Intermittent Hypoxic Training Increases and Prolongs Exercise Benefits in Adult Untrained Women.

Alba Camacho-Cardenosa, Marta Camacho-Cardenosa, Johannes Burtscher, Pedro R. Olivares, Guillermo Olcina, and Javier Brazo-Sayavera. Intermittent hypoxic training increases and prolongs exercise benefits in adult untrained women. High Alt Med Biol. 00:00-00, 2024. Background: Exercising in hypoxia may confer multiple health benefits, but the evidence for specific benefits is scarce. Methods: We investigated effects of intermittent hypoxic training (IHT) on the quality of life and functional fitness of healthy adult women, in a double-blind, randomized, placebo-controlled study. Subjects performed 36 sessions of IHT (experimental group, n = 41; fraction of inspired oxygen [FIO2]: 0.17) or the same training in normoxia (control group, n = 41; FIO2: 0.21). Health-related quality of life, fitness tests, and hemoglobin levels were assessed before (T1), directly after (T2), and 4 weeks after (T3) cessation. Results: At T2, upper body strength (+14.96%), lower body strength (+26.20%), and agility (-4.94%) increased significantly in the experimental group compared to baseline but not in controls. The experimental group improved lower body strength more (by 9.85%) than controls at T2 and performed significantly better in walking (by 2.92%) and upper body strength testing (by 16.03%), and agility (by 4.54%) at T3. Perceived general health and vitality was significantly greater in the experimental group at T2 and T3 compared with T1. None of these improvements were observed in the control group. Conclusions: IHT is a promising strategy to induce long-lasting fitness benefits in healthy adult women.

Effects of Different Protocols of Moderate-Intensity Intermittent Hypoxic Training on Mental Health and Quality of Life in Brazilian Adults Recovered from COVID-19: The AEROBICOVID Double-Blind Randomized Controlled Study.

The aim of this study was to investigate the effects of different protocols of moderate-intensity intermittent hypoxic training in patients who had recovered from COVID-19 on quality of life (QoL) and mental health. The sample of this clinical trial-controlled double-blind study consisted of 67 participants aged 30-69 years, who were organized randomly according to Normoxia, Hypoxia, Hypoxia Recovery or Control Group. Eight weeks of cycle ergometer training were performed with a frequency of three training sessions per week in normoxic or hypoxic conditions (with or without hypoxic recovery). Health-related QoL and Mental Health Status were evaluated by 12-Item Short Form Survey and Depression Anxiety and Stress Scale instruments, respectively. All training groups improved the QoL's physical dimensions (Baseline-Post: Normoxia Group 42.1 (11.0)-48.7 (7.0), Hypoxia Group 46.9 (11.8)-53.5 (6.6) and Hypoxia Recovery Group 45.8 (9.2)-51.1 (5.3)) and mental dimensions (Baseline-Post: Normoxia Group 48.8 (7.9)-54.6 (4.6), Hypoxia Group 45.2 (7.7)-53.2 (3.8) and Hypoxia Recovery Group 46.5 (9.7)-52.0 (9.9)). Regarding mental health outcomes, all training groups decreased depressive symptoms (66.7% Normoxia, 31.2% Hypoxia Recovery and 31% Hypoxia groups), anxiety symptoms (46.5% Normoxia, 45.9% Hypoxia Recovery and 39.5% in the Hypoxia groups) and stress symptoms (40.6% Normoxia, 36.3% Hypoxia Recovery and 22.1% Hypoxia groups). Significant statistical difference was not found between groups. Normoxic and hypoxic training showed a similar effect on QoL and the mental health of Brazilian adults who had recovered from COVID-19.

