Chapitre 14. LES CONTRE-MESURES: Prévenir les altérations physiologiques induites par l’environnement spatial

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Myopathie métabolique généralisée dans l'insuffisance cardiaque (facteurs impliqués et conséquences fonctionnelles)

Les patients souffrant d'insuffisance cardiaque (IC) se plaignent d'une incapacité à l'exercice physique. Les travaux précédents dans notre laboratoire ont montré une myopathie métabolique généralisée dans l'IC. Le caractère généralisé de la myopathie dans l'IC suggère l'implication de facteurs systémiques. Dans ce travail, nous avons étudié l'implication éventuelle de deux agents [nitrique oxyde (NO) produit par la nitrique oxyde synthase endothéliale (NOSe) et l'angiotensine II (AngII)] considérablement altérés dans l'IC et dans le développement de la myopathie métabolique généralisée. Les résultats obtenus suggèrent que l'action bénéfique des inhibiteurs de l'enzyme de conversion sur le profil métabolique musculaire nécessite une diminution de la " post-charge " cardiaque. Nous avons également montré le rôle important du NO produit par la NOSe dans le métabolisme énergétique du muscle squelettique oxydatif ainsi que dans le maintien de la capacité physique de l'organismePatients suffering from heart failure (HF) complain of intolerance to exercise. Previous work in our laboratory has shown that HF (by aortic stenosis) in rats is associated with a myopathy that alters energy metabolism in different muscles. The generalized character of the metabolic myopathy in HF suggests that some systemic factors could be involved. Angiotensin II (AngII) and nitric oxide produced by endothelial nitric oxide synthase (eNOS) are two systemic factors whose production is greatly changed in heart failure. Angiotensin converting enzyme inhibitors (IEC) are known to improve the mortality and morbidity rates in HF. Our results have shown that the beneficial effect of IEC on the metabolic myopathy is probably associated with a reduction in afterload. We have shown that eNOS deficiency induces a significant reduction of mitochondrial oxidative capacity specifically in slow-twitch muscle and we have demonstrated that eNOS is necessary for maintaining normal physical activity.CHATENAY M.-PARIS 11-BU Pharma. (920192101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

Chapitre 14. LES CONTRE-MESURES: Prévenir les altérations physiologiques induites par l’environnement spatial

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Effect of prior treatment with resveratrol on density and structure of rat long bones under tail-suspension

International audiencePhysical inactivity during space flight or prolonged bed rest causes rapid and marked loss of bone mass in humans. Resveratrol, a red wine polyphenol that is currently under study for its therapeutic antioxidant properties, has been shown to significantly modulate biomarkers of bone metabolism, i.e., to promote osteoblast differentiation and to prevent bone loss induced by estrogen deficiency. However, there is no direct evidence supporting its inhibitory effect toward bone loss during physical inactivity. In the present study, effects of resveratrol on bone mineral density (BMD), bone mineral content, and bone structure were examined in the femora and tibiae of tail-suspended and unsuspended rats using X-ray micro-computed tomography (micro-CT). Rats were treated with 400 mg/kg/day of resveratrol for 45 days and half of them were suspended during the last 2 weeks of treatment. Suspension caused a decrease in tibial and femoral BMD and deterioration of trabecular and cortical bone. Bone deterioration during suspension was paralleled by increased bone marrow area, which could be caused by an increase in stromal cells with osteoclastogenic potential or in adipocytes. Resveratrol had a preventive effect against bone loss induced by hindlimb immobilization. In particular, trabecular bone in the proximal tibial metaphysis was totally preserved in rats treated with resveratrol before tail-suspension

Endothelial nitric oxide synthase (NOS) deficiency affects energy metabolism pattern in murine oxidative skeletal muscle.

