Publications by authors named "Ylva Hellsten"

131 Publications

AXIN1 knockout does not alter AMPK/mTORC1 regulation and glucose metabolism in mouse skeletal muscle.

J Physiol 2021 Apr 29. Epub 2021 Apr 29.

Section for Molecular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

Key Points: Tamoxifen-inducible skeletal muscle-specific AXIN1 knockout (AXIN1 imKO) in mouse does not affect whole-body energy substrate metabolism. AXIN1 imKO does not affect AICAR or insulin-stimulated glucose uptake in adult skeletal muscle AXIN1 imKO does not affect adult skeletal muscle AMPK or mTORC1 signaling during AICAR/insulin/amino acid incubation, contraction and exercise. During exercise, α2/β2/γ3AMPK and AMP/ATP ratio show greater increases in AXIN1 imKO than wild-type in gastrocnemius muscle.

Abstract: AXIN1 is a scaffold protein known to interact with >20 proteins in signal transduction pathways regulating cellular development and function. Recently, AXIN1 was proposed to assemble a protein complex essential to catabolic-anabolic transition by coordinating AMPK activation and inactivation of mTORC1 and to regulate glucose uptake-stimulation by both AMPK and insulin. To investigate whether AXIN1 is permissive for adult skeletal muscle function, a phenotypic in vivo and ex vivo characterization of tamoxifen-inducible skeletal muscle-specific AXIN1 knockout (AXIN1 imKO) mice was conducted. AXIN1 imKO did not influence AMPK/mTORC1 signaling or glucose uptake stimulation, neither at rest nor in response to different exercise/contraction protocols, pharmacological AMPK activation, insulin or amino acids stimulation. The only genotypic difference observed was in exercising gastrocnemius muscle, where AXIN1 imKO displayed elevated α2/β2/γ3 AMPK activity and AMP/ATP ratio compared to wild-type mice. Our work shows that AXIN1 imKO generally does not affect skeletal muscle AMPK/mTORC1 signaling and glucose metabolism, likely due to functional redundancy of its homolog AXIN2. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1113/JP281187DOI Listing
April 2021

Effect of aerobic exercise training on asthma control in postmenopausal women (the ATOM-study): protocol for an outcome assessor, randomised controlled trial.

BMJ Open 2021 Apr 22;11(4):e049477. Epub 2021 Apr 22.

Centre for Physical Activity Research, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark.

Introduction: Late-onset asthma in postmenopausal women is characterised by poor disease control with daily symptoms and reduced quality of life despite treatment with inhaled antiasthma therapies. These patients represent a phenotype that is characterised by low eosinophilic airway inflammation, severe symptoms, moderate obesity and poor response to inhaled antiasthma therapies, which highlights the need of identification of alternative treatment strategies. Thus, this study aims to evaluate if regular high-intensity aerobic exercise improves symptom control in postmenopausal women with asthma.

Methods And Analysis: This is an ongoing randomised controlled trial planning to enrol 40 postmenopausal women with late-onset asthma. Participants are randomised 1:1 either to supervised exercise training (spinning) three times per week for 12 weeks or to usual care. The primary outcome is change from baseline to follow-up in the Asthma Control Questionnaire. Secondary outcomes are changes in markers of systemic inflammation, airway inflammation, body composition and right ventricular function of the heart.

Ethics And Dissemination: The study is approved by the Ethics Committee in the Capital Region of Denmark nr. H-18028966 and the Danish Data Protection Agency nr. VD-2019-59. The methods used in the study are well known and have a low risk with a chance of substantial improvement in disease control in this patient group. Results are planned to be published in an international peer-reviewed medical journal regardless of outcome.

Trial Registration Number: NCT03747211.
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http://dx.doi.org/10.1136/bmjopen-2021-049477DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8070869PMC
April 2021

Histamine H and H receptors are essential transducers of the integrative exercise training response in humans.

Sci Adv 2021 Apr 14;7(16). Epub 2021 Apr 14.

Department of Movement and Sports Sciences, Ghent University, Ghent 9000, Belgium.

Exercise training is a powerful strategy to prevent and combat cardiovascular and metabolic diseases, although the integrative nature of the training-induced adaptations is not completely understood. We show that chronic blockade of histamine H/H receptors led to marked impairments of microvascular and mitochondrial adaptations to interval training in humans. Consequently, functional adaptations in exercise capacity, whole-body glycemic control, and vascular function were blunted. Furthermore, the sustained elevation of muscle perfusion after acute interval exercise was severely reduced when H/H receptors were pharmaceutically blocked. Our work suggests that histamine H/H receptors are important transducers of the integrative exercise training response in humans, potentially related to regulation of optimal post-exercise muscle perfusion. These findings add to our understanding of how skeletal muscle and the cardiovascular system adapt to exercise training, knowledge that will help us further unravel and develop the exercise-is-medicine concept.
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http://dx.doi.org/10.1126/sciadv.abf2856DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8046361PMC
April 2021

A High Activity Level Is Required for Augmented Muscle Capillarization in Older Women.

Med Sci Sports Exerc 2021 May;53(5):894-903

Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, DENMARK.

Purpose: This study aimed to evaluate the influence of lifelong regular physical activity on skeletal muscle capillarization in women.

Methods: Postmenopausal women, 61±4 yr old, were divided according to self-reported physical activity level over the past 20 yrs: sedentary (SED; n = 14), moderately active (MOD; n = 12), and very active (VERY; n = 15). Leg blood flow (LBF) was determined by ultrasound Doppler, and blood samples were drawn from the femoral artery and vein for calculation of leg oxygen uptake (LVO2) at rest and during one-legged knee extensor exercise. A skeletal muscle biopsy was obtained from the vastus lateralis and analyzed for capillarization and vascular endothelial growth factor (VEGF) and mitochondrial OXPHOS proteins. Platelets were isolated from venous blood and analyzed for VEGF content and effect on endothelial cell proliferation.

Results: The exercise-induced rise in LBF and LVO2 was faster (P = 0.008) in VERY compared with SED and MOD. Steady-state LBF and LVO2 were lower (P < 0.04) in MOD and VERY compared with SED. Capillary-fiber ratio and capillary density were greater (P < 0.03) in VERY (1.65 ± 0.48 and 409.3 ± 57.5) compared with MOD (1.30 ± 0.19 and 365.0 ± 40.2) and SED (1.30 ± 0.30 and 356.2 ± 66.3). Skeletal muscle VEGF and OXPHOS complexes I, II, and V were ~1.6-fold and ~1.25-fold (P < 0.01) higher, respectively, in VERY compared with SED. Platelets from all groups induced an approximately nine-fold (P < 0.001) increase in endothelial cell proliferation.