Secuelas de salud a medio plazo en brasileños recuperados de COVID-19 según gravedad / Medium-term health consequences in Brazilians recovered from COVID-19 according to severity

The aims were to identify the symptoms and comorbidities predictive for severe illness and analyse the mild-term health sequelae in Brazilian recovered from COVID-19. Eighty-four participants were divided into mild (n = 16), moderate (n = 51), severe (n = 9) or critical (n = 8) gravity. A standardized assessment included: anamnesis to identify the symptoms and comorbidities; and cardiorespiratory system, body composition, haematological and immunological indicators, and physical fitness to analyze the mild-term health sequelae. Participants with higher gravity presented fever, fatigue and dyspnoea. Diabetes (p = 0.003), hypertension (p < 0.001) and metabolic syndrome (p = 0.010) were the comorbidities significantly associated for severe or critical illness. People with critical gravity reported a significant higher waist/hip ratio and level of visceral fat compared with mild and moderate severity. Severe and critical participants reported worst results in agility and balance test compared with mild (p = 0.015; p = < 0.001, respectively) and moderate (p = 0.014; p = < 0.001, respectively) gravity. Fever, fatigue and dyspnoea; and diabetes, hypertension and metabolic syndrome were the symptoms and comorbidities associated with higher gravity. Mild-term, altered values of body composition, physical functioning, enhanced glucose, reticulocytes, and lymphocytes levels were reported. (AU)

Bariatric surgery and calcifediol treatment, Gordian knot of severe-obesity-related comorbidities treatment.

Background: Obesity (OB) is a chronic metabolic disease with important associated comorbidities and mortality. Vitamin D supplementation is frequently administered after bariatric surgery (BS), so as to reduce OB-related complications, maybe including chronic inflammation. Aim: This study aimed to explore relations between vitamin D metabolites and components of the inflammasome machinery in OB before and after BS and their relations with the improvement of metabolic comorbidities. Patients and methods: Epidemiological/clinical/anthropometric/biochemical evaluation was performed in patients with OB at baseline and 6 months after BS. Evaluation of i) vitamin-D metabolites in plasma and ii) components of the inflammasome machinery and inflammatory-associated factors [NOD-like-receptors (NLRs), inflammasome-activation-components, cytokines and inflammation/apoptosis-related components, and cell-cycle and DNA-damage regulators] in peripheral blood mononuclear cells (PBMCs) was performed at baseline and 6 months after BS. Clinical and molecular correlations/associations were analyzed. Results: Significant correlations between vitamin D metabolites and inflammasome-machinery components were observed at baseline, and these correlations were significantly reduced 6 months after BS in parallel to a decrease in inflammation markers, fat mass, and body weight. Treatment with calcifediol remarkably increased 25OHD levels, despite 24,25(OH)2D3 remained stable after BS. Several inflammasome-machinery components were associated with improvement in metabolic comorbidities, especially hypertension and dyslipidemia. Conclusion: The beneficial effects of vitamin D on OB-related comorbidities after BS patients are associated with significant changes in the molecular expression of key inflammasome-machinery components. The expression profile of these inflammasome components can be dynamically modulated in PBMCs after BS and vitamin D supplementation, suggesting that this profile could likely serve as a sensor and early predictor of the reversal of OB-related complications after BS.

Mechanisms underlying the health benefits of intermittent hypoxia conditioning.

Intermittent hypoxia (IH) is commonly associated with pathological conditions, particularly obstructive sleep apnoea. However, IH is also increasingly used to enhance health and performance and is emerging as a potent non-pharmacological intervention against numerous diseases. Whether IH is detrimental or beneficial for health is largely determined by the intensity, duration, number and frequency of the hypoxic exposures and by the specific responses they engender. Adaptive responses to hypoxia protect from future hypoxic or ischaemic insults, improve cellular resilience and functions, and boost mental and physical performance. The cellular and systemic mechanisms producing these benefits are highly complex, and the failure of different components can shift long-term adaptation to maladaptation and the development of pathologies. Rather than discussing in detail the well-characterized individual responses and adaptations to IH, we here aim to summarize and integrate hypoxia-activated mechanisms into a holistic picture of the body's adaptive responses to hypoxia and specifically IH, and demonstrate how these mechanisms might be mobilized for their health benefits while minimizing the risks of hypoxia exposure.

Comparative Study of the Efficacy of EHO-85, a Hydrogel Containing Olive Tree (Olea europaea) Leaf Extract, in Skin Wound Healing.

