Heart rate recovery to assess fitness: comparison of different calculation methods in a large cross-sectional study.

We propose a cross-sectional study based on 980 maximal effort tests to quantify the effect of the calculation method of heart rate recovery (HRR) on its association with cardiorespiratory fitness (CRF). For five different time t0 after exercise cessation, HRR has been calculated as: the difference and the ratio between maximal measured heart rate and heart rate (HR) at t0HR at t0the decay time of an exponential decay encompassing the first t0 minutes of the HR recovery.The associations between HRR indices and CRF were estimated from generalized estimating equations stratified by gender and adjusted for age and body mass index. For HRR indices based on exponential regression, no significant association with CRF was found, whereas the other HRR indices are associated with CRF when t0 is at least 1 minute and is maximum for t0 = 2 minutes for females and t0 = 3 minutes for males.

AKR1B10, One of the Triggers of Cytokine Storm in SARS-CoV2 Severe Acute Respiratory Syndrome.

Preventing the cytokine storm observed in COVID-19 is a crucial goal for reducing the occurrence of severe acute respiratory failure and improving outcomes. Here, we identify Aldo-Keto Reductase 1B10 (AKR1B10) as a key enzyme involved in the expression of pro-inflammatory cytokines. The analysis of transcriptomic data from lung samples of patients who died from COVID-19 demonstrates an increased expression of the gene encoding AKR1B10. Measurements of the AKR1B10 protein in sera from hospitalised COVID-19 patients suggests a significant link between AKR1B10 levels and the severity of the disease. In macrophages and lung cells, the over-expression of AKR1B10 induces the expression of the pro-inflammatory cytokines Interleukin-6 (IL-6), Interleukin-1ß (IL-1ß) and Tumor Necrosis Factor a (TNFα), supporting the biological plausibility of an AKR1B10 involvement in the COVID-19-related cytokine storm. When macrophages were stressed by lipopolysaccharides (LPS) exposure and treated by Zopolrestat, an AKR1B10 inhibitor, the LPS-induced production of IL-6, IL-1ß, and TNFα is significantly reduced, reinforcing the hypothesis that the pro-inflammatory expression of cytokines is AKR1B10-dependant. Finally, we also show that AKR1B10 can be secreted and transferred via extracellular vesicles between different cell types, suggesting that this protein may also contribute to the multi-organ systemic impact of COVID-19. These experiments highlight a relationship between AKR1B10 production and severe forms of COVID-19. Our data indicate that AKR1B10 participates in the activation of cytokines production and suggest that modulation of AKR1B10 activity might be an actionable pharmacological target in COVID-19 management.

Association between Adverse Childhood Experiences and Muscle Strength in Older Age.

BACKGROUND: Muscle weakness - a biomarker of health - may have its origins in early life and be related to factors such as adverse childhood experiences (ACE), which refer to a set of early-life traumatic and stressful psychosocial events out of the child's control. To date, evidence of an association between ACE and muscle strength in older age is lacking. -Objective: Here, we assessed the associations between ACE during the first 15 years of life and the risk of low muscle strength (LMS) later in life. We also examined whether adult-life socioeconomic circumstances (i.e., educational attainment, main occupational position, and satisfaction with household financial situation) and unhealthy behaviors (i.e., physical inactivity, unhealthy eating, smoking, and high level of alcohol consumption) explained this association. METHODS: We used data from the Survey of Health, Ageing, and Retirement in Europe, a 12-year cohort study with 6 -repeated measurements between 2004 and 2015. Muscle strength was measured using a handheld dynamometer. Confounder-adjusted logistic mixed-effect models were used to examine the associations between ACE (child in care, parental death, parental mental illness, parental drinking, period of hunger, or property taken away) and the risk of LMS in older age. -Results: 24,179 participants (96,372 observations; 13,477 women; aged 50-96 years) living in 14 countries were included. LMS increased with age for both genders. For women, there was a gradual increase in the risk of LMS with the number of experienced ACE (ORs = 1.22 for 1 ACE, 1.74 for ≥2 ACE compared to no ACE). However, there was no significant association among men. This association was only slightly attenuated when adjusting for socioeconomic circumstances and unhealthy behaviors in adulthood. CONCLUSIONS: ACE are associated with later-life muscle weakness among women. These associations were not compensated by the adoption of healthy behaviors or an improvement in socioeconomic circumstances in adulthood. These results suggest that tackling these early-life risk factors in women could promote long-term grip strength, a biomarker of aging.