Oxidative capacity of muscles correlates with capillary density and with microcirculation, which in turn depend on various regulatory factors, including NO generated by endothelial nitric oxide synthase (eNOS). To determine the role of eNOS in patterns of regulation of energy metabolism in various muscles, we studied mitochondrial respiration in situ in saponin-permeabilized fibres as well as the energy metabolism enzyme profile in the cardiac, soleus (oxidative) and gastrocnemius (glycolytic) muscles isolated from mice lacking eNOS (eNOS(-/-)). In soleus muscle, the absence of eNOS induced a marked decrease in both basal mitochondrial respiration without ADP (-32%; P <0.05) and maximal respiration in the presence of ADP (-29%; P <0.05). Furthermore, the eNOS(-/-) soleus muscle showed a decrease in total creatine kinase (-29%; P <0.05), citrate synthase (-31%; P <0.01), adenylate kinase (-27%; P <0.05), glyceraldehyde-3-phosphate dehydrogenase (-43%; P <0.01) and pyruvate kinase (-26%; P <0.05) activities. The percentage of myosin heavy chains I (slow isoform) was significantly increased from 24.3+/-1.5% in control to 30.1+/-1.1% in eNOS(-/-) soleus muscle ( P <0.05) at the expense of a slight non-significant decrease in the three other (fast) isoforms. Besides, eNOS(-/-) soleus showed a 28% loss of weight. Interestingly, we did not find differences in any parameters in cardiac and gastrocnemius muscles compared with respective controls. These results show that eNOS knockout has an important effect on muscle oxidative capacity as well on the activities of energy metabolism enzymes in oxidative (soleus) muscle. The absence of such effects in cardiac and glycolytic (gastrocnemius) muscle suggests a specific role for eNOS-produced NO in oxidative skeletal muscle

Mitochondrial biogenesis in fast skeletal muscle of CK deficient mice: Mitochondrial biogenesis in CK deficient mice

International audienceCreatine kinase (CK) is a phosphotransfer kinase that catalyzes the reversible transfer of a phosphate moiety between ADP and creatine and that is highly expressed in skeletal muscle. In fast glycolytic skeletal muscle, deletion of the cytosolic M isoform of CK in mice (M-CK-/-) leads to a massive increase in the oxidative capacity and of mitochondrial volume. This study was aimed at investigating the transcriptional pathways leading to mitochondrial biogenesis in response to CK deficiency. Wild type and M-CK-/- mice of eleven months of age were used for this study. Gastrocnemius muscles of M-CK-/- mice exhibited a dramatic increase in citrate synthase (+120%) and cytochrome oxidase (COX, +250%) activity, and in mitochondrial DNA (+60%), showing a clear activation of mitochondrial biogenesis. Similarly, mRNA expression of the COXI (mitochondria-encoded) and COXIV (nuclear-encoded) subunits were increased by +103 and +94 % respectively. This was accompanied by an increase in the expression of the nuclear respiratory factor (NRF2Α and the mitochondrial transcription factor (mtTFA). Expression of the co-activator PGC-1Α, a master gene in mitochondrial biogenesis was not significantly increased while that of PGC-1Β and PRC, two members of the same family, was moderately increased (+45% and +55% respectively). While the expression of the modulatory calcineurin-interacting protein 1 (MCIP1) was dramatically decreased (minus 68%) suggesting inactivation of the calcineurin pathway, the metabolic sensor AMPK was activated (+86%) in M-CK-/- mice. These results evidence that mitochondrial biogenesis in response to a metabolic challenge exhibits a unique pattern of regulation, involving activation of the AMPK pathway

Effect of contrasted levels of habitual physical activity on metabolic flexibility.

International audienceThe factors regulating the body's ability to switch from fat to carbohydrate oxidation in response to fuel availability changes, or metabolic flexibility (MF), are currently intensively investigated in the context of metabolic diseases. Although numerous metabolic diseases are associated with sedentary behaviours and metabolic inflexibility, the effect of habitual physical activity level (PAL) on MF regulation is surprisingly poorly known. We investigated how PAL affects MF in cross-sectional and interventional studies. MF was assessed in 44 subjects: normal-weight and overweight sedentary men submitted to 2-months of exercise at current recommendations, normal-weight active men submitted to 1-month of reduced PAL and normal-weight women submitted to 1-month of bed-rest with or without exercise. MF was evaluated, before and after interventions, following two standard meals as the relationship between individual mathematical variances in insulin and non-protein respiratory quotient (NPRQ) daily kinetics. Daily NPRQ and insulin variances differed according to habitual PAL (p=0.002 and p=0.009, respectively); active subjects had higher variances in NPRQ for lower variances in insulin than sedentary subjects, indicating a better MF. Detraining increased insulin variance (p=0.009) and decreased NPRQ variance (p=0.003), while training tended to have opposite effects. Insulin and NPRQ variances were negatively related along the PAL continuum (R(2)=0.70, p<0.001). Variance in NPRQ was also positively related to PAL (R(2)=0.52, p<0.001). By assessing MF with mathematical surrogates in conditions of daily pattern in meal's intake, we showed that habitual PAL is associated with MF status and that MF is modulated by changes in PAL

the [1-13]acetate recovery factor to correct tracer-derived dietary fat oxidation is lower in overweight insulin-resistant subjects