Olive tree (Olea europaea) leaf extract (OELE) has important antioxidant and anti-inflammatory properties, supporting its use in human clinical practice. We recently designed an amorphous hydrogel called EHO-85 (EHO indicates olive leaf extract in Spanish) containing OELE for skin ulcer treatments. Yet, its effectiveness has not been previously compared with other products used in routine clinical practice. This is necessary to evaluate its potential translation to the human clinic. Thus, in this study, the effect of EHO-85 on healing was evaluated in comparison with treatments containing Indian/Asiatic pennywort (Centella asiatica), hyaluronic acid, or dexpanthenol in a rat model. The speed of wound closure and histological parameters after seven and 14 days were analyzed. All treatments accelerated wound closure, but there were differences between them. Dexpanthenol after seven days produced the highest epithelialization and the lowest inflammation and vascularization. EHO-85 also promoted epithelialization and reduced vascularization. After 14 days, wounds treated with EHO-85 showed less inflammation and higher levels of collagen in the extracellular matrix. This indicates a higher degree of maturity in the regenerated tissue. In conclusion, the effect of EHO-85 on healing was equal to or superior to that of other treatments routinely used in human clinical practice. Therefore, these results, together with previous data on the effects of this hydrogel on ulcer healing in humans, indicate that EHO-85 is a suitable, low-cost, and efficient therapeutic option for wound healing.

Non-Specific Inhibition of Dipeptidyl Peptidases 8/9 by Dipeptidyl Peptidase 4 Inhibitors Negatively Affects Mesenchymal Stem Cell Differentiation.

DPP4 may play a relevant role in MSC differentiation into osteoblasts or adipocytes. Dipeptidyl peptidase 4 (DPP4) inhibitors (DPP4i), such as sitagliptin and vildagliptin, are used as antidiabetic drugs. However, vildagliptin is not a specific DPP4i and also inhibits DPP8/9, which is involved in energy metabolism and immune regulation. The aim of this study is to evaluate how sitagliptin, vildagliptin or 1G244 (a DPP8/9 specific inhibitor) may influence cell viability, as well as osteogenic and adipogenic differentiation in human mesenchymal stem cells (MSC). Viability, apoptosis, osteoblastogenesis and adipogenesis markers, as well as protein synthesis of ß-catenin, were studied in MSC cultures induced to differentiate into osteoblasts or adipocytes in the presence or absence of sitagliptin, vildagliptin or 1G244. The two tested DPP4i did not affect MSC viability, but 1G244 significantly decreased it in MSC and osteoblast-induced cells. Additionally, 1G244 and vildagliptin inhibited osteogenesis and adipogenesis, unlike sitagliptin. Therefore, inhibition of DPP4 did not affect MSC viability and differentiation, whereas inhibition of DPP8/9 negatively affected MSC. To the best of our knowledge, these results show for the first time that DPP8/9 have an important role in the viability and differentiation of human MSC. This data can be considered for human clinical use of drugs affecting DPP8/9 activity.

Clinical Potential of Mesenchymal Stem Cell-Derived Exosomes in Bone Regeneration.

Bone metabolism is regulated by osteoblasts, osteoclasts, osteocytes, and stem cells. Pathologies such as osteoporosis, osteoarthritis, osteonecrosis, and traumatic fractures require effective treatments that favor bone formation and regeneration. Among these, cell therapy based on mesenchymal stem cells (MSC) has been proposed. MSC are osteoprogenitors, but their regenerative activity depends in part on their paracrine properties. These are mainly mediated by extracellular vesicle (EV) secretion. EV modulates regenerative processes such as inflammation, angiogenesis, cell proliferation, migration, and differentiation. Thus, MSC-EV are currently an important tool for the development of cell-free therapies in regenerative medicine. This review describes the current knowledge of the effects of MSC-EV in the different phases of bone regeneration. MSC-EV has been used by intravenous injection, directly or in combination with different types of biomaterials, in preclinical models of bone diseases. They have shown great clinical potential in regenerative medicine applied to bone. These findings should be confirmed through standardization of protocols, a better understanding of the mechanisms of action, and appropriate clinical trials. All that will allow the translation of such cell-free therapy to human clinic applications.

