Maximizing anaerobic performance with repeated-sprint training in hypoxia: In search of an optimal altitude based on pulse oxygen saturation monitoring.

Purpose: Repeated-sprint training in hypoxia (RSH) leads to great improvements in anaerobic performance. However, there is no consensus about the optimal level of hypoxia that should be used during training to maximize subsequent performances. This study aimed to establish whether such an optimal altitude can be determined and whether pulse oxygen saturation during RSH is correlated with training-induced improvement in performance. Methods: Peak and mean power outputs of healthy young males [age (mean ± SD) 21.7 ± 1.4 years] were measured during a Wingate (30 s) and a repeated-sprint ability (RSA; 10 x 6-s sprint with 24-s recovery) test before and after RSH. Participants performed six cycling sessions comprising three sets of 8 x 6-s sprint with 24-s recovery in normobaric hypoxia at a simulated altitude of either 1,500 m, 2,100 m, or 3,200 m (n = 7 per group). Heart rate variability was assessed at rest and during recovery from Wingate test before and after RSH. Results: The subjective rating of perceived exertion and the relative exercise intensity during training sessions did not differ between the three groups, contrary to pulse oxygen saturation (p < 0.001 between each group). Mean and peak power outputs were significantly increased in all groups after training, except for the mean power in the RSA test for the 3200 m group. Change in mean power on RSA test (+8.1 ± 6.6%) was the only performance parameter significantly correlated with pulse oxygen saturation during hypoxic training (p < 0.05, r = 0.44). The increase in LnRMSSD during recovery from the Wingate test was enhanced after training in the 1,500 m (+22%) but not in the two other groups (≈- 6%). Moreover, the increase in resting heart rate with standing after training was negatively correlated with SpO2 (p < 0.01, r =-0.63) suggesting that hypoxemia level during training differentially altered autonomic nervous system activity. Conclusion: These data indicate that RSH performed as early as 1,500 m of altitude is effective in improving anaerobic performance in moderately trained subjects without strong association with pulse oxygen saturation monitoring during training.

Effects of Repeated Sprint Training With Progressive Elastic Resistance on Sprint Performance and Anterior-Posterior Force Production in Elite Young Soccer Players.

ABSTRACT: Le Scouarnec, J, Samozino, P, Andrieu, B, Thubin, T, Morin, JB, and Favier, FB. Effects of repeated sprint training with progressive elastic resistance on sprint performance and anterior-posterior force production in elite young soccer players. J Strength Cond Res 36(6): 1675-1681, 2022-This study aimed to determine whether repeated sprint training with progressive high elastic resistance could improve sprint performance and anterior-posterior (AP) force production capacities of elite young soccer players. Seven elite U19 soccer players underwent 10 sessions of elastic-resisted repeated sprints on 8 weeks, whereas 8 U17 players from the same academy (control group) followed the same protocol without elastic bands. Sprint performance and mechanical parameters were recorded on a 30-m sprint before and after training. The control group did not show change for any of the measured variables. In contrast, the elastic-resisted training resulted in a significant improvement of the sprint time (-2.1 ± 1.3%; p = 0.026; Hedges' g = -0.49) and maximal velocity (Vmax; +3.9 ± 2%; p = 0.029; Hedges' g = 0.61) reached during the 30-m sprint. These enhancements were concurrent with an increase in the maximal power output related to AP force (Pmax; +4.9 ± 5.1%%; p = 0.026; Hedges' g = 0.42). Although the theoretical maximal AP force (F0) remained unchanged in both groups, there was a medium but nonsignificant increase in theoretical maximal velocity (V0; +3.7 ± 2.5%; p = 0.13; Hedges' g = 0.5) only in the elastic group. Therefore, the present results show that sprint capacity of elite young soccer players can be further improved by adding incremental resistance against runner displacement to raise the ability to produce AP force, rather at high velocity in the final phase of the acceleration.

Hypothalamic-pituitary-adrenal axis activation and glucocorticoid-responsive gene expression in skeletal muscle and liver of Apc mice.