Inhibition of BET Proteins Reduces Right Ventricle Hypertrophy and Pulmonary Hypertension Resulting from Combined Hypoxia and Pulmonary Inflammation.

Pulmonary hypertension is a co-morbidity, which strongly participates in morbi-mortality in patients with chronic obstructive pulmonary disease (COPD). Recent findings showed that bromodomain-containing proteins, in charge of reading histone acetylation, could be involved in pulmonary arterial hypertension. Our aim was to study the effect of I-BET151, an inhibitor of bromodomain and extra-terminal domain (BET), on the right ventricle hypertrophy and pulmonary hypertension, induced by a combination of chronic hypoxia and pulmonary inflammation, as the two main stimuli encountered in COPD. Adult Wistar male rats, exposed to chronic hypoxia plus pulmonary inflammation (CHPI), showed a significant right ventricle hypertrophy (+57%, p < 0.001), an increase in systolic pressure (+46%, p < 0.001) and in contraction speed (+36%, p < 0.001), when compared to control animals. I-BET151 treated animals (CHPI-iB) showed restored hemodynamic parameters to levels similar to control animals, despite chronic hypoxia plus exposure to pulmonary inflammation. They displayed lower right ventricle hypertrophy and hematocrit compared to the CHPI group (respectively -16%, p < 0.001; and -9%, p < 0.05). Our descriptive study shows a valuable effect of the inhibition of bromodomain and extra-terminal domain proteins on hemodynamic parameters, despite the presence of chronic hypoxia and pulmonary inflammation. This suggests that such inhibition could be of potential interest for COPD patients with pulmonary hypertension. Further studies are needed to unravel the underlying mechanisms involved and the net benefits of inhibiting adaptations to chronic hypoxia.

SIRT1 may play a crucial role in overload-induced hypertrophy of skeletal muscle.

KEY POINTS: Silent mating type information regulation 2 homologue 1 (SIRT1) activity and content increased significantly in overload-induced hypertrophy. SIRT1-mediated signalling through Akt, the endothelial nitric oxide synthase mediated pathway, regulates anabolic process in the hypertrophy of skeletal muscle. The regulation of catabolic signalling via forkhead box O 1 and protein ubiquitination is SIRT1 dependent. Overload-induced changes in microRNA levels regulate SIRT1 and insulin-like growth factor 1 signalling. ABSTRACT: Significant skeletal muscle mass guarantees functional wellbeing and is important for high level performance in many sports. Although the molecular mechanism for skeletal muscle hypertrophy has been well studied, it still is not completely understood. In the present study, we used a functional overload model to induce plantaris muscle hypertrophy by surgically removing the soleus and gastrocnemius muscles in rats. Two weeks of muscle ablation resulted in a 40% increase in muscle mass, which was associated with a significant increase in silent mating type information regulation 2 homologue 1 (SIRT1) content and activity (P < 0.001). SIRT1-regulated Akt, endothelial nitric oxide synthase and GLUT4 levels were also induced in hypertrophied muscles, and SIRT1 levels correlated with muscle mass, paired box protein 7 (Pax7), proliferating cell nuclear antigen (PCNA) and nicotinamide phosphoribosyltransferase (Nampt) levels. Alternatively, decreased forkhead box O 1 (FOXO1) and increased K48 polyubiquitination also suggest that SIRT1 could be involved in the catabolic process of hypertrophy. Furthermore, increased levels of K63 and muscle RING finger 2 (MuRF2) protein could also be important enhancers of muscle mass. We report here that the levels of miR1 and miR133a decrease in hypertrophy and negatively correlate with muscle mass, SIRT1 and Nampt levels. Our results reveal a strong correlation between SIRT1 levels and activity, SIRT1-regulated pathways and overload-induced hypertrophy. These findings, along with the well-known regulatory roles that SIRT1 plays in modulating both anabolic and catabolic pathways, allow us to propose the hypothesis that SIRT1 may actually play a crucial causal role in overload-induced hypertrophy of skeletal muscle. This hypothesis will now require rigorous direct and functional testing.

Matrix design for optimal pancreatic ß cells transplantation.