Conclusion: A very active lifestyle is associated with superior skeletal muscle exercise hemodynamics and greater potential for oxygen extraction concurrent with a higher skeletal muscle capillarization and mitochondrial capacity.
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http://dx.doi.org/10.1249/MSS.0000000000002566DOI Listing
May 2021

The Impact of Lower Limb Immobilization and Rehabilitation on Angiogenic Proteins and Capillarization in Skeletal Muscle.

Med Sci Sports Exerc 2021 Mar 25. Epub 2021 Mar 25.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark Technical University of Munich, Germany. Sylvia Lawry Centre for Multiple Sclerosis Research, Munich, Germany.

Purpose: Skeletal muscle vascularization is important for tissue regeneration after injury and immobilization. We examined whether complete immobilization influences capillarization and oxygen delivery to the muscle and assessed the efficacy of rehabilitation by aerobic exercise training.

Methods: Young healthy males had one leg immobilized for 14 days and subsequently completed four weeks of intense aerobic exercise training. Biopsies were obtained from m.vastus lateralis and a-v blood sampling for assessment of oxygen extraction and leg blood flow during exercise was done before and after immobilization and training. Muscle capillarization, muscle and platelet content of vascular endothelial growth factor (VEGF) and muscle thrombospondin-1 were determined.

Results: Immobilization did not have a significant impact on capillary per fiber ratio or capillary density. The content of VEGF protein in muscle samples was reduced by 36% (P=0.024) and VEGF to thrombospondin-1 ratio was 94 % lower (P=0.046). The subsequent four-week training period increased the muscle VEGF content and normalized the muscle VEGF to thrombospondin-1 ratio but did not influence capillarization. Platelet VEGF content followed the trend of muscle VEGF. At the functional level, oxygen extraction, blood flow and oxygen delivery at rest and during submaximal exercise were not affected by immobilization or training.

Conclusion: The results demonstrate that just two weeks of leg immobilization leads to a strongly reduced angiogenic potential as evidenced by reduced muscle and platelet VEGF content and a reduced muscle VEGF to thrombospondin-1 ratio. Moreover, a subsequent period of intensive aerobic exercise training fails to increase capillarization in the previously immobilized leg, possibly due to the angiostatic condition caused by immobilization.
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http://dx.doi.org/10.1249/MSS.0000000000002665DOI Listing
March 2021

Does Exercise Influence the Susceptibility to Arterial Thrombosis? An Integrative Perspective.

Front Physiol 2021 23;12:636027. Epub 2021 Feb 23.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

Arterial thrombosis is the primary cause of death worldwide, with the most important risk factors being smoking, unhealthy diet, and physical inactivity. However, although there are clear indications in the literature of beneficial effects of physical activity in lowering the risk of cardiovascular events, exercise can be considered a double-edged sword in that physical exertion can induce an immediate pro-thrombotic environment. Epidemiological studies show an increased risk of cardiovascular events after acute exercise, a risk, which appear to be particularly apparent in individuals with lifestyle-related disease. Factors that cause the increased susceptibility to arterial thrombosis with exercise are both chemical and mechanical in nature and include circulating catecholamines and vascular shear stress. Exercise intensity plays a marked role on such parameters, and evidence in the literature accordingly points at a greater susceptibility to thrombus formation at high compared to light and moderate intensity exercise. Of importance is, however, that the susceptibility to arterial thrombosis appears to be lower in exercise-conditioned individuals compared to sedentary individuals. There is currently limited data on the role of acute and chronic exercise on the susceptibility to arterial thrombosis, and many studies include incomplete assessments of thrombogenic clotting profile. Thus, further studies on the role of exercise, involving valid biomarkers, are clearly warranted.
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http://dx.doi.org/10.3389/fphys.2021.636027DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940832PMC
February 2021

Effects of High-Intensity Exercise Training on Adipose Tissue Mass, Glucose Uptake and Protein Content in Pre- and Post-menopausal Women.

Front Sports Act Living 2020 17;2:60. Epub 2020 Jun 17.

Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark.

The menopausal transition is accompanied by changes in adipose tissue storage, leading to an android body composition associated with increased risk of type 2 diabetes and cardiovascular disease in post-menopausal women. Estrogens probably affect local adipose tissue depots differently. We investigated how menopausal status and exercise training influence adipose tissue mass, adipose tissue insulin sensitivity and adipose tissue proteins associated with lipogenesis/lipolysis and mitochondrial function. Healthy, normal-weight pre- ( = 21) and post-menopausal ( = 20) women participated in high-intensity exercise training three times per week for 12 weeks. Adipose tissue distribution was determined by dual-energy x-ray absorptiometry and magnetic resonance imaging. Adipose tissue glucose uptake was assessed by positron emission tomography/computed tomography (PET/CT) by the glucose analog [18F]fluorodeoxyglucose ([18F]FDG) during continuous insulin infusion (40 mU·m·min). Protein content associated with insulin signaling, lipogenesis/lipolysis, and mitochondrial function were determined by western blotting in abdominal and femoral white adipose tissue biopsies. The mean age difference between the pre- and the post-menopausal women was 4.5 years. Exercise training reduced subcutaneous (~4%) and visceral (~6%) adipose tissue masses similarly in pre- and post-menopausal women. Insulin-stimulated glucose uptake, assessed by [18F]FDG-uptake during PET/CT, was similar in pre- and post-menopausal women in abdominal, gluteal, and femoral adipose tissue depots, despite skeletal muscle insulin resistance in post- compared to pre-menopausal women in the same cohort. Insulin-stimulated glucose uptake in adipose tissue depots was not changed after 3 months of high-intensity exercise training, but insulin sensitivity was higher in visceral compared to subcutaneous adipose tissue depots (~139%). Post-menopausal women exhibited increased hexokinase and adipose triglyceride lipase content in subcutaneous abdominal adipose tissue. Physical activity in the early post-menopausal years reduces abdominal obesity, but insulin sensitivity of adipose tissue seems unaffected by both menopausal status and physical activity.
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http://dx.doi.org/10.3389/fspor.2020.00060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739715PMC
June 2020

Assessment of diabetic foot ulcers based on pictorial material: an interobserver study.

J Wound Care 2020 Nov;29(11):658-663

Department of Orthopedic Surgery, Zealand University Hospital; Department of Clinical Medicine, University of Copenhagen.

Objective: The frequent change in clinicians, and the emerging use of photographic documentation in wound management, could require a more diverse treatment of patients due to poor interobserver agreement. The aim of this study was to assess the interobserver agreement of a commonly used classification system for diabetic foot ulcers (DFUs), the Meggitt-Wagner classification, and to compare the agreement on classification with the agreement in treatment recommendations.