BACKGROUND: Cancer patients at advanced stages experience a severe depletion of skeletal muscle compartment together with a decrease in muscle function, known as cancer cachexia. Cachexia contributes to reducing quality of life, treatment efficiency, and lifespan of cancer patients. However, the systemic nature of the syndrome is poorly documented. Here, we hypothesize that glucocorticoids would be important systemic mediators of cancer cachexia. METHODS: To explore the role of glucocorticoids during cancer cachexia, biomolecular analyses were performed on several tissues (adrenal glands, blood, hypothalamus, liver, and skeletal muscle) collected from ApcMin/+ male mice, a mouse model of intestine and colon cancer, aged of 13 and 23 weeks, and compared with wild type age-matched C57BL/6J littermates. RESULTS: Twenty-three-week-old Apc mice recapitulated important features of cancer cachexia including body weight loss (-16%, P < 0.0001), muscle atrophy (gastrocnemius muscle: -53%, P < 0.0001), and weakness (-50% in tibialis anterior muscle force, P < 0.0001), increased expression of atrogens (7-fold increase in MuRF1 transcript level, P < 0.0001) and down-regulation of Akt-mTOR pathway (3.3-fold increase in 4EBP1 protein content, P < 0.0001), together with a marked transcriptional rewiring of hepatic metabolism toward an increased expression of gluconeogenic genes (Pcx: +90%, Pck1: +85%), and decreased expression of glycolytic (Slc2a2: -40%, Gk: -30%, Pklr: -60%), ketogenic (Hmgcs2: -55%, Bdh1: -80%), lipolytic/fatty oxidation (Lipe: -50%, Mgll: -60%, Cpt2: -60%, Hadh: -30%), and lipogenic (Acly: -30%, Acacb: -70%, Fasn: -45%) genes. The hypothalamic pituitary-adrenal axis was activated, as evidenced by the increase in the transcript levels of genes encoding corticotropin-releasing hormone in the hypothalamus (2-fold increase, P < 0.01), adrenocorticotropic hormone receptor (3.4-fold increase, P < 0.001), and steroid biosynthesis enzymes (Cyp21a1, P < 0.0001, and Cyp11b1, P < 0.01) in the adrenal glands, as well as by the increase in corticosterone level in the serum (+73%, P < 0.05), skeletal muscle (+17%, P < 0.001), and liver (+24%, P < 0.05) of cachectic 23-week-old Apc mice. A comparative transcriptional analysis with dexamethasone-treated C57BL/6J mice indicated that the activation of the hypothalamic-pituitary-adrenal axis in 23-week-old ApcMin/+ mice was significantly associated with the transcription of glucocorticoid-responsive genes in skeletal muscle (P < 0.05) and liver (P < 0.001). The transcriptional regulation of glucocorticoid-responsive genes was also observed in the gastrocnemius muscle of Lewis lung carcinoma tumour-bearing mice and in KPC mice (tibialis anterior muscle and liver). CONCLUSIONS: These findings highlight the role of the hypothalamic-pituitary-adrenal-glucocorticoid pathway in the transcriptional regulation of skeletal muscle catabolism and hepatic metabolism during cancer cachexia. They also provide the paradigm for the design of new therapeutic strategies.

Usefulness of Home Screening for Promoting Awareness of Impaired Glycemic Status and Utilization of Primary Care in a Low Socio-Economic Setting: A Follow-Up Study in Reunion Island.

BACKGROUND: Low socio-economic settings are characterized by high prevalence of diabetes and difficulty in accessing healthcare. In these contexts, proximity health services could improve healthcare access for diabetes prevention. Our primary objective was to evaluate the usefulness of home screening for promoting awareness of impaired glycemic status and utilization of primary care among adults aged 18-79 in a low socio-economic setting. METHODS: This follow-up study was conducted in 2015-2016 in Reunion Island, a French overseas department in the Indian Ocean. Enrollment and screening occurred on the same day at the home of participants (N=907). Impaired glycemic status was defined as [glycated hemoglobin (HbA1c) ≥5.7%] OR [fasting capillary blood glucose (FCBG) ≥1.10 g/L] OR [HbA1c=5.5-5.6% and FCBG=1.00-1.09 g/L]. Medical, socio-cultural, and socio-economic characteristics were collected via a face-to-face questionnaire. A one-month telephone follow-up survey was conducted to determine whether participants had consulted a general practitioner (GP) for confirmation of screening results. A multinomial polytomous logistic regression model was used to identify factors independently associated with non-use of GP consultation for confirmation of screening results and nonresponse to the telephone follow-up survey. RESULTS: Prevalence of glycemic abnormalities was 46.0% (95% CI = 42.7-49.2%). Among participants with impaired glycemic status (N=417), 77.7% (95% CI=73.7-81.7%) consulted a GP for confirmation of screening results, 12.5% (95% CI=9.3-15.6%) did not, and 9.8% failed to respond to the follow-up survey. Factors independently associated with non-use of GP consultation for confirmation of screening results were self-reported unwillingness to consult a GP (adjusted odds ratio [OR]: 4.86, 95% CI=1.70-13.84), usual GP consultation frequency of less than once a year (adjusted OR: 4.13, 95% CI=1.56-10.97), and age 18-39 years (adjusted OR: 3.09, 95% CI=1.46-6.57). CONCLUSION: Home screening for glycemic abnormalities is a useful proximity health service for diabetes prevention in low socio-economic settings. Further efforts, including health literacy interventions, are needed to increase utilization of primary care.