Efecto de vesículas extracelulares derivadas de células madre mesenquimales humanas precondicionadas en hipoxia sobre la osteoblastogénesis y la adipogénesis in vitro / Effect of stem cell-derived extracellular vesicles human mesenchymal cells preconditioned in hypoxia on osteoblastogenesis and adipogenesis in vitro

Objetivos: las células madre mesenquimales (MSC) se caracterizan por su actividad antiinflamatoria, inmunosupresora y sucapacidad de diferenciación. Esto las convierten en una interesante herramienta terapéutica en terapia celular y medicinaregenerativa. En parte, el efecto terapéutico de las MSC, está mediado por la secreción de vesículas extracelulares (EV). Elprecondicionamiento en hipoxia de las MSC puede mejorar la capacidad regenerativa de las EV secretadas. En este con-texto, el objetivo del estudio ha sido evaluar si EV derivadas de MSC humanas cultivadas en hipoxia y normoxia afectan ala osteoblastogénesis y adipogénesis de las MSC.Material y métodos: se aislaron EV de MSC mantenidas 48 h en normoxia o hipoxia (3 % O2) mediante ultrafiltración ycromatografía de exclusión por tamaño. Las EV fueron caracterizadas por “Western blot”, microscopía electrónica y análisisde seguimiento de nanopartículas. En cultivos de MSC se evaluó el efecto de las EV sobre la viabilidad por ensayo con MTT,la migración por “Oris assay” y la diferenciación a osteoblastos y adipocitos.Resultados: las EV aumentaron la viabilidad y migración, pero no hubo diferencias entre las derivadas de normoxia ehipoxia. Las EV, principalmente las derivadas de hipoxia, aumentaron la mineralización y la expresión de genes osteoblás-ticos. Sin embargo, no afectaron significativamente a la adipogénesis.Conclusiones: las EV derivadas de MSC en hipoxia no afectan a la adipogénesis, pero tienen una mayor capacidad de inducirla osteoblastogénesis. Por lo tanto, podrían potencialmente ser utilizadas en terapias de regeneración ósea y tratamientosde patologías óseas como la osteoporosis.(AU)

Training zones through muscle oxygen saturation during a graded exercise test in cyclists and triathletes.

Use of muscle oxygen saturation (SmO2) has been validated as a performance factor during incremental exercise with portable near-infrared stereoscopy (NIRS) technology. However, there is little knowledge about the use of SmO2 to identify training zones. The objective of this study was to evaluate the metabolic zones by SmO2: maximum lipid oxidation zone (Fatmax), ventilatory thresholds (VT1 and VT2) and maximum aerobic power (MAP) during a graded exercise test (GXT). Forty trained cyclists and triathletes performed a GXT. Output power (W), heart rate (HR), oxygen consumption (VO2), energy expenditure (kcal/min) and SmO2 were measured. Data were analysed using the ANOVA test, ROC curves and multiple linear regressions. Significance was established at p ≤ 0.05. SmO2 decreases were observed from baseline (LB) to Fatmax (Δ = -16% p < 0.05), Fatmax to VT1 (Δ = -16% p < 0.05) and VT1 to VT2 (Δ = -45% p < 0.01). Furthermore, SmO2 together with weight, HR and output power have the ability to predict VO2 and energy expenditure by 89% and 90%, respectively. We conclude that VO2 and energy expenditure values can be approximated using SmO2 together with other physiological parameters and SmO2 measurements can be a complementary parameter to discriminate aerobic workload and anaerobic workload in athletes.

Effects of Moderate-Intensity Training Under Cyclic Hypoxia on Cardiorespiratory Fitness and Hematological Parameters in People Recovered From COVID-19: The AEROBICOVID Study.