New therapeutic approaches to treat type 1 diabetes mellitus relies on pancreatic islet transplantation. Here, developing immuno-isolation strategies is essential to eliminate the need for systemic immunosuppression after pancreatic islet grafts. A solution is the macro-encapsulation of grafts in semipermeable matrixes with a double function: separating islets from host immune cells and facilitating the diffusion of insulin, glucose, and other metabolites. This study aims to synthesize and characterize different types of gelatin-collagen matrixes to prepare a macro-encapsulation device for pancreatic islets that fulfill these functions. While natural polymers exhibit superior biocompatibility compared to synthetic ones, their mechanical properties are challenging to reproduce. To address this issue, we conducted a comparative analysis between photo-crosslinked gelatin matrixes and chemically crosslinked collagen matrixes. We show that the different crosslinkers and polymerization methods influence the survival and glucose-stimulated insulin production of pancreatic ß cells (INS1) in vitro, as well as the in vitro and in vivo stability of the matrix and the immuno-isolation in vivo. Among the matrixes, the stiff multilayer GelMA matrixes (8.5 kPa), fabricated by digital light processing, were the best suited for pancreatic ß cells macro-encapsulation regarding these parameters. Within the alveoli of this matrix, pancreatic ß cells spontaneously formed aggregates.

Decrease of heart rate variability during exercise: An index of cardiorespiratory fitness.

The present study proposes to measure and quantify the heart rate variability (HRV) changes during effort as a function of the heart rate and to test the capacity of the produced indices to predict cardiorespiratory fitness measures. Therefore, the beat-to-beat cardiac time interval series of 18 adolescent athletes (15.2 ± 2.0 years) measured during maximal graded effort test were detrended using a dynamical first-order differential equation model. HRV was then calculated as the standard deviation of the detrended RR intervals (SDRR) within successive windows of one minute. The variation of this measure of HRV during exercise is properly fitted by an exponential decrease of the heart rate: the SDRR is divided by 2 every increase of heart rate of 20 beats/min. The HR increase necessary to divide by 2 the HRV is linearly inversely correlated with the maximum oxygen consumption (r = -0.60, p = 0.006), the maximal aerobic power (r = -0.62, p = 0.006), and, to a lesser extent, to the power at the ventilatory thresholds (r = -0.53, p = 0.02 and r = -0.47, p = 0.05 for the first and second threshold). It indicates that the decrease of the HRV when the heart rate increases is faster among athletes with better fitness. This analysis, based only on cardiac measurements, provides a promising tool for the study of cardiac measurements generated by portable devices.

Structural insights into p300 regulation and acetylation-dependent genome organisation.

Histone modifications are deposited by chromatin modifying enzymes and read out by proteins that recognize the modified state. BRD4-NUT is an oncogenic fusion protein of the acetyl lysine reader BRD4 that binds to the acetylase p300 and enables formation of long-range intra- and interchromosomal interactions. We here examine how acetylation reading and writing enable formation of such interactions. We show that NUT contains an acidic transcriptional activation domain that binds to the TAZ2 domain of p300. We use NMR to investigate the structure of the complex and found that the TAZ2 domain has an autoinhibitory role for p300. NUT-TAZ2 interaction or mutations found in cancer that interfere with autoinhibition by TAZ2 allosterically activate p300. p300 activation results in a self-organizing, acetylation-dependent feed-forward reaction that enables long-range interactions by bromodomain multivalent acetyl-lysine binding. We discuss the implications for chromatin organisation, gene regulation and dysregulation in disease.

Temperate Air Breathing Increases Cycling Performance in Hot and Humid Climate Environment.

Practicing physical activity in a hot and humid climate (HHC) is becoming increasingly common due to anthropogenic climate change and the growing number of international sports events held in warm countries. The aim of this study was to understand the physiological and psychological effects of breathing two air temperatures during cycling exercise in HHC. Ten male athletes performed two sessions of exercise in HHC (T°: 32.0 ± 0.5 °C, relative humidity: 78.6 ± 0.7%) during which they breathed hot air (HA, 33.2 ± 0.06 °C) or temperate air (TA, 22.6 ± 0.1 °C). Each session was composed of 30 min of pre-fatigue cycling at constant intensity, followed by a 10 min self-regulated performance. During pre-fatigue, TA induced a better feeling score and a lower rating of perceived effort (respectively, +0.9 ± 0.2, p < 0.05; 1.13 ± 0.21; p < 0.05) with no changes in physiological parameters. During performance, oxygen consumption and mechanical workload were increased by TA (respectively, +0.23 ± 0.1 L min-1, p < 0.05 and +19.2 ± 6.1 W, p < 0.01), whereas no significant differences were observed for psychological parameters. Reducing the breathed air temperature decreased the discomfort induced by HHC during exercise and increased the performance capacity during self-regulated exercise. Thus, breathed air temperature perception is linked to the hardship of training sessions and directly contributes to the performance decrease in HHC.