Is REDD1 a metabolic double agent? Lessons from physiology and pathology.

The Akt/mechanistic target of rapamycin (mTOR) signaling pathway governs macromolecule synthesis, cell growth, and metabolism in response to nutrients and growth factors. Regulated in development and DNA damage response (REDD)1 is a conserved and ubiquitous protein, which is transiently induced in response to multiple stimuli. Acting like an endogenous inhibitor of the Akt/mTOR signaling pathway, REDD1 protein has been shown to regulate cell growth, mitochondrial function, oxidative stress, and apoptosis. Recent studies also indicate that timely REDD1 expression limits Akt/mTOR-dependent synthesis processes to spare energy during metabolic stresses, avoiding energy collapse and detrimental consequences. In contrast to this beneficial role for metabolic adaptation, REDD1 chronic expression appears involved in the pathogenesis of several diseases. Indeed, REDD1 expression is found as an early biomarker in many pathologies including inflammatory diseases, cancer, neurodegenerative disorders, depression, diabetes, and obesity. Moreover, prolonged REDD1 expression is associated with cell apoptosis, excessive reactive oxygen species (ROS) production, and inflammation activation leading to tissue damage. In this review, we decipher several mechanisms that make REDD1 a likely metabolic double agent depending on its duration of expression in different physiological and pathological contexts. We also discuss the role played by REDD1 in the cross talk between the Akt/mTOR signaling pathway and the energetic metabolism.

REDD1 deficiency protects against nonalcoholic hepatic steatosis induced by high-fat diet.

Nonalcoholic fatty liver disease is a chronic liver disease which is associated with obesity and insulin resistance. We investigated the implication of REDD1 (Regulated in development and DNA damage response-1), a stress-induced protein in the development of hepatic steatosis. REDD1 expression was increased in the liver of obese mice and morbidly obese patients, and its expression correlated with hepatic steatosis and insulin resistance in obese patients. REDD1 deficiency protected mice from the development of hepatic steatosis induced by high-fat diet (HFD) without affecting body weight gain and glucose intolerance. This protection was associated with a decrease in the expression of lipogenic genes, SREBP1c, FASN, and SCD-1 in liver of HFD-fed REDD1-KO mice. Healthy mitochondria are crucial for the adequate control of lipid metabolism and failure to remove damaged mitochondria is correlated with liver steatosis. Expression of markers of autophagy and mitophagy, Beclin, LC3-II, Parkin, BNIP3L, was enhanced in liver of HFD-fed REDD1-KO mice. The number of mitochondria showing colocalization between LAMP2 and AIF was increased in liver of HFD-fed REDD1-KO mice. Moreover, mitochondria in liver of REDD1-KO mice were smaller than in WT. These results are correlated with an increase in PGC-1α and CPT-1 expression, involved in fatty acid oxidation. In conclusion, loss of REDD1 protects mice from the development of hepatic steatosis.

Endurance exercise decreases protein synthesis and ER-mitochondria contacts in mouse skeletal muscle.