BACKGROUND: Recent studies have indicated that people who live at altitude have a lower incidence of coronavirus disease (COVID-19) and lesser severity in infection cases. HYPOTHESIS: Hypoxia exposure could lead to health benefits, and it could be used in the recovery process as an additional stimulus to physical training to improve cardiorespiratory fitness (CRF). STUDY DESIGN: Randomized controlled clinical trial. LEVEL OF EVIDENCE: Level 2. METHODS: The 43 participants, aged 30 to 69 years, were divided into control group (CG, n = 18) and 2 training groups: normoxia (NG, n = 9) and hypoxia (HG, n = 16). Before and after the intervention were evaluated the lactate threshold 2 (L2), peak oxygen uptake (VO2peak), and a blood sample was collected at rest to evaluate hematological adaptation. Both groups performed an 8-week moderate-intensity physical training on a bike. The HG were trained under normobaric hypoxic conditions (fractional inspired oxygen [FiO2] = 13.5%). RESULTS: The 8-week intervention promoted a similar improvement in CRF of people recovered from COVID-19 in the HG (L2 = 34.6%; VO2peak = 16.3%; VO2peak intensity = 24.6%) and NG (L2 = 42.6%; VO2peak = 16.7%; VO2peak intensity = 36.9%). Only the HG presented differences in hematological variables (erythropoietin = 191.7%; reticulocytes = -32.4%; off-score = 28.2%) in comparison with the baseline. CONCLUSION: The results of the present study provide evidence that moderate-intensity training in normoxia or hypoxia promoted similar benefits in CRF of people recovered from COVID-19. Furthermore, the hypoxia offered an additional stimulus to training promoting erythropoietin increase and hematological stimulation. CLINICAL RELEVANCE: The present exercise protocol can be used for the rehabilitation of people recovered from COVID-19, with persistent low CRF. In addition, this is the first study demonstrating that physical training combined with hypoxia, as well as improving CRF, promotes greater hematological stimulation in people recovered from COVID-19.

Effectiveness, implementation, and monitoring variables of intermittent hypoxic bicycle training in patients recovered from COVID-19: The AEROBICOVID study.

Hypoxic exposure is safely associated with exercise for many pathological conditions, providing additional effects on health outcomes. COVID-19 is a new disease, so the physiological repercussions caused by exercise in affected patients and the safety of exposure to hypoxia in these conditions are still unknown. Due to the effects of the disease on the respiratory system and following the sequence of AEROBICOVID research work, this study aimed to evaluate the effectiveness, tolerance and acute safety of 24 bicycle training sessions performed under intermittent hypoxic conditions through analysis of peripheral oxyhemoglobin saturation (SpO2), heart rate (HR), rate of perceived exertion (RPE), blood lactate concentration ([La-]) and symptoms of acute mountain sickness in patients recovered from COVID-19. Participants were allocated to three training groups: the normoxia group (GN) remained in normoxia (inspired fraction of O2 (FiO2) of ∼20.9%, a city with 526 m altitude) for the entire session; the recovery hypoxia group (GHR) was exposed to hypoxia (FiO2 ∼13.5%, corresponding to 3,000 m altitude) all the time except during the effort; the hypoxia group (GH) trained in hypoxia (FiO2 ∼13.5%) throughout the session. The altitude simulation effectively reduced SpO2 mean with significant differences between groups GN, GHR, and GH, being 96.9(1.6), 95.1(3.1), and 87.7(6.5), respectively. Additionally, the proposed exercise and hypoxic stimulus was well-tolerated, since 93% of participants showed no or moderate acute mountain sickness symptoms; maintained nearly 80% of sets at target heart rate; and most frequently reporting session intensity as an RPE of "3" (moderate). The internal load calculation, analyzed through training impulse (TRIMP), calculated using HR [TRIMPHR = HR * training volume (min)] and RPE [TRIMPRPE = RPE * training volume (min)], showed no significant difference between groups. The current strategy effectively promoted the altitude simulation and monitoring variables, being well-tolerated and safely acute exposure, as the low Lake Louise scores and the stable HR, SpO2, and RPE values showed during the sessions.

Effects of repeated-sprint hypoxic training on physical fitness ofactive adults / Efectos del entrenamiento de esprints repetidos en hipoxia sobrela condición física de adultos activos

Due to the time is, commonly, a barrier to exercise, the scientific community has paid attention to a new model of training. Repeated-sprint hypoxic training is now considered an effective time-efficient method for improving physical performance in different sport modalities. However, few researchers have studied the effect of this strategy in healthy untrained or moderately trained individuals. Depending of the prior fitness status, different findings may be obtained. Therefore, this study determined the effects of 4 weeks of repeated-sprint in hypoxia on cardiorespiratory fitness and anaerobic capacity in healthy men. Twenty-four physically active males (were randomly assigned to repeated-sprint in normoxia (n=8; 0.20 FiO2 ), in hypoxia (n=8; 0.14 FiO2 ) or a control group (n=8). Participants of both exercise groups developed eight training sessions consisted of 2 sets of 5 all-out cycling sprints of 10 s with a recovery of 20 s between sprints and 10 min between sets. Repeated sprint ability, vertical jump performance and estimated maximal oxygen consumption were tested at baseline, 7 days and 2 weeks after the last session. Seven days after the last sessions, significant differences (p<0.05) between normoxia (+7.8%; p<0.001; ES=1.66) and hypoxia groups (+9.9%; p=0.000; ES=1.42) compared with control group were found in estimated maximal oxygen consumption. In the hypoxia group, the number of sprints to exhaustion (7 days Post +55.6%; ES=1.40; 2 weeks Post +10.0%; ES=1.80) improved with a large effect size at 7 days and 2 weeks after the last sessions compared with baseline. Eight sessions of repeated-sprint training in hypoxia conditions could produce improvements and delayed effects on anaerobic capacity.(AU)