Method: An interobserver study was conducted based on a questionnaire linked to 30 photographs of DFUs. Different groups of observers were tested to investigate whether there was a difference between professions or level of education: experienced orthopaedic wound care doctors (n=7); nurses specialised in wound care (n=8) and untrained nurses assigned to a diabetic wound care training course (n=23). Krippendorff's alpha was used to calculate interobserver agreement, and an agreement of >0.67 was defined as substantial.

Results: The Krippendorff's alpha value for interobserver agreement on the Meggitt-Wagner classification was 0.52 for the doctors group, 0.67 for the specialised nurses and 0.61 for the untrained nurses. The corresponding values regarding agreement on recommendation of surgical revision of the wound were 0.35, 0.22 and 0.15, respectively. The choice of dressing type or antibiotic treatment had even lower interobserver agreement.

Conclusions: The interobserver agreement on the Meggitt-Wagner classification was substantial in the specialised nurse group, but the evaluation and treatment of DFUs should not be exclusively based on pictorial materials.
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http://dx.doi.org/10.12968/jowc.2020.29.11.658DOI Listing
November 2020

Ischemic Preconditioning Improves Microvascular Endothelial Function in Remote Vasculature by Enhanced Prostacyclin Production.

J Am Heart Assoc 2020 08 29;9(15):e016017. Epub 2020 Jul 29.

Section of Integrative Physiology Department of Nutrition, Exercise and Sports University of Copenhagen Denmark.

BACKGROUND The mechanisms underlying the effect of preconditioning on remote microvasculature remains undisclosed. The primary objective was to document the remote effect of ischemic preconditioning on microvascular function in humans. The secondary objective was to test if exercise also induces remote microvascular effects. METHODS AND RESULTS A total of 12 healthy young men and women participated in 2 experimental days in a random counterbalanced order. On one day the participants underwent 4×5 minutes of forearm ischemic preconditioning, and on the other day they completed 4×5 minutes of hand-grip exercise. On both days, catheters were placed in the brachial and femoral artery and vein for infusion of acetylcholine, sodium nitroprusside, and epoprostenol. Vascular conductance was calculated from blood flow measurements with ultrasound Doppler and arterial and venous blood pressures. Ischemic preconditioning enhanced (<0.05) the remote vasodilator response to intra-arterial acetylcholine in the leg at 5 and 90 minutes after application. The enhanced response was associated with a 6-fold increase (<0.05) in femoral venous plasma prostacyclin levels and with a transient increase (<0.05) in arterial plasma levels of brain-derived neurotrophic factor and vascular endothelial growth factor. In contrast, hand-grip exercise did not influence remote microvascular function. CONCLUSIONS These findings demonstrate that ischemic preconditioning of the forearm improves remote microvascular endothelial function and suggest that one of the underlying mechanisms is a humoral-mediated potentiation of prostacyclin formation.
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http://dx.doi.org/10.1161/JAHA.120.016017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7792245PMC
August 2020

Inducible deletion of skeletal muscle AMPKα reveals that AMPK is required for nucleotide balance but dispensable for muscle glucose uptake and fat oxidation during exercise.

Mol Metab 2020 10 3;40:101028. Epub 2020 Jun 3.

Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, DK-2100, Copenhagen, Denmark. Electronic address:

Objective: Evidence for AMP-activated protein kinase (AMPK)-mediated regulation of skeletal muscle metabolism during exercise is mainly based on transgenic mouse models with chronic (lifelong) disruption of AMPK function. Findings based on such models are potentially biased by secondary effects related to a chronic lack of AMPK function. To study the direct effect(s) of AMPK on muscle metabolism during exercise, we generated a new mouse model with inducible muscle-specific deletion of AMPKα catalytic subunits in adult mice.

Methods: Tamoxifen-inducible and muscle-specific AMPKα1/α2 double KO mice (AMPKα imdKO) were generated by using the Cre/loxP system, with the Cre under the control of the human skeletal muscle actin (HSA) promoter.

Results: During treadmill running at the same relative exercise intensity, AMPKα imdKO mice showed greater depletion of muscle ATP, which was associated with accumulation of the deamination product IMP. Muscle-specific deletion of AMPKα in adult mice promptly reduced maximal running speed and muscle glycogen content and was associated with reduced expression of UGP2, a key component of the glycogen synthesis pathway. Muscle mitochondrial respiration, whole-body substrate utilization, and muscle glucose uptake and fatty acid (FA) oxidation during muscle contractile activity remained unaffected by muscle-specific deletion of AMPKα subunits in adult mice.

Conclusions: Inducible deletion of AMPKα subunits in adult mice reveals that AMPK is required for maintaining muscle ATP levels and nucleotide balance during exercise but is dispensable for regulating muscle glucose uptake, FA oxidation, and substrate utilization during exercise.
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http://dx.doi.org/10.1016/j.molmet.2020.101028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356270PMC
October 2020

Microvascular Function Is Impaired after Short-Term Immobilization in Healthy Men.

Med Sci Sports Exerc 2020 10;52(10):2107-2116

Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, DENMARK.

Purpose: We examined whether 2 wk of one-leg immobilization would impair leg microvascular function and to what extent a subsequent period of intense aerobic cycle training could restore function.

Methods: Study participants were healthy young men (n = 12; 20-24 yr of age). Leg microvascular function was determined before the intervention, after the immobilization period, and after a 4-wk exercise training period. Microvascular function was assessed as the vasodilator response to intra-arterial infusion of acetylcholine and sodium nitroprusside and as the vasoconstrictor response to endogenous noradrenaline release induced by tyramine infusion. Vasodilator enzymes as well as prooxidant and antioxidant enzymes were assessed by protein analysis in skeletal muscle samples: endothelial nitric oxide synthase, NADPH oxidase (NOX p67 and NOX gp91), and superoxide dismutase 2 (SOD2).

Results: The acetylcholine-induced change in vascular conductance was reduced after the 2 wk of immobilization (P = 0.003), tended to increase (P = 0.061), and was back to baseline levels after the subsequent 4 wk of exercise training. Plasma prostacyclin levels in response to acetylcholine infusion were lower after immobilization than before (P = 0.041). The changes in vascular conductance with sodium nitroprusside and tyramine were similar during all conditions. Skeletal muscle protein levels of endothelial nitric oxide synthase in the experimental leg were unchanged with immobilization and subsequent training but increased 47% in the control leg with training (P = 0.002). NOX p67, NOX gp91, and SOD2 in the experimental leg remained unaltered with immobilization, and SOD2 was higher than preimmobilization after 4 wk of training (P < 0.001).