Exercise is important to maintain skeletal muscle mass through stimulation of protein synthesis, which is a major ATP-consuming process for cells. However, muscle cells have to face high energy demand during contraction. The present study aimed to investigate protein synthesis regulation during aerobic exercise in mouse hindlimb muscles. Male C57Bl/6J mice ran at 12 m/min for 45 min or at 12 m/min for the first 25 min followed by a progressive increase in velocity up to 20 m/min for the last 20 min. Animals were injected intraperitoneally with 40 nmol/g of body weight of puromycin and euthanized by cervical dislocation immediately after exercise cessation. Analysis of gastrocnemius, plantaris, quadriceps, soleus, and tibialis anterior muscles revealed a decrease in protein translation assessed by puromycin incorporation, without significant differences among muscles or running intensities. The reduction of protein synthesis was associated with a marked inhibition of mammalian target of rapamycin complex 1 (mTORC1)-dependent phosphorylation of eukaryotic translation initiation factor 4E-binding protein 1, a mechanism consistent with reduced translation initiation. A slight activation of AMP-activated protein kinase consecutive to the running session was measured but did not correlate with mTORC1 inhibition. More importantly, exercise resulted in a strong upregulation of regulated in development and DNA damage 1 (REDD1) protein and gene expressions, whereas transcriptional regulation of other recognized exercise-induced genes (IL-6, kruppel-like factor 15, and regulator of calcineurin 1) did not change. Consistently with the recently discovered role of REDD1 on mitochondria-associated membranes, we observed a decrease in mitochondria-endoplasmic reticulum interaction following exercise. Collectively, these data raise questions concerning the role of mitochondria-associated endoplasmic reticulum membrane disruption in the regulation of muscle proteostasis during exercise and, more generally, in cell adaptation to metabolic stress.NEW & NOTEWORTHY How muscles regulate protein synthesis to cope with the energy demand during contraction is poorly documented. Moreover, it is unknown whether protein translation is differentially affected among mouse hindlimb muscles under different physiological exercise modalities. We showed here that 45 min of running decreases puromycin incorporation similarly in 5 different mouse muscles. This decrease was associated with a strong increase in regulated in development and DNA damage 1 protein expression and a significant disruption of the mitochondria and sarcoplasmic reticulum interaction.

Glucocorticoid-dependent REDD1 expression reduces muscle metabolism to enable adaptation under energetic stress.

BACKGROUND: Skeletal muscle atrophy is a common feature of numerous chronic pathologies and is correlated with patient mortality. The REDD1 protein is currently recognized as a negative regulator of muscle mass through inhibition of the Akt/mTORC1 signaling pathway. REDD1 expression is notably induced following glucocorticoid secretion, which is a component of energy stress responses. RESULTS: Unexpectedly, we show here that REDD1 instead limits muscle loss during energetic stresses such as hypoxia and fasting by reducing glycogen depletion and AMPK activation. Indeed, we demonstrate that REDD1 is required to decrease O2 and ATP consumption in skeletal muscle via reduction of the extent of mitochondrial-associated endoplasmic reticulum membranes (MAMs), a central hub connecting energy production by mitochondria and anabolic processes. In fact, REDD1 inhibits ATP-demanding processes such as glycogen storage and protein synthesis through disruption of the Akt/Hexokinase II and PRAS40/mTORC1 signaling pathways in MAMs. Our results uncover a new REDD1-dependent mechanism coupling mitochondrial respiration and anabolic processes during hypoxia, fasting, and exercise. CONCLUSIONS: Therefore, REDD1 is a crucial negative regulator of energy expenditure that is necessary for muscle adaptation during energetic stresses. This present study could shed new light on the role of REDD1 in several pathologies associated with energetic metabolism alteration, such as cancer, diabetes, and Parkinson's disease.

Sexual dimorphism in the association between gestational diabetes mellitus and overweight in offspring at 5-7 years: The OBEGEST cohort study.