La comunidad científica ha prestado atención en los últimos años a un nuevo modelo de entrenamiento, debido a que la falta de tiempo es comúnmente la principal barrera para la práctica deportiva. En este contexto, el entrenamiento de esprint repetidos en hipoxia es considerado como una prometedora estrategia para mejorar el rendimiento físico en diferentes modalidades deportivas. Sin embargo, existen pocos estudios que investiguen los efectos sobre población moderadamente entrenada o sedentaria. Así, este estudio determina los efectos de un entrenamiento de esprint repetidos en hipoxia sobre la condición física de hombres sanos. Veinticuatro hombres fueron asignados aleatoriamente a un grupo normoxia (n=8; 0.20 FiO2 ), hipoxia (n=8; 0.14 FiO2 ) o control (n=8). Después de ocho sesiones de esprint repetido en cicloergómetros de 10s, la habilidad de esprint repetido, el rendimiento en el salto vertical, así como el consumo de oxígeno fueron evaluados en la línea base y a los días y 2 semanas de la última sesión de entrenamiento. A los 7 días, se observaron diferencias significativas entre normoxia (+7,8%; p<0.001; ES=1,66) e hipoxia (+9,9%; p=0,000; ES=1,42) comparado con el grupo control en el consumo máximo de oxígeno estimado. En hipoxia, el número de esprint hasta la extenuación (7 días Post +55,6%; ES=1,40; 2 semanas Post +10,0%; ES=1,80) también mejoró con tamaño del efecto elevado a los 7 días y 2 semanas de la última sesión comparado con la línea base. El protocolo de 8 sesiones de esprines repetido en hipoxia podría producir mejoras y retrasar los efectos sobre el rendimiento anaeróbico de hombres sanos. (AU)

Resistance circuit training combined with hypoxia stimulates bone system of older adults: A randomized trial.

PURPOSE: Aging leads to gradual irreversible decline in bone mass. As adherence to pharmacological treatment is poor, hypoxia combined with strength training has been suggested for therapeutic benefit for clinical populations. The present study investigated the effects of normobaric cyclic hypoxic exposure combined with resistance circuit training on bone of older adults. METHODS: Healthy older adults (n = 50) were randomly assigned to a (1) control group (CON; n = 20), who were instructed to continue with their normal daily activities, (2) a group that performed resistance training in normoxia (RTN; n = 17) and (3) a group that performed resistance training in hypoxia (RTH; n = 13). During 24 weeks, RTH group performed resistance training with elastic bands under normobaric hypoxic conditions (16.1 % FiO2). A session of both exercise groups included nine exercises of several body areas with a structure of 3 sets × 12-15 repetitions per exercise, with a 1-minute rest between sets. Bone mineral density (g·cm-2) was measured using dual-energy X-ray absorptiometry. Bone turnover markers of formation (N-terminal propeptide of type I procollagen; PINP) and resorption (C-terminal telopeptide of type I collagen; bCTX) were analysed with enzyme-linked immunosorbent assay (ELISA) microplate reader. RESULTS: Values of bCTX and bCTX/PINP significant decreased in RTN (bCTX: 47.79 %; p = 0.002; bCTX/PINP: 61.43 %; p = 0.007) and RTH (bCTX: 59.09 %; p = 0.001; bCTX/PINP: 62.61 %; p = 0.003) groups compared with CON group. Change in bone mineral density was not significantly different between groups. Based on clinically significant change, 23 % of the participants in the RTH group reached this value for femoral neck and trochanter bone mineral density (vs 0 % and 6 % of the RTN group, respectively). CONCLUSIONS: 24-Weeks of normobaric cyclic hypoxic exposure combined with resistance circuit training has potential to generate positive effects on bone in older adults. TRIAL REGISTRATION NUMBER: NCT04281264 (date of registration: February 24, 2020).