Menthol as an Adjuvant to Help Athletes Cope With a Tropical Climate: Tracks From Heat Experiments With Special Focus on Guadeloupe Investigations.

Endurance and prolonged exercise are altered by hot climate. In hot and dry climate, thermoregulation processes, including evapotranspiration, normally maintain a relatively constant body core temperature. In hot and wet climate (usually called "tropical"), the decrease in evapotranspiration efficacy increases the sweating rate, which can rapidly induce severe hypohydration without efficiently reducing core temperature. The negative effects of tropical environment on long-duration exercise have been well documented, with clear demonstrations that they exceed the acclimation possibilities: both acclimated athletes and natives to tropical climate show impaired performances compared with that in neutral climate. New countermeasures, applicable during competitive events, are therefore needed to limit these negative effects. We studied the effects of several countermeasures in outdoor or natural tropical climates and noted that the easiest method to apply is cooling with cold (-1 to 3°C) beverage. Moreover, adding menthol increased the cold sensation induced by the beverage temperature, optimizing the positive effects on performance. We also demonstrated that efficient pre-cooling with cold menthol beverage requires drinking for 1 h instead of 30 min before the exercise. The optimal cooling method seems to be 1 h of cold + menthol pre-cooling ingestion followed by menthol + ice-slurry per-cooling. However, limitations should be noted: (1) the menthol concentration seems to be crucial, with positive effects for a 0.05% solution, whereas higher concentrations need to be explored; and (2) because it acts as a cold adjuvant without decreasing core temperature, menthol can lead to decreased thermoregulatory processes, thus inducing hyperthermia. Last, if menthol is added to cooling processes, athletes should first test them in training conditions for the maximal cooling effect to ensure optimal performance in competition in tropical climate.

Disadvantaged Early-Life Socioeconomic Circumstances Are Associated With Low Respiratory Function in Older Age.

BACKGROUND: Poor lung function in late life may stem from early-life risk factors, but the epidemiological evidence is inconsistent. We investigated whether individuals who experienced disadvantageous socioeconomic circumstances (SEC) in early life showed lower levels of respiratory function in older age, a steeper decline over time, and whether these relationships were explained by adult-life SEC, body mass index, and physical inactivity in older age. METHODS: We used data from the Survey of Health Ageing and Retirement in Europe (2004-2015). Participants' peak expiratory flow (PEF) was assessed with a mini-Wright peak flow meter at second, fourth, and sixth waves. Confounder-adjusted linear mixed-effect models were used to examine the associations between early-life SEC and PEF in older age. A total of 21,734 adults aged 50-96 years (46,264 observations) were included in the analyses. RESULTS: Older adults with disadvantaged early-life SEC showed lower levels of PEF compared with those with advantaged early-life SEC. The association between early-life SEC and late-life PEF persisted after adjusting for adult-life SEC, smoking, physical inactivity, and body mass index. PEF declined with age, but the effect of early-life SEC on this decline was not consistent across robustness and sensitivity analyses. CONCLUSIONS: Early life is a sensitive period for respiratory health. Further considering the effect of SEC arising during this period may improve the prevention of chronic respiratory diseases.

New Automatized Method of 3D Multiculture Viability Analysis Based on Confocal Imagery: Application to Islets and Mesenchymal Stem Cells Co-Encapsulation.

Co-encapsulation of pancreatic islets with mesenchymal stem cells in a three-dimensional biomaterial's structure is a promising technique to improve transplantation efficacy and to decrease immunosuppressant therapy. Currently, evaluation of graft quality after co-encapsulation is only based on insulin secretion. Viability measurement in a 3D conformation structure involving two different cell types is complex, mainly performed manually, highly time consuming and examiner dependent. Standardization of encapsulated graft viability analysis before transplantation is a key point for the translation of the method from the bench side to clinical practice. In this study, we developed an automated analysis of islet viability based on confocal pictures processing of cells stained with three probes (Hoechst, propidium iodide, and PKH67). When compared with results obtained manually by different examiners, viability results show a high degree of similarity (under 3% of difference) and a tight correlation (r = 0.894; p < 0.001) between these two techniques. The automated technique offers the advantage of reducing the analysis time by 6 and avoids the examiner's dependent variability factor. Thus, we developed a new efficient tool to standardize the analysis of islet viability in 3D structure involving several cell types, which is a key element for encapsulated graft analysis in clinical practice.

Alterations to mitochondrial fatty-acid use in skeletal muscle after chronic exposure to hypoxia depend on metabolic phenotype.