Evidence from literature is mixed regarding a possible association of maternal gestational diabetes mellitus (GDM) and overweight in the offspring. Sexual dimorphism, or sex disparities in the pathogenesis linking GDM exposure to overweight, could be at play. The objective of this study was to investigate the association between GDM and child overweight at 5-7 years. Six hundred pairs (1:1) of Reunionese liveborn singletons selected from a hospital-based birth registry, matched for sex, gestational age, and birth period, underwent a prospective in-home follow-up and were analyzed with respect to their exposure to GDM. The primary outcome was child overweight at 5-7 years, as defined by the International Obesity Task Force. The association between GDM exposure and child overweight was estimated by the odds ratio (OR) using conditional logistic regression models. For the subset of children exposed to GDM with available maternal glycemic data, we analyzed the relationship between maternal glycemic levels during pregnancy and child body mass index (BMI) at 5-7 years with a linear regression model. In light of the significant interaction between sex and GDM, all statistical analyses were then stratified by sex. After controlling for pre-pregnancy BMI and maternal sociodemographic characteristics, the risk of overweight increased with exposure to GDM for boys (adjusted OR: 2.34; 95% confidence interval = 1.26-4.34, P = 0.007) but not for girls (adjusted OR: 0.56; 95%CI = 0.28-1.10, P = 0.093). Consistent with this, the linear increase of boys' BMI at 5-7 years with maternal blood glucose levels during pregnancy, in the exposed group, displayed a dose-response relationship. Our findings indicate that exposure to GDM is a risk factor for childhood overweight in boys but not in girls, which adds to the growing body of evidence suggesting greater sensitivity of male offspring to intrauterine hyperglycemia.

Rheumatic manifestations associated with Chikungunya virus infection: A study of 307 patients with 32-month follow-up (RHUMATOCHIK study).

OBJECTIVES: In the wake of the Chikungunya epidemic which struck Reunion Island in 2005 and 2006, we conducted a prospective, multicentre study (RHUMATOCHIK) whose main objective was analyse the characteristics and progression of rheumatic manifestations in patients with post-Chikungunya joint pain. METHODS: A cohort of 307 consecutively included patients underwent rheumatological examinations for pain secondary to Chikungunya virus infection. The long-term evaluation was conducted by telephone survey 1 and 2 years after the onset of the viral infection. RESULTS: At inclusion, mean age was 54 years (24-87) and 83.1% of the patients were female. Chronic joint pain was associated with synovitis in 64.2% of the patients, affecting primarily the wrists, the proximal interphalangeal joints of the fingers, and the ankles. Attempts to detect the viral genome in joint fluid (10 patients) and synovial tissue (6 patients) using the RT-PCR technique were repeatedly unsuccessful. With a mean follow-up of 32 months, joint pain persisted in 83.1% of the patients. Functional impairment, however, was moderate, with a HAQ score of 0.44±0.5. CONCLUSION: Chikungunya virus infection is frequently the cause of joint manifestations that can persist for several months, or even several years. In some cases, the clinical symptoms closely resemble those usually associated with rheumatoid arthritis. Further studies are necessary to improve the therapeutic management of these patients.

[To analyse the transferability of an intervention : applying the functions/implementation/context model on a diabetes prevention programme]. / Analyser la transférabilité d'une intervention : application du modèle fonctions clés/implémentation/contexte à un programme de prévention du diabète.

INTRODUCTION: A type 2 diabetes primary prevention programme that was shown to be feasible and effective in 2003 was transferred to another vulnerable district of Reunion Island in 2004, but its short-term effectiveness could not be reproduced. Based on this example, this article analyses whether the key functions/implementation/context model can be useful to : 1- more accurately describe an evaluated intervention ; and 2- identify the factors involved in the transferability of this intervention. METHODS: The causality model of the initial programme is described. We then identified the key functions (or theoretical processes) of this initial programme, implementation of these functions, and the context in which the intervention took place. Transfer was analysed by focusing on the differences between the initial programme and the transferred programme in terms of key functions, implementation and context. RESULTS: The causality model involves individual, meso-social, and environmental health determinants. Our analysis of programme transfer highlights differences in : key functions (two key functions dropped, one key function added, one key function modified), implementation (failure to implement, loss/improvement of quality), and context (population and socioeconomic level of the district concerned). CONCLUSION: This work supports the hypothesis that the key functions/implementation/context model can be useful to improve the description of an intervention, and analyse the factors involved in its transferability.

Cancer-induced cardiac cachexia: Pathogenesis and impact of physical activity (Review).