International audienceBackground&aims: An acetate recovery factor (ARF) is utilized to correct tracer-derived fat oxidation when 13C is used. We showed that when 13C labelled fatty acid are given orally, dietary fat oxidation can be accurately corrected by using an averaged dietary ARF (dARF) derived from 56 lean healthy subjects, instead of individual dARF. The extent to which this factor is valid in overweight insulin resistant subjects is unknown. Methods: [1-13C]dARF and [1-13C]fatty acid recoveries were assessed before and after physical activity/ inactivity interventions in overweight insulin-resistant (n ¼ 11) and lean subjects (n ¼ 70) in five studies herein compiled. Results: Overweight dARF was lower compared to lean subjects (45.3 1.5% vs. 50.6 0.6%; P ¼ 0.002). Physical activity intervention did not impact dARF. dARF correlated negatively with %body fat (r2 ¼ 0.10; P ¼ 0.005) and fasting insulin to glucose ratio (r2 ¼ 0.08; P ¼ 0.02). Applying the lean average [1-13C] dARF induced an 11.5% (P ¼ 0.006) average error in fatty acid oxidation rate. Conclusions: Overweight insulin resistant subjects have lower dARF than lean individuals. An average dARF derived from lean subjects cannot be applied in overweight subjects to calculate dietary fat oxidation. We recommend that individual dARF are measured in subjects with metabolic disorder

Regulation of Energy Balance during Long-Term Physical Inactivity Induced by Bed Rest with and without Exercise Training.

International audienceBackground: Short-term physical inactivity affects energy balance and is considered conducive to weigh gain. Long-term effects are unknown. Objective: The objective of the study was to use a bed-rest model to determine the long-term effects of physical inactivity on energy balance regulation and test the effect of exercise training on energy balance adjustment to physical inactivity. Design: Sixteen lean women were divided into two groups (n = 8 each): a control group subjected to a strict 60-d bed rest and an exercise group subjected to a combined aerobic/resistive exercise training concomitantly to bed rest. Body composition, spontaneous energy intake, hunger, total energy expenditure (TEE), and fasting gut hormones were measured. Results: Based on bed-rest-induced body composition changes, the control group were in slight negative energy balance (-0.4 +/- 0.4 MJ/d; P = 0.01 vs. zero), essentially due to muscle atrophy (P < 0.001 vs. zero). The stable fat mass (P = 0.19 vs. zero), and the matching between spontaneous energy intake and TEE indicated, however, a stable energy balance. Hunger and gut hormones remained unchanged during the bed rest. In the exercise group, TEE was 24% higher than in the control group (P = 0.004). Unexpectedly, desire to consume food (P = 0.025) decreased and spontaneous energy intake (P = NS) was not stimulated, promoting a negative energy balance (-1.1 +/- 0.5 MJ/d, P = 0.0003 vs. zero). Conclusions: Energy balance is regulated during 2 months of physical inactivity, contrasting with short-term experiments. Conversely, exercise-induced energy expenditure in bed-resting subjects who have no spontaneous physical activity did not induce hunger and promoted a negative energy balance, suggesting a potential role of nonexercise physical activities in energy balance regulation

Towards human exploration of space: the THESEUS review series on cardiovascular, respiratory, and renal research priorities

International audienceThe THESEUS project (Towards Human Exploration of Space: aEUropean Strategy) was initiated within the seventh FrameworkProgramme by the European Commission. This project aimed toprovide a cross-cutting, life science-based roadmap for Europe’sstrategy towards human exploration of space, especially for deepspace missions and its relevance to applications on Earth. Toaddress these challenges, relevance of space research on thecardiovascular system, the lungs and kidneys, was discussed in anexpert group and its principal conclusions will be presented in thisarticle