Role of hypoxia preconditioning in therapeutic potential of mesenchymal stem-cell-derived extracellular vesicles.

The use of mesenchymal stem-cells (MSC) in cell therapy has received considerable attention because of their properties. These properties include high expansion and differentiation in vitro, low immunogenicity, and modulation of biological processes, such as inflammation, angiogenesis and hematopoiesis. Curiously, the regenerative effect of MSC is partly due to their paracrine activity. This has prompted numerous studies, to investigate the therapeutic potential of their secretome in general, and specifically their extracellular vesicles (EV). The latter contain proteins, lipids, nucleic acids, and other metabolites, which can cause physiological changes when released into recipient cells. Interestingly, contents of EV can be modulated by preconditioning MSC under different culture conditions. Among them, exposure to hypoxia stands out; these cells respond by activating hypoxia-inducible factor (HIF) at low O2 concentrations. HIF has direct and indirect pleiotropic effects, modulating expression of hundreds of genes involved in processes such as inflammation, migration, proliferation, differentiation, angiogenesis, metabolism, and cell apoptosis. Expression of these genes is reflected in the contents of secreted EV. Interestingly, numerous studies show that MSC-derived EV conditioned under hypoxia have a higher regenerative capacity than those obtained under normoxia. In this review, we show the implications of hypoxia responses in relation to tissue regeneration. In addition, hypoxia preconditioning of MSC is being evaluated as a very attractive strategy for isolation of EV, with a high potential for clinical use in regenerative medicine that can be applied to different pathologies.

Acute physiological response to a normobaric hypoxic exposure: sex differences.

Although preliminary studies suggested sex-related differences in physiological responses to altitude/hypoxia, controlled studies from standardised exposures to normobaric hypoxia are largely lacking. Hence, the goals of this study were to provide information on cardiorespiratory responses to a 7-h normobaric hypoxia exposure and to explore potential differences between men and women. In this crossover study, a total of 15 men and 14 women were subjected to a 7-h exposure in normoxia (FiO2: 21%) and normobaric hypoxia (FiO2: 15%). Values of peripheral oxygen saturation, heart rate, systolic and diastolic blood pressure and respiratory gases were recorded every hour (8 time points), and oxygen saturation every 30 min (15 time points). Compared to normoxia, exposure to hypoxia significantly increased minute ventilation from baseline to hour 7 in males (+ 71%) and females (+ 40%), significantly greater in men (p < 0.05). A steeper decrease in peripheral oxygen saturation until 2.5 h in hypoxia was seen in females compared to males (p < 0.05). In conclusion, the ventilatory response to hypoxia was more pronounced in men compared to women. Moreover, during the first hours in hypoxia, peripheral oxygen saturation dropped more markedly in women than in men, likely due an initially lower and/or less efficient ventilatory response to moderate hypoxia. Those findings should be considered when performing interventions for therapy or prevention in normobaric hypoxia. Nevertheless, further large-scaled and well-controlled studies are needed.

Haematological responses to repeated sprints in hypoxia across different sporting modalities.

The aim was to determine the effects of repeated-sprint training in hypoxia on haematocrit and haemoglobin in different sporting modalities. Seventy-two participants were randomly allocated to Active-Repeated sprint in hypoxia (A-RSH, n= 8); Active-Repeated sprint in normoxia (A-RSN, n= 8); Active-Control (A-CON, n= 8); Team Sports-RSH (T-RSH, n= 8); Team Sports-RSN (T-RSN, n= 8); Team Sports-Control (T-CON, n= 8); Endurance-RSH (E-RSH, n= 8); Endurance-RSN (E-RSN, n= 8); Endurance-Control (E-CON, n= 8). Sessions consisted of two sets of five sprints of 10 swith recovery of 20 sbetween sprints and 10 min between sets. Blood samples for haematocrit and haemoglobin concentrations were obtained before and after, and 2 weeks after cessation. Haematocrit and haemoglobin were lower for the E-RSN group following 2 weeks of cessation of protocol compared with E-RSH (p = 0.035) and E-CON (p = 0.045). Haematocrit of the A-RSH group was higher compared with baseline (p = 0.05) and Post (p = 0.05). Similarly, the T-RSH group demonstrated increases in haematocrit following 2 weeks of cessation compared with Post (p = 0.04). Repeated Sprint Training in Hypoxia had different haematological effects depending on sporting modality.