Cachexia is a wasting syndrome observed in many patients suffering from several chronic diseases including cancer. In addition to the progressive loss of skeletal muscle mass, cancer cachexia results in cardiac function impairment. During the severe stage of the disease, patients as well as animals bearing cancer cells display cardiac atrophy. Cardiac energy metabolism is also impeded with disruption of mitochondrial homeostasis and reduced oxidative capacity, although the available data remain equivocal. The release of inflammatory cytokines by tumor is a key mechanism in the initiation of heart failure. Oxidative stress, which results from the combination of chemotherapy, inadequate antioxidant consumption and chronic inflammation, will further foster heart failure. Protein catabolism is due to the concomitant activation of proteolytic systems and inhibition of protein synthesis, both processes being triggered by the deactivation of the Akt/mammalian target of rapamycin pathway. The reduction in oxidative capacity involves AMP-activated protein kinase and peroxisome proliferator-activated receptor gamma coactivator 1α dysregulation. The nuclear factor-κB transcription factor plays a prominent role in the coordination of these alterations. Physical exercise appears as an interesting non-pharmaceutical way to counteract cancer cachexia-induced-heart failure. Indeed, aerobic training has anti-inflammatory effects, increases anti-oxidant defenses, prevents atrophy and promotes oxidative metabolism. The present review points out the importance of better understanding the concurrent structural and metabolic changes within the myocardium during cancer and the protective effects of exercise against cardiac cachexia.

Prevalence, treatment and control of hypertension in La Réunion: the RÉDIA population-based cohort study.

A better knowledge of prevalence, management and determinants of hypertension is needed in regions in epidemiological transition to adapt the strategies of public health screening and prevention, and to reduce the burden of cardiovascular diseases. We conducted a prospective cohort study including 4610 participants aged between 18 and 69 years and representative of the general population of La Réunion, a French overseas island located in the western Indian Ocean. The median time between inclusion and follow-up was 7.4 years. Blood pressure data at baseline and follow-up of 3087 participants were analyzed. We found a high prevalence of hypertension, especially in women (36.7% [34.5-39.0]) and in men (40.3% [37.6-43.0]) and in the under 30s (17.1% [14.0-20.5]), with an increase of 10% at follow-up. Treatment rates were very low in men (19.5% versus 39.1% in women) as was awareness of their condition (25.7% versus 44.6%). Blood pressure control rates were similar (18% at baseline and 34% at follow-up for both sexes). Diagnosis of hypertension at follow-up among subjects normotensive at baseline was independently associated with obesity at baseline (relative risk (RR) = 1.40 [1.12-1.75] for BMI between 27 and 30 kg/m2 and 1.72 [1.33-2.25] for BMI ≥30 kg/m2 as compared with BMI <27 kg/m2) and HbA1C (RR =1.12 [1.05-1.19] per %), suggesting a prominent role of insulin resistance in our population. Our study provides original data that cannot be assimilated to any existing model and should guide the implementation of original community-based programs in such countries.

Long-Term Effectiveness of a Lifestyle Intervention for the Primary Prevention of Type 2 Diabetes in a Low Socio-Economic Community--An Intervention Follow-Up Study on Reunion Island.

In type 2 diabetes (T2D) prevention research, evidence for maintenance of risk factor reduction after three years of follow-up is needed. The objective of this study was to evaluate the long-term effectiveness of a combined lifestyle intervention aiming at controlling body weight (BW) and waist circumference (WC) in non-diabetic, overweight/obese adults living in a low socio-economic community. On Reunion Island, 445 adults living in deprived areas, aged 18-40 and at high-risk for T2D, were included in an intervention versus control trial for primary prevention (2001-2002). The intervention promoted a healthy diet and moderate regular physical activity, through actions strengthening individuals or community and improving living conditions. The control group received a one-shot medical information and nutritional advices. After the end of the trial (2003), 259 of the subjects participated in a follow-up study (2010-2011). The outcomes were the nine-year changes from baseline in BW, body mass index (BMI) and WC measurements, separately. Statistical analyses were performed on an intention-to-treat basis, using available and imputed datasets. At inclusion, T2D risk factors were prevalent: family history of diabetes in first-degree relatives (42%), women with a personal history of gestational diabetes (11%), total obesity (43%, median BMI 29.1 kg/m²) and central obesity (71%). At follow-up, the adjusted effect on imputed dataset was significant for WC -2.4 cm (95% confidence interval: -4.7 to -0.0 cm, p = 0.046), non-significant for BW -2.2 kg (-4.6 to +0.2 kg, p = 0.073) and BMI -0.81 kg/m² (-1.69 to +0.08 kg/m², p = 0.074). A specific long-term effect was the increased likelihood of reduction in adiposity: BW loss, BMI reduction, and WC reduction were more frequent in the intervention group. In the context of low socio-economic communities, our data support the assumption of long-term effect of lifestyle interventions targeting total obesity and central obesity two major drivers of T2D.