Conclusions: The study shows that 2 wk of immobilization impairs leg microvascular endothelial function and prostacyclin formation but that 4 wk of intense aerobic exercise training restores the function. The underlying mechanism may reside in the prostacyclin system.
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http://dx.doi.org/10.1249/MSS.0000000000002369DOI Listing
October 2020

Effect of aerobic exercise training on asthma in adults: a systematic review and meta-analysis.

Eur Respir J 2020 07 30;56(1). Epub 2020 Jul 30.

Dept of Physical and Occupational Therapy, Copenhagen University Hospital Bispebjerg-Frederiksberg, Copenhagen, Denmark.

Objective: To evaluate the effect of aerobic exercise training on asthma control, lung function and airway inflammation in adults with asthma.

Design: Systematic review and meta-analysis.

Methods: Randomised controlled trials investigating the effect of ≥8 weeks of aerobic exercise training on outcomes for asthma control, lung function and airway inflammation in adults with asthma were eligible for study. MEDLINE, Embase, CINAHL, PEDro and the Cochrane Central Register of Controlled Trials (CENTRAL) were searched up to April 3, 2019. Risk of bias was assessed using the Cochrane Risk of Bias Tool.

Results: We included 11 studies with a total of 543 adults with asthma. Participants' mean (range) age was 36.5 (22-54) years; 74.8% of participants were female and the mean (range) body mass index was 27.6 (23.2-38.1) kg·m. Interventions had a median (range) duration of 12 (8-12) weeks and included walking, jogging, spinning, treadmill running and other unspecified exercise training programmes. Exercise training improved asthma control with a standard mean difference (SMD) of -0.48 (-0.81--0.16). Lung function slightly increased with an SMD of -0.36 (-0.72-0.00) in favour of exercise training. Exercise training had no apparent effect on markers of airway inflammation (SMD -0.03 (-0.41-0.36)).

Conclusions: In adults with asthma, aerobic exercise training has potential to improve asthma control and lung function, but not airway inflammation.
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http://dx.doi.org/10.1183/13993003.00146-2020DOI Listing
July 2020

Early time course of change in angiogenic proteins in human skeletal muscle and vascular cells with endurance training.

Scand J Med Sci Sports 2020 Jul 20;30(7):1117-1131. Epub 2020 Apr 20.

Integrative Physiology Section, Cardiovascular Physiology, Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

Angiogenic, mitochondrial, and related transcriptional proteins were assessed in human skeletal muscle and isolated vascular cells during the early phase of endurance training. Thigh muscle biopsies were obtained in healthy young subjects, after one acute bout (n = 9) and after 3, 5, 7, and 14 days (n = 9) of cycle ergometer training. Whole muscle homogenates were analyzed for angiogenic, mitochondrial, and regulatory mRNA and protein levels. Angiogenic proteins were determined in muscle-derived endothelial cells and pericytes sorted by fluorescence-activated cell sorting. Acute exercise induced an increase in whole muscle mRNA of peroxisome proliferator-activated receptor gamma coactivator 1α (4.5-fold; P = .002) and vascular endothelial growth factor (VEGF) (2.4-fold; P = .001) at 2 hours post. After 14 days of training, there was an increase in CD31 protein (63%; P = .010) in whole muscle indicating capillary growth. There was also an increase in muscle VEGF receptor 2 (VEGFR2) (1.5-fold; P = .013), in OXPHOS proteins (complex I, II, IV, V; 1.4- to 1.9-fold; P < .05) after 14 days of training and an increase in estrogen-related receptorα protein (1.5-fold; P = .039) at 14 days compared to 5 days of training. Both endothelial cells and pericytes expressed VEGF and other angiogenic factors at the protein level but with a distinctively lower expression of VEGFR2 and thrombospondin-1 (TSP-1) in pericytes. The findings illustrate that initiation of capillary and mitochondrial adaptations occurs within 14 days of training and suggest that sustained changes in angiogenic proteins including VEGF and TSP-1 are moderate in whole muscle and vascular cells.
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http://dx.doi.org/10.1111/sms.13665DOI Listing
July 2020

The impact of acute remote ischaemic preconditioning on cerebrovascular function.

Eur J Appl Physiol 2020 Mar 13;120(3):603-612. Epub 2020 Jan 13.

Research Institute of Sport and Exercise Science, Liverpool John Moores University, Tom Reilly Building, Byrom Street, Liverpool, L3 3AF, UK.

Purpose: Remote ischaemic preconditioning (RIPC) refers to the protection conferred to tissues and organs via brief periods of ischaemia in a remote vascular territory, including the brain. Recent studies in humans report that RIPC provides neuroprotection against recurrent (ischaemic) stroke. To better understand the ability of RIPC to improve brain health, the present study explored the potential for RIPC to acutely improve cerebrovascular function.

Methods: Eleven young healthy (females n = 6, age; 28.1 ± 3.7 years) and 9 older individuals (females n = 4, age 52.5 ± 6.7 years) at increased risk for stroke (cardiovascular disease risk factors) underwent assessments of cerebrovascular function, assessed by carbon dioxide (CO) reactivity and cerebral autoregulation during normo- and hypercapnia (5% CO) following 40 mins of bilateral arm RIPC or a sham condition. Squat-to-stand manoeuvres were performed to induce changes in blood pressure to assess cerebral autoregulation (0.10 Hz) and analysed via transfer function.

Results: We found no change in middle cerebral artery velocity or blood pressure across 40 mins of RIPC. Application of RIPC resulted in no change in CO reactivity slopes (sham vs RIPC, 1.97 ± 0.88 vs 2.06 ± 0.69 cm/s/mmHg P = 0.61) or parameters of cerebral autoregulation during normocapnia (sham vs RIPC, normalised gain%, 1.27 ± 0.25 vs 1.22 ± 0.35, P = 0.46).

Conclusion: This study demonstrates that a single bout of RIPC does not influence cerebrovascular function acutely in healthy individuals, or those at increased cardiovascular risk. Given the previously reported protective role of RIPC on stroke recurrence in humans, it is possible that repeated bouts of RIPC may be necessary to impart beneficial effects on cerebrovascular function.
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http://dx.doi.org/10.1007/s00421-019-04297-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7042189PMC
March 2020

Assessment of resistance vessel function in human skeletal muscle: guidelines for experimental design, Doppler ultrasound, and pharmacology.

Am J Physiol Heart Circ Physiol 2020 02 30;318(2):H301-H325. Epub 2019 Dec 30.

Department of Nutrition and Exercise Physiology, University of Missouri, Columbia, Missouri.