Effect of hypoxic conditioning on functional fitness, balance and fear of falling in healthy older adults: a randomized controlled trial.

BACKGROUND: Hypoxic conditioning has been proposed as a new tool to mitigate the sarcopenia and enhance health-related function, but decrements in standing balance have been observed during hypoxia exposure. The aim of the study was to evaluate the effect of a hypoxic conditioning training on functional fitness, balance and fear of falling in healthy older adults. METHODS: A total of 54 healthy older adults (aged 65-75 years), who voluntarily participated in the study, were randomly divided into three groups: the control group (CON), the normoxia training group (NT) that performed strength training in normoxia, and the hypoxia training group (HT) that trained under moderate hypoxic conditions at a simulated altitude of 2500 m asl. The training programme that was performed during 24 weeks was similar in both experimental groups and consisted of a full-body workout with elastic bands and kettlebells (three sets × 12-15 reps). The Senior Fitness Test (SFT), the Single Leg Stance test (SLS) and the Short Falls Efficacy Scale-International (FES-I) were assessed before and after the intervention. RESULTS: Results showed that after training, either in normoxia or in hypoxia, the participants increased upper and lower body strength, and the aerobic endurance, and decreased the fear of falling. CONCLUSIONS: The moderate hypoxic conditioning seems to be a useful tool to increase the functional capacity in healthy older adults without observing a decline in balance. TRIAL REGISTRATION: ClinicalTrials.gov NCT04281264 . Registered February 9, 2019-Retrospectively registered.

Effects of moderate-intensity intermittent hypoxic training on health outcomes of patients recovered from COVID-19: the AEROBICOVID study protocol for a randomized controlled trial.

BACKGROUND: Recent studies point to a lower number and reduced severity of cases in higher altitude cities with decreased oxygen concentration. Specific literature has shown several benefits of physical training, so, in this sense, physical training with hypoxic stimulus appears as an alternative that supports the conventional treatments of the COVID-19 patient's recovery. Thus, this study's primary aim is to analyze the effects of moderate-intensity intermittent hypoxic training on health outcomes in COVID-19 recovered patients. METHODS: A clinical trial controlled double-blind study was designed. Participants (30-69 years old) will be recruited among those with moderate to severe COVID-19 symptoms, approximately 30 days after recovery. They will be included in groups according to the training (T) and recovery (R) association with hypoxia (H) or normoxia (N): (a) TH:RH, (b) TN:RH, (c) TN:RN, and last (d) the control group. The 8-week exercise bike intervention will be carried out with a gradual load increase according to the established periods, three times a week in sets of 5 min, 90 to 100% of the anaerobic threshold (AT), and a 2.5-min break. Blood will be collected for genotyping. First, after 4 weeks (partial), after 8 weeks, and later, 4 weeks after the end of the physical training intervention, participants will perform assessments. The primary outcome is the maximum oxygen consumption (VO2peak). The secondary outcomes include lung function, inflammatory mediators, hematological, autonomic parameters, AT, body composition analysis, quality of life, mental health, anthropometric measurements, and physical fitness. The statistical analysis will be executed using the linear regression model with mixed effects at a 5% significance level. DISCUSSION: This study is designed to provide evidence to support the clinical benefits of moderate-intensity intermittent hypoxic training as a part of the treatment of patients recovered from COVID-19. It may also provide evidence on the efficacy and safety of intermittent hypoxic training in different health conditions. Lastly, this study presents an innovative strategy enabling up to 16 participants in the same training session. TRIAL REGISTRATION: ClinicalTrials.gov RBR-5d7hkv. Registered after the start of inclusion on 3 November 2020 with the Brazilian Clinical Trials Registry.