Endurance training prevents negative effects of the hypoxia mimetic dimethyloxalylglycine on cardiac and skeletal muscle function.

Hypoxic preconditioning is a promising strategy to prevent hypoxia-induced damages to several tissues. This effect is related to prior stabilization of the hypoxia-inducible factor-1α via inhibition of the prolyl-hydroxylases (PHDs), which are responsible for its degradation under normoxia. Although PHD inhibition has been shown to increase endurance performance in rodents, potential side effects of such a therapy have not been explored. Here, we investigated the effects of 1 wk of dimethyloxalylglycine (DMOG) treatment (150 mg/kg) on exercise capacity, as well as on cardiac and skeletal muscle function in sedentary and endurance-trained rats. DMOG improved maximal aerobic velocity and endurance in both sedentary and trained rats. This effect was associated with an increase in red blood cells without significant alteration of skeletal muscle contractile properties. In sedentary rats, DMOG treatment resulted in enhanced left ventricle (LV) weight together with impairment in diastolic function, LV relaxation, and pulse pressure. Moreover, DMOG decreased maximal oxygen uptake (state 3) of isolated mitochondria from skeletal muscle. Importantly, endurance training reversed the negative effects of DMOG treatment on cardiac function and restored maximal mitochondrial oxygen uptake to the level of sedentary placebo-treated rats. In conclusion, we provide here evidence that the PHD inhibitor DMOG has detrimental influence on myocardial and mitochondrial function in healthy rats. However, one may suppose that the deleterious influence of PHD inhibition would be potentiated in patients with already poor physical condition. Therefore, the present results prompt us to take into consideration the potential side effects of PHD inhibitors when administrated to patients.

Individualized Exercise Training at Maximal Fat Oxidation Combined with Fruit and Vegetable-Rich Diet in Overweight or Obese Women: The LIPOXmax-Réunion Randomized Controlled Trial.

OBJECTIVES: Lifestyle combined interventions are a key strategy for preventing type-2 diabetes (T2DM) in overweight or obese subjects. In this framework, LIPOXmax individualized training, based on maximal fat oxidation [MFO], may be a promising intervention to promote fat mass (FM) reduction and prevent T2DM. Our primary objective was to compare three training programs of physical activity combined with a fruit- and vegetable-rich diet in reducing FM in overweight or obese women. DESIGN AND SETTING: A five months non-blinded randomized controlled trial (RCT) with three parallel groups in La Réunion Island, a region where metabolic diseases are highly prevalent. SUBJECTS: One hundred and thirty-six non-diabetic obese (body mass index [BMI]: 27-40 kg/m2) young women (aged 20-40) were randomized (G1: MFO intensity; G2: 60% of VO2-peak intensity; G3: free moderate-intensity at-home exercise following good physical practices). OUTCOMES: Anthropometry (BMI, bodyweight, FM, fat-free mass), glucose (fasting plasma glucose, insulin, HOMA-IR) and lipid (cholesterol and triglycerides) profiles, and MFO values were measured at month-0, month-3 and month-5. RESULTS: At month-5, among 109 women assessed on body composition, the three groups exhibited a significant FM reduction over time (G1: -4.1±0.54 kg; G2: -4.7±0.53 kg; G3: -3.5±0.78 kg, p<0.001, respectively) without inter-group differences (p = 0.135). All groups exhibited significant reductions in insulin levels or HOMA-IR index, and higher MFO values over time (p<0.001, respectively) but glucose control improvement was higher in G1 than in G3 while MFO values were higher in G1 than in G2 and G3. Changes in other outcome measures and inter-group differences were not significant. CONCLUSION: In our RCT the LIPOXmax intervention did not show a superiority in reducing FM in overweight or obese women but is associated with higher MFO and better glucose control improvements. Other studies are required before proposing LIPOXmax training for the prevention of T2DM in overweight or obese women. TRIAL REGISTRATION: ClincialTrials.gov NCT01464073.