The introduction of duplex Doppler ultrasound almost half a century ago signified a revolutionary advance in the ability to assess limb blood flow in humans. It is now widely used to assess blood flow under a variety of experimental conditions to study skeletal muscle resistance vessel function. Despite its pervasive adoption, there is substantial variability between studies in relation to experimental protocols, procedures for data analysis, and interpretation of findings. This guideline results from a collegial discussion among physiologists and pharmacologists, with the goal of providing general as well as specific recommendations regarding the conduct of human studies involving Doppler ultrasound-based measures of resistance vessel function in skeletal muscle. Indeed, the focus is on methods used to assess resistance vessel function and not upstream conduit artery function (i.e., macrovasculature), which has been expertly reviewed elsewhere. In particular, we address topics related to experimental design, data collection, and signal processing as well as review common procedures used to assess resistance vessel function, including postocclusive reactive hyperemia, passive limb movement, acute single limb exercise, and pharmacological interventions.
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http://dx.doi.org/10.1152/ajpheart.00649.2019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7052621PMC
February 2020

Early sarcomere and metabolic defects in a zebrafish cardiac arrhythmia model.

Proc Natl Acad Sci U S A 2019 11 8;116(48):24115-24121. Epub 2019 Nov 8.

Laboratory for Molecular Cardiology, Department of Cardiology, Vascular, Pulmonary and Infectious Diseases, University Hospital of Copenhagen, 2100 Copenhagen, Denmark;

Atrial fibrillation (AF) is the most common type of cardiac arrhythmia. The major AF susceptibility locus 4q25 establishes long-range interactions with the promoter of , a transcription factor gene with critical functions during cardiac development. While many AF-linked loci have been identified in genome-wide association studies, mechanistic understanding into how genetic variants, including those at the 4q25 locus, increase vulnerability to AF is mostly lacking. Here, we show that loss of in zebrafish leads to adult cardiac phenotypes with substantial similarities to pathologies observed in AF patients, including arrhythmia, atrial conduction defects, sarcomere disassembly, and altered cardiac metabolism. These phenotypes are also observed in a subset of fish, mimicking the situation in humans. Most notably, the onset of these phenotypes occurs at an early developmental stage. Detailed analyses of loss- and gain-of-function embryonic hearts reveal changes in sarcomeric and metabolic gene expression and function that precede the onset of cardiac arrhythmia first observed at larval stages. We further find that antioxidant treatment of larvae significantly reduces the incidence and severity of cardiac arrhythmia, suggesting that metabolic dysfunction is an important driver of conduction defects. We propose that these early sarcomere and metabolic defects alter cardiac function and contribute to the electrical instability and structural remodeling observed in adult fish. Overall, these data provide insight into the mechanisms underlying the development and pathophysiology of some cardiac arrhythmias and importantly, increase our understanding of how developmental perturbations can predispose to functional defects in the adult heart.
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http://dx.doi.org/10.1073/pnas.1913905116DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6883774PMC
November 2019

Insulin-induced membrane permeability to glucose in human muscles at rest and following exercise.

J Physiol 2020 01 9;598(2):303-315. Epub 2020 Jan 9.

Section of Molecular Physiology, Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.

Key Points: Increased insulin action is an important component of the health benefits of exercise, but its regulation is complex and not fully elucidated. Previous studies of insulin-stimulated GLUT4 translocation to the skeletal muscle membrane found insufficient increases to explain the increases in glucose uptake. By determination of leg glucose uptake and interstitial muscle glucose concentration, insulin-induced muscle membrane permeability to glucose was calculated 4 h after one-legged knee-extensor exercise during a submaximal euglycaemic-hyperinsulinaemic clamp. It was found that during submaximal insulin stimulation, muscle membrane permeability to glucose in humans increases twice as much in previously exercised vs. rested muscle and outstrips the supply of glucose, which then becomes limiting for glucose uptake. This methodology can now be employed to determine muscle membrane permeability to glucose in people with diabetes, who have reduced insulin action, and in principle can also be used to determine membrane permeability to other substrates or metabolites.

Abstract: Increased insulin action is an important component of the health benefits of exercise, but the regulation of insulin action in vivo is complex and not fully elucidated. Previously determined increases in skeletal muscle insulin-stimulated GLUT4 translocation are inconsistent and mostly cannot explain the increases in insulin action in humans. Here we used leg glucose uptake (LGU) and interstitial muscle glucose concentration to calculate insulin-induced muscle membrane permeability to glucose, a variable not previously possible to quantify in humans. Muscle membrane permeability to glucose, measured 4 h after one-legged knee-extensor exercise, increased ∼17-fold during a submaximal euglycaemic-hyperinsulinaemic clamp in rested muscle (R) and ∼36-fold in exercised muscle (EX). Femoral arterial infusion of N -monomethyl l-arginine acetate or ATP decreased and increased, respectively, leg blood flow (LBF) in both legs but did not affect membrane glucose permeability. Decreasing LBF reduced interstitial glucose concentrations to ∼2 mM in the exercised but only to ∼3.5 mM in non-exercised muscle and abrogated the augmented effect of insulin on LGU in the EX leg. Increasing LBF by ATP infusion increased LGU in both legs with uptake higher in the EX leg. We conclude that it is possible to measure functional muscle membrane permeability to glucose in humans and it increases twice as much in exercised vs. rested muscle during submaximal insulin stimulation. We also show that muscle perfusion is an important regulator of muscle glucose uptake when membrane permeability to glucose is high and we show that the capillary wall can be a significant barrier for glucose transport.
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http://dx.doi.org/10.1113/JP278600DOI Listing
January 2020

Seven-day remote ischaemic preconditioning improves endothelial function in patients with type 2 diabetes mellitus: a randomised pilot study.

Eur J Endocrinol 2019 Dec;181(6):659-669

Research Institute of Sport and Exercise Science, Liverpool John Moores University, Liverpool, UK.

Background: Remote ischaemic preconditioning (rIPC) may improve cardiac/cerebrovascular outcomes of ischaemic events. Ischaemic damage caused by cardiovascular/cerebrovascular disease are primary causes of mortality in type 2 diabetes mellitus (T2DM). Due to the positive effects from a bout of rIPC within the vasculature, we explored if daily rIPC could improve endothelial and cerebrovascular function. The aim of this pilot study was to obtain estimates for the change in conduit artery and cerebrovascular function following a 7-day rIPC intervention.