We investigated the effects of chronic hypoxia on the maximal use of and sensitivity of mitochondria to different substrates in rat slow-oxidative (soleus, SOL) and fast-glycolytic (extensor digitorum longus, EDL) muscles. We studied mitochondrial respiration in situ in permeabilized myofibers, using pyruvate, octanoate, palmitoyl-carnitine (PC), or palmitoyl-coenzyme A (PCoA). The hypophagia induced by hypoxia may also alter metabolism. Therefore, we used a group of pair-fed rats (reproducing the same caloric restriction, as observed in hypoxic animals), in addition to the normoxic control fed ad libitum. The resting respiratory exchange ratio decreased after 21 days of exposure to hypobaric hypoxia (simulated elevation of 5,500 m). The respiration supported by pyruvate and octanoate were unaffected. In contrast, the maximal oxidative respiratory rate for PCoA, the transport of which depends on carnitine palmitoyltransferase 1 (CPT-1), decreased in the rapid-glycolytic EDL and increased in the slow-oxidative SOL, although hypoxia improved affinity for this substrate in both muscle types. PC and PCoA were oxidized similarly in normoxic EDL, whereas chronic hypoxia limited transport at the CPT-1 step in this muscle. The effects of hypoxia were mediated by caloric restriction in the SOL and by hypoxia itself in the EDL. We conclude that improvements in mitochondrial affinity for PCoA, a physiological long-chain fatty acid, would facilitate fatty-acid use at rest after chronic hypoxia independently of quantitative alterations of mitochondria. Conversely, decreasing the maximal oxidation of PCoA in fast-glycolytic muscles would limit fatty-acid use during exercise.NEW & NOTEWORTHY Affinity for low concentrations of long-chain fatty acids (LCFA) in mitochondria skeletal muscles increases after chronic hypoxia. Combined with a lower respiratory exchange ratio, this suggests facility for fatty acid utilization at rest. This fuel preference is related to caloric restriction in oxidative muscle and to hypoxia in glycolytic one. In contrast, maximal oxidation for LCFA is decreased by chronic hypoxia in glycolytic muscle and can explain glucose dependence at exercise.

Muscle hypertrophy in hypoxia with inflammation is controlled by bromodomain and extra-terminal domain proteins.

Some of the Chronic Obstructive Pulmonary Disease (COPD) patients engaged in exercise-based muscle rehabilitation programs are unresponsive. To unravel the respective role of chronic hypoxia and pulmonary inflammation on soleus muscle hypertrophic capacities, we challenged male Wistar rats to repeated lipopolysaccharide instillations, associated or not with a chronic hypoxia exposure. Muscle hypertrophy was initiated by bilateral ablation of soleus agonists 1 week before sacrifice. To understand the role played by the histone acetylation, we also treated our animals with an inhibitor of bromodomains and extra terminal proteins (I-BET) during the week after surgery. Pulmonary inflammation totally inhibited this hypertrophy response under both normoxic and hypoxic conditions (26% lower than control surgery, p < 0.05), consistent with the S6K1 and myogenin measurements. Changes in histone acetylation and class IIa histone deacetylases expression, following pulmonary inflammation, suggested a putative role for histone acetylation signaling in the altered hypertrophy response. The I-BET drug restored the hypertrophy response suggesting that the non-response of muscle to a hypertrophic stimulus could be modulated by epigenetic mechanisms, including histone-acetylation dependant pathways. Drugs targeting such epigenetic mechanisms may open therapeutic perspectives for COPD patients with systemic inflammation who are unresponsive to rehabilitation.

A low-cost system to easily measure spontaneous physical activity in rodents.

Spontaneous physical activity (SPA) can be responsible for variations of a lot of physiological parameters at the molecular, cellular, tissue, and systemic levels. It is increasingly recognized that good understanding of a large part of experimental results requires weighting them by SPA in order to reduce variability and thus to decrease the number of animals necessary to conduct a study. However, because of the high cost of this equipment, only a few laboratories are equipped with such equipment to measure the SPA of their animals. Here we present an effective, adaptable, and affordable system to measure SPA in rodents based on video acquisition of the animal in its own environment. We compared results obtained with our system to those collected at the same time with a commercial system of actimetry recording, and we found a high degree of correlation between these two approaches (r = 0.93; P < 0.001). We also were able to detect small variations of SPA induced by a special environment like chronic hypoxia exposure (25% less spontaneous activity compared with animals in normoxia, P < 0.05) or during the circadian cycle (107% more activity during the nocturnal phase compared with the diurnal phase, P < 0.05).