Modeling the responses to resistance training in an animal experiment study.

The aim of the present study was to test whether systems models of training effects on performance in athletes can be used to explore the responses to resistance training in rats. 11 Wistar Han rats (277 ± 15 g) underwent 4 weeks of resistance training consisting in climbing a ladder with progressive loads. Training amount and performance were computed from total work and mean power during each training session. Three systems models relating performance to cumulated training bouts have been tested: (i) with a single component for adaptation to training, (ii) with two components to distinguish the adaptation and fatigue produced by exercise bouts, and (iii) with an additional component to account for training-related changes in exercise-induced fatigue. Model parameters were fitted using a mixed-effects modeling approach. The model with two components was found to be the most suitable to analyze the training responses (R(2) = 0.53; P < 0.001). In conclusion, the accuracy in quantifying training loads and performance in a rodent experiment makes it possible to model the responses to resistance training. This modeling in rodents could be used in future studies in combination with biological tools for enhancing our understanding of the adaptive processes that occur during physical training.

Combined Strategies for Maintaining Skeletal Muscle Mass and Function in Aging: Myostatin Inactivation and AICAR-Associated Oxidative Metabolism Induction.

Myostatin (mstn) blockade, resulting in muscle hypertrophy, is a promising therapy to counteract age-related muscle loss. However, oxidative and mitochondrial deficit observed in young mice with myostatin inhibition could be detrimental with aging. The aim of this study was (a) to bring original data on metabolic and mitochondrial consequences of mstn inhibition in old mice, and (b) to examine whether 4-weeks of AICAR treatment, a pharmacological compound known to upregulate oxidative metabolism, may be useful to improve exercise capacity and mitochondrial deficit of 20-months mstn KO versus wild-type (WT) mice. Our results show that despite the enlarged muscle mass, the oxidative and mitochondrial deficit associated with reduced endurance running capacity is maintained in old mstn KO mice but not worsened by aging. Importantly, AICAR treatment induced a significant beneficial effect on running limit time only in old mstn KO mice, with a marked increase in PGC-1α expression and slight beneficial effects on mitochondrial function. We showed that AICAR effects were autophagy-independent. This study underlines the relevance of aged muscle remodelling by complementary approaches that impact both muscle mass and function, and suggest that mstn inhibition and aerobic metabolism activators should be co-developed for delaying age-related deficits in skeletal muscle.

REDD1 deletion prevents dexamethasone-induced skeletal muscle atrophy.

REDD1 (regulated in development and DNA damage response 1) has been proposed to inhibit the mechanistic target of rapamycin complex 1 (mTORC1) during in vitro hypoxia. REDD1 expression is low under basal conditions but is highly increased in response to several catabolic stresses, like hypoxia and glucocorticoids. However, REDD1 function seems to be tissue and stress dependent, and its role in skeletal muscle in vivo has been poorly characterized. Here, we investigated the effect of REDD1 deletion on skeletal muscle mass, protein synthesis, proteolysis, and mTORC1 signaling pathway under basal conditions and after glucocorticoid administration. Whereas skeletal muscle mass and typology were unchanged between wild-type (WT) and REDD1-null mice, oral gavage with dexamethasone (DEX) for 7 days reduced tibialis anterior and gastrocnemius muscle weights as well as tibialis anterior fiber size only in WT. Similarly, REDD1 deletion prevented the inhibition of protein synthesis and mTORC1 activity (assessed by S6, 4E-BP1, and ULK1 phosphorylation) observed in gastrocnemius muscle of WT mice following single DEX administration for 5 h. However, our results suggest that REDD1-mediated inhibition of mTORC1 in skeletal muscle is not related to the modulation of the binding between TSC2 and 14-3-3. In contrast, our data highlight a new mechanism involved in mTORC1 inhibition linking REDD1, Akt, and PRAS40. Altogether, these results demonstrated in vivo that REDD1 is required for glucocorticoid-induced inhibition of protein synthesis via mTORC1 downregulation. Inhibition of REDD1 may thus be a strategy to limit muscle loss in glucocorticoid-mediated atrophy.