Methods: Twenty-one patients with T2DM were randomly allocated to either 7-day daily upper-arm rIPC (4 × 5 min 220 mmHg, interspaced by 5-min reperfusion) or control. We examined peripheral endothelial function using flow mediated dilation (FMD) before and after ischemia-reperfusion injury (IRI, 20 min forearm ischaemic-20 min reperfusion) and cerebrovascular function, assessed by dynamic cerebral autoregulation (dCA) at three time points; pre, post and 8 days post intervention.

Results: For exploratory purposes, we performed statistical analysis on our primary comparison (pre-to-post) to provide an estimate of the change in the primary and secondary outcome variables. Using pre-intervention data as a covariate, the change from pre-post in FMD was 1.3% (95% CI: 0.69 to 3.80; P = 0.09) and 0.23 %cm/s %/mmHg mmHg/% (-0.12, 0.59; P = 0.18) in dCA normalised gain with rIPC versus control. Based upon this, a sample size of 20 and 50 for FMD and normalised gain, respectively, in each group would provide 90% power to detect statistically significant (P < 0.05) between-group difference in a randomised controlled trial.

Conclusion: We provide estimates of sample size for a randomised control trial exploring the impact of daily rIPC for 7 days on peripheral endothelial and cerebrovascular function. The directional changes outline from our pilot study suggest peripheral endothelial function can be enhanced by daily rIPC in patients with T2DM.
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http://dx.doi.org/10.1530/EJE-19-0378DOI Listing
December 2019

Lifelong Physical Activity Determines Vascular Function in Late Postmenopausal Women.

Med Sci Sports Exerc 2020 03;52(3):627-636

Department of Nutrition Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.

Introduction: The study evaluated the role of lifelong physical activity for leg vascular function in postmenopausal women (61 ± 1 yr).

Method: The study design was cross-sectional with three different groups based on self-reported physical activity level with regard to intensity and volume over the past decade: inactive (n = 14), moderately active (n = 12), and very active (n = 15). Endothelial-dependent and smooth muscle-dependent leg vascular function were assessed by ultrasound Doppler measurements of the femoral artery during infusion of acetylcholine (Ach), the nitric oxide (NO) donor sodium nitroprusside and the prostacyclin analog epoprostenol. Thigh muscle biopsies, arterial and venous plasma samples were obtained for assessment of vasodilator systems.

Results: The very active group was found to have 76% greater responsiveness to Ach compared with the sedentary group accompanied by 200% higher prostacyclin synthesis during Ach infusion. Smooth muscle cell responsiveness to sodium nitroprusside and epoprostenol was not different between groups. The protein amount of endothelial NO synthase and endogenous antioxidant enzymes in muscle tissue was higher in the very active than the inactive group. The moderately active group had a similar endothelial and smooth muscle cell responsiveness as the inactive group. A secondary comparison with a smaller group (n = 5) of habitually active young (24 ± 2 yr) women indicated that smooth muscle cell responsiveness and endothelial responsiveness are affected by age per se.

Conclusions: This study shows that leg vascular function and the potential to form prostacyclin and NO in late postmenopausal women, is influenced by the extent of lifelong physical activity.
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http://dx.doi.org/10.1249/MSS.0000000000002180DOI Listing
March 2020

Hyperinsulinemia does not cause de novo capillary recruitment in rat skeletal muscle.

Microcirculation 2020 02 12;27(2):e12593. Epub 2019 Oct 12.

Department of Medical Biophysics, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Canada.

Objective: The effect of insulin on blood flow distribution within muscle microvasculature has been suggested to be important for glucose metabolism. However, the "capillary recruitment" hypothesis is still controversial and relies on studies using indirect contrast-enhanced ultrasound (CEU) methods.

Methods: We studied how hyperinsulinemia effects capillary blood flow in rat extensor digitorum longus (EDL) muscle during euglycemic hyperinsulinemic clamp using intravital video microscopy (IVVM). Additionally, we modeled blood flow and microbubble distribution within the vascular tree under conditions observed during euglycemic hyperinsulinemic clamp experiments.

Results: Euglycemic hyperinsulinemia caused an increase in erythrocyte (80 ± 25%, P < .01) and plasma (53 ± 12%, P < .01) flow in rat EDL microvasculature. We found no evidence of de novo capillary recruitment within, or among, capillary networks supplied by different terminal arterioles; however, erythrocyte flow became slightly more homogenous. Our computational model predicts that a decrease in asymmetry at arteriolar bifurcations causes redistribution of microbubble flow among capillaries already perfused with erythrocytes and plasma, resulting in 25% more microbubbles flowing through capillaries.

Conclusions: Our model suggests increase in CEU signal during hyperinsulinemia reflects a redistribution of arteriolar flow and not de novo capillary recruitment. IVVM experiments support this prediction showing increases in erythrocyte and plasma flow and not capillary recruitment.
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http://dx.doi.org/10.1111/micc.12593DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064932PMC
February 2020

Oestrogen, exercise and vascular function.

Authors:
Ylva Hellsten

J Physiol 2019 10;597(19):4871

Department of Nutrition, Exercise and Sports, Integrative Physiology Section, University of Copenhagen, Denmark.

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http://dx.doi.org/10.1113/JP278605DOI Listing
October 2019

On the horizon of aging and physical activity research.

Appl Physiol Nutr Metab 2020 Feb 17;45(2):113-117. Epub 2019 Jul 17.

Department of Kinesiology and Physical Education, Wilfrid Laurier University, Waterloo, ON N2L 3C5, Canada.

This viewpoint is the result of a Horizon Round Table discussion of Exercise and Aging held during the 2017 Saltin International Graduate School in Exercise and Clinical Physiology in Gatineau, Quebec. This expert panel discussed key issues and approaches to future research into aging, across human physiological systems, current societal concerns, and funding approaches. Over the 60-min round table discussion, 3 major themes emerged that the panel considered to be "On the Horizon" of aging research. These themes include () aging is a process that extends from womb to tomb; () the importance of longitudinal experimental studies; and () the ongoing need to investigate multiple systems using an integrative approach between scientists, clinicians, and knowledge brokers. With a focus on these themes, we aim to identify critical questions, challenges, and opportunities that face scientists in advancing the understanding of exercise and aging.
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http://dx.doi.org/10.1139/apnm-2018-0738DOI Listing
February 2020

Muscle-strain injury exudate favors acute tissue healing and prolonged connective tissue formation in humans.

FASEB J 2019 09 18;33(9):10369-10382. Epub 2019 Jun 18.

Department of Orthopedic Surgery M, Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark.

