling in the vasculature and could lead to novel treatment options with recombinant FXYD1 for redox-dependent vascular disease.
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FXYD1 protects against redox dependent endothelial dysfunction and angiotensin ii induced hypertension
Free Radical Biology and Medicine, 2016Co-Authors: Kristen J Bubb, Gemma A. Figtree, Keyvan Karimi Galougahi, Thomas Hansen, Owen TangAbstract:Background Protein S-glutathionylation (GSS) can increase the generation of reactive oxygen species and cause eNOS uncoupling, thereby reducing nitric oxide (NO) bioavailability. Thus, mechanisms that protect against eNOS-GSS could improve vascular function and cardiovascular health. We hypothesised that caveolar co-localisation of FXYD1 with eNOS may result in functional interaction and ‘protective’ redox signalling in the vasculature. Methods and results: Blood pressure (MABP), measured by arterial cannulation was not different between anaesthetised FXYD1 wildtype (WT) and knockout (KO) mice (MABP (mmHg): WT 88.7±1.3 vs. KO 91.1 ± 2.2, n=7); confirmed by telemetry in conscious mice. Endothelium-dependent vasodilation, determined by MABP changes after increasing bolus doses of bradykinin acetate, was impaired in KO mice (max ΔmmHg at 10 µg/kg: KO -9.6±1.4 vs. WT -16.6±1.7, P Conclusions We have identified a functional partnership of FXYD1 with eNOS, protecting this vital enzyme from GSS-mediated eNOS uncoupling. This could lead to novel treatment options with recombinant FXYD1 for redox-dependent vascular disease.