Traumatic strain injury in skeletal muscle is often associated with fluid accumulation at the site of rupture, but the role of this injury exudate (EX) in cellular responses and healing is unknown. We aimed to characterize the EX sampled from human hamstring or calf muscles following a strain injury ( = 12). The cytokine and growth-factor profile, gene expression, and transcriptome analysis of EX-derived cells were compared with blood taken simultaneously from the same individuals. Cellular responses to the EX were tested in 3-dimensional (3D) culture based on primary human fibroblasts and myoblasts isolated from hamstring muscles. The EX contained a highly proinflammatory profile with a substantial expression of angiogenic factors. The proinflammatory profile was present in samples taken early postinjury and in samples aspirated several weeks postinjury, suggesting persistent inflammation. Cells derived from the EX demonstrated an increased expression of fibrogenic, adipogenic, and angiogenesis-related genes in comparison with blood cells. The injury EX stimulated fibroblast proliferation 2-fold compared with plasma, whereas such an effect was not seen for myoblasts. Finally, in 3D cell culture, the EX induced an up-regulation of connective tissue-related genes. In summary, EX formation following a muscle-strain injury stimulates fibroblast proliferation and the synthesis of connective tissue in fibroblasts. This suggests that the EX promotes an acute tissue-healing response but potentially also contributes to the formation of fibrotic tissue in the later phases of tissue repair.-Bayer, M. L., Bang, L., Hoegberget-Kalisz, M., Svensson, R. B., Olesen, J. L., Karlsson, M. M., Schjerling, P., Hellsten, Y., Hoier, B., Magnusson, S. P., Kjaer, M. Muscle-strain injury exudate favors acute tissue healing and prolonged connective tissue formation in humans.
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http://dx.doi.org/10.1096/fj.201900542RDOI Listing
September 2019

Regulatory Mechanisms of Estrogen on Vascular Ageing.

Oxid Med Cell Longev 2019;2019:4859082. Epub 2019 Apr 28.

Department of Nutrition, Exercise and Sports, University of Copenhagen, Denmark.

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http://dx.doi.org/10.1155/2019/4859082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6512012PMC
January 2020

Cardiac perfusion and function after high-intensity exercise training in late premenopausal and recent postmenopausal women: an MRI study.

J Appl Physiol (1985) 2019 05 14;126(5):1272-1280. Epub 2019 Mar 14.

Functional Imaging Unit, Department of Clinical Physiology, Nuclear Medicine and PET, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen , Copenhagen , Denmark.

We examined the influence of recent menopause and aerobic exercise training in women on myocardial perfusion, left ventricular (LV) dimension, and function. Two groups ( = 14 each) of healthy late premenopausal (50.2 ± 2.1 yr) and recent postmenopausal (54.2 ± 2.8 yr) women underwent cardiac magnetic resonance imaging (cMRI) at baseline and after 12 wk of high-intensity aerobic training. Measurements included LV morphology, systolic function, and myocardial perfusion at rest and during an adenosine stress test. At baseline, resting myocardial perfusion was lower in the postmenopausal than the premenopausal group (77 ± 3 vs. 89 ± 3 ml·100 g·min; = 0.01), while adenosine-induced myocardial perfusion was not different ( = 0.81). After exercise training, resting myocardial perfusion was lower in both groups (66 ± 2; = 0.002 vs. 81 ± 3 ml·100 g·min; = 0.03). The adenosine-induced change in myocardial perfusion was lower in the groups combined (by 402 ± 17 ml·100 g·min; = 0.02), and the adenosine-induced increase in heart rate was 10 ± 2 beats/min lower ( < 0.0001) in both groups after training. Normalization of myocardial perfusion using an estimate of cardiac work eliminated the differences in perfusion between the premenopausal and postmenopausal groups and the effect of training. Left ventricle mass was higher in both groups ( = 0.03; = 0.006), whereas LV end-diastolic ( = 0.02) and stroke ( = 0.045) volumes were higher in the postmenopausal group after training. Twelve weeks of exercise training increased left ventricle mass and lowered resting and adenosine-induced myocardial perfusion, an effect that was likely related to cardiac work. The current data also suggest that the early menopausal transition has limited impact on cardiac function and structure. This study provides for the first time estimates of myocardial perfusion in late premenopausal and recent postmenopausal women before and after a period of intense aerobic training. Resting myocardial perfusion was lower in postmenopausal than premenopausal women. Training lowered myocardial resting and stress perfusion in both groups, an effect that was likely influenced by the lower heart rate.
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http://dx.doi.org/10.1152/japplphysiol.01089.2017DOI Listing
May 2019

Copenhagen Consensus statement 2019: physical activity and ageing.

Br J Sports Med 2019 Jul 21;53(14):856-858. Epub 2019 Feb 21.

Department of Physiology, Universitat de Valencia, Valencia, Spain.

From 19th to 22nd November 2018, 26 researchers representing nine countries and a variety of academic disciplines met in Snekkersten, Denmark, to reach evidence-based consensus about physical activity and older adults. It was recognised that the term 'older adults' represents a highly heterogeneous population. It encompasses those that remain highly active and healthy throughout the life-course with a high intrinsic capacity to the very old and frail with low intrinsic capacity. The consensus is drawn from a wide range of research methodologies within epidemiology, medicine, physiology, neuroscience, psychology and sociology, recognising the strength and limitations of each of the methods. Much of the evidence presented in the statements is based on longitudinal associations from observational and randomised controlled intervention studies, as well as quantitative and qualitative social studies in relatively healthy community-dwelling older adults. Nevertheless, we also considered research with frail older adults and those with age-associated neurodegenerative diseases, such as Alzheimer's and Parkinson's disease, and in a few cases molecular and cellular outcome measures from animal studies. The consensus statements distinguish between physical activity and exercise. is used as an umbrella term that includes both structured and unstructured forms of leisure, transport, domestic and work-related activities. Physical activity entails body movement that increases energy expenditure relative to rest, and is often characterised in terms of intensity from light, to moderate to vigorous. is defined as a subset of structured physical activities that are more specifically designed to improve cardiorespiratory fitness, cognitive function, flexibility balance, strength and/or power. This statement presents the consensus on the effects of physical activity on older adults' fitness, health, cognitive functioning, functional capacity, engagement, motivation, psychological well-being and social inclusion. It also covers the consensus on physical activity implementation strategies. While it is recognised that adverse events can occur during exercise, the risk can be minimised by carefully choosing the type of activity undertaken and by consultation with the individual's physician when warranted, for example, when the individual is frail, has a number of co-morbidities, or has exercise-related symptoms, such as chest pain, heart arrhythmia or dizziness. The consensus was obtained through an iterative process that began with the presentation of the state-of-the-science in each domain, followed by group and plenary discussions. Ultimately, the participants reached agreement on the 30-item consensus statements.
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http://dx.doi.org/10.1136/bjsports-2018-100451DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6613739PMC
July 2019

The Endothelial Mechanotransduction Protein Platelet Endothelial Cell Adhesion Molecule-1 Is Influenced by Aging and Exercise Training in Human Skeletal Muscle.

Front Physiol 2018 18;9:1807. Epub 2018 Dec 18.

Department of Nutrition, Exercise and Sports, Section for Integrative Physiology, University of Copenhagen, Copenhagen, Denmark.

The aim was to determine the role of aging and exercise training on endothelial mechanosensor proteins and the hyperemic response to shear stress by passive leg movement. We examined the expression of mechanosensor proteins and vascular function in young ( = 14, 25 ± 3 years) and old ( = 14, 72 ± 5 years) healthy male subjects with eight weeks of aerobic exercise training. Before and after training, the hyperaemic response to passive leg movement was determined and a thigh muscle biopsy was obtained before and after passive leg movement to assess the acute effect of increased shear stress. Biopsies were analyzed for protein amount and phosphorylation of mechanosensor proteins; Platelet endothelial cell adhesion molecule-1 (PECAM-1), Vascular endothelial cadherin, Vascular endothelial growth factor receptor-2 and endothelial nitric oxide synthase (eNOS). Before training, the old group presented a lower hyperaemic response to passive leg movement and a 35% lower ( < 0.05) relative basal phosphorylation level of PECAM-1 whereas there was no difference for the other mechanosensor proteins. After training, the eNOS protein amount, the amount of PECAM-1 protein and the passive leg movement-induced phosphorylation of PECAM-1 were higher in both groups. The hyperaemic response to passive leg movement was higher after training in the young group only. Aged individuals have a lower hyperaemic response to passive leg movement and a lower relative basal phosphorylation of PECAM-1 than young. The higher PECAM-1 phosphorylation despite a similar hyperemic level in the aged observed after training, suggests that training improved shear stress responsiveness of this mechanotransduction protein.
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http://dx.doi.org/10.3389/fphys.2018.01807DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6305393PMC
December 2018

Reduced skeletal-muscle perfusion and impaired ATP release during hypoxia and exercise in individuals with type 2 diabetes.

Diabetologia 2019 03 3;62(3):485-493. Epub 2019 Jan 3.

Department of Cardiovascular and Renal Research, Institute of Molecular Medicine, University of Southern Denmark, Winslowparken 21 3, 5000, Odense, Denmark.

Aims/hypothesis: Plasma ATP is a potent vasodilator and is thought to play a role in the local regulation of blood flow. Type 2 diabetes is associated with reduced tissue perfusion. We aimed to examine whether individuals with type 2 diabetes have reduced plasma ATP concentrations compared with healthy control participants (case-control design).

Methods: We measured femoral arterial and venous plasma ATP levels with the intravascular microdialysis technique during normoxia, hypoxia and one-legged knee-extensor exercise (10 W and 30 W) in nine participants with type 2 diabetes and eight control participants. In addition, we infused acetylcholine (ACh), sodium nitroprusside (SNP) and ATP into the femoral artery to assess vascular function and ATP signalling.

Results: Individuals with type 2 diabetes had a lower leg blood flow (LBF; 2.9 ± 0.1 l/min) compared with the control participants (3.2 ± 0.1 l/min) during exercise (p < 0.05), in parallel with lower venous plasma ATP concentration (205 ± 35 vs 431 ± 72 nmol/l; p < 0.05). During systemic hypoxia, LBF increased from 0.35 ± 0.04 to 0.54 ± 0.06 l/min in control individuals, whereas it did not increase (0.25 ± 0.04 vs 0.31 ± 0.03 l/min) in the those with type 2 diabetes and was lower than in the control individuals (p < 0.05). Hypoxia increased venous plasma ATP levels in both groups (p < 0.05), but the increase was higher in control individuals (90 ± 26 nmol/l) compared to those with type 2 diabetes (18 ± 5 nmol/l). LBF and vascular conductance were lower during ATP (0.15 and 0.4 μmol min [kg leg mass]) and ACh (100 μg min [kg leg mass]) infusion in individuals with type 2 diabetes compared with the control participants (p < 0.05), whereas there was no difference during SNP infusion.

Conclusions/interpretation: These findings demonstrate that individuals with type 2 diabetes have lower plasma ATP concentrations during exercise and hypoxia compared with control individuals, and this occurs in parallel with lower blood flow. Moreover, individuals with type 2 diabetes have a reduced vasodilatory response to infused ATP. These impairments in the ATP system are both likely to contribute to the reduced tissue perfusion associated with type 2 diabetes.

Trial Registration: ClinicalTrials.gov NCT02001766.
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http://dx.doi.org/10.1007/s00125-018-4790-0DOI Listing
March 2019

The effect of two exercise modalities on skeletal muscle capillary ultrastructure in individuals with type 2 diabetes.

Scand J Med Sci Sports 2019 Mar 4;29(3):360-368. Epub 2019 Jan 4.

Institute of Physiology, Charité-Universitätsmedizin Berlin, Berlin, Germany.

Type 2 diabetes is associated with microvascular dysfunction, but little is known about how capillary ultrastructure is affected by exercise training. To investigate the effect of two types of exercise training on skeletal muscle capillary ultrastructure and capillarization in individuals with type 2 diabetes, 21 individuals with type 2 diabetes were allocated (randomized controlled trial) to 11 weeks of aerobic exercise training consisting of either moderate-intensity endurance training (END; n = 10) or low-volume high-intensity interval training (HIIT; n = 11). Skeletal muscle biopsies (m vastus lateralis) were obtained before and after the training intervention. At baseline, there was no difference in capillarization, capillary structure, and exercise hyperemia between the two groups. After the training intervention, capillary-to-fiber ratio increased by 8% ± 3% in the END group (P < 0.05) and was unchanged in the HIIT group with no difference between groups. Endothelium thickness increased (P < 0.05), basement membrane thickness decreased (P < 0.05), and the capillary lumen tended (P = 0.07) to increase in the END group, whereas these structural indicators were unchanged after HIIT. In contrast, skeletal muscle endothelial nitric oxide synthase (eNOS) increased after HIIT (P < 0.05), but not END, whereas there was no change in vascular endothelial growth factor (VEGF), superoxide dismutase (SOD)-2, or NADPH oxidase after both training protocols. In contrast to END training, HIIT did not alter capillarization or capillary structure in individuals with type 2 diabetes. In conclusion, HIIT appears to be a less effective strategy to treat capillary rarefaction and reduce basement thickening in type 2 diabetes.
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http://dx.doi.org/10.1111/sms.13348DOI Listing
March 2019