The impact of 60 days of -6° head down tilt bed rest on mitochondrial content, respiration and regulators of mitochondrial dynamics.

It is unclear how skeletal muscle metabolism and mitochondrial function adapt to long duration bed rest and whether changes can be prevented by nutritional intervention. The present study aimed (1) to assess the effect of prolonged bed rest on skeletal muscle mitochondrial function and dynamics and (2) to determine whether micronutrient supplementation would mitigate the adverse metabolic effect of bed rest. Participants were maintained in energy balance throughout 60 days of bed rest with micronutrient supplementation (INT) (body mass index: 23.747 ± 1.877 kg m-2 ; 34.80 ± 7.451 years; n = 10) or without (control) (body mass index: 24.087 ± 2.088 kg m-2 ; 33.50 ± 8.541 years; n = 10). Indirect calorimetry and dual-energy x-ray absorptiometry were used for measures of energy expenditure, exercise capacity and body composition. Mitochondrial respiration was determined by high-resolution respirometry in permeabilized muscle fibre bundles from vastus lateralis biopsies. Protein and mRNA analysis further examined the metabolic changes relating to regulators of mitochondrial dynamics induced by bed rest. INT was not sufficient in preserving whole body metabolic changes conducive of a decrease in body mass, fat-free mass and exercise capacity within both groups. Mitochondrial respiration, OPA1 and Drp1 protein expression decreased with bed rest, with an increase pDrp1s616 . This reduction in mitochondrial respiration was explained through an observed decrease in mitochondrial content (mtDNA:nDNA). Changes in regulators of mitochondrial dynamics indicate an increase in mitochondrial fission driven by a decrease in inner mitochondrial membrane fusion (OPA1) and increased pDrp1s616 . KEY POINTS: Sixty days of -6° head down tilt bed rest leads to significant changes in body composition, exercise capacity and whole-body substrate metabolism. Micronutrient supplementation throughout bed rest did not preserve whole body metabolic changes. Bed rest results in a decrease in skeletal muscle mitochondrial respiratory capacity, mainly as a result of an observed decrease in mitochondrial content. Prolonged bed rest ensues changes in key regulators of mitochondrial dynamics. OPA1 and Drp1 are significantly reduced, with an increase in pDrp1s616 following bed rest indicative of an increase in mitochondrial fission. Given the reduction in mitochondrial content following 60 days of bed rest, the maintenance of regulators of mitophagy in line with the increase in regulators of mitochondrial fission may act to maintain mitochondrial respiration to meet energy demands.

Effectiveness of Resistive Vibration Exercise and Whey Protein Supplementation Plus Alkaline Salt on the Skeletal Muscle Proteome Following 21 Days of Bed Rest in Healthy Males.

Muscle atrophy is a deleterious consequence of physical inactivity and is associated with increased morbidity and mortality. The aim of this study was to decipher the mechanisms involved in disuse muscle atrophy in eight healthy men using a 21 day bed rest with a cross-over design (control, with resistive vibration exercise (RVE), or RVE combined with whey protein supplementation and an alkaline salt (NEX)). The main physiological findings show a significant reduction in whole-body fat-free mass (CON -4.1%, RVE -4.3%, NEX -2.7%, p < 0.05), maximal oxygen consumption (CON -20.5%, RVE -6.46%, NEX -7.9%, p < 0.05), and maximal voluntary contraction (CON -15%, RVE -12%, and NEX -9.5%, p < 0.05) and a reduction in mitochondrial enzyme activity (CON -30.7%, RVE -31.3%, NEX -17%, p < 0.05). The benefits of nutrition and exercise countermeasure were evident with an increase in leg lean mass (CON -1.7%, RVE +8.9%, NEX +15%, p < 0.05). Changes to the vastus lateralis muscle proteome were characterized using mass spectrometry-based label-free quantitative proteomics, the findings of which suggest alterations to cell metabolism, mitochondrial metabolism, protein synthesis, and degradation pathways during bed rest. The observed changes were partially mitigated during RVE, but there were no significant pathway changes during the NEX trial. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium with the dataset identifier PXD006882. In conclusion, resistive vibration exercise, when combined with whey/alkalizing salt supplementation, could be an effective strategy to prevent skeletal muscle protein changes, muscle atrophy, and insulin sensitivity during medium duration bed rest.

Evaluation of an Antioxidant and Anti-inflammatory Cocktail Against Human Hypoactivity-Induced Skeletal Muscle Deconditioning.

Understanding the molecular pathways involved in the loss of skeletal muscle mass and function induced by muscle disuse is a crucial issue in the context of spaceflight as well as in the clinical field, and development of efficient countermeasures is needed. Recent studies have reported the importance of redox balance dysregulation as a major mechanism leading to muscle wasting. Our study aimed to evaluate the effects of an antioxidant/anti-inflammatory cocktail (741 mg of polyphenols, 138 mg of vitamin E, 80 µg of selenium, and 2.1 g of omega-3) in the prevention of muscle deconditioning induced by long-term inactivity. The study consisted of 60 days of hypoactivity using the head-down bed rest (HDBR) model. Twenty healthy men were recruited; half of them received a daily antioxidant/anti-inflammatory supplementation, whereas the other half received a placebo. Muscle biopsies were collected from the vastus lateralis muscles before and after bedrest and 10 days after remobilization. After 2 months of HDBR, all subjects presented muscle deconditioning characterized by a loss of muscle strength and an atrophy of muscle fibers, which was not prevented by cocktail supplementation. Our results regarding muscle oxidative damage, mitochondrial content, and protein balance actors refuted the potential protection of the cocktail during long-term inactivity and showed a disturbance of essential signaling pathways (protein balance and mitochondriogenesis) during the remobilization period. This study demonstrated the ineffectiveness of our cocktail supplementation and underlines the complexity of redox balance mechanisms. It raises interrogations regarding the appropriate nutritional intervention to fight against muscle deconditioning.

Freeze-dried bilberry (Vaccinium myrtillus) dietary supplement improves walking distance and lipids after myocardial infarction: an open-label randomized clinical trial.

Bilberries, Vaccinium myrtillus, have a high content of phenolic compounds including anthocyanins, which could provide cardiometabolic health benefits following acute myocardial infarction (AMI). We hypothesized that standard medical therapy supplemented with freeze-dried bilberry after AMI would have a more beneficial effect on cardiovascular risk markers and exercise capacity than medical therapy alone. Patients were allocated in a 1:1 ratio within 24 hours of percutaneous coronary intervention in an 8-week trial either to V myrtillus powder (40 g/d, equivalent to 480 g fresh bilberries) and standard medical therapy or to a control group receiving standard medical therapy alone. High-sensitivity C-reactive protein and exercise capacity measured with the 6-minute walk test were the primary biochemical and clinical end points, respectively. Fifty subjects completed the study. No statistically significant difference in high-sensitivity C-reactive protein was detected between groups. The mean 6-minute walk test distance increased significantly more in the bilberry group compared to the control group: mean difference 38 m at follow-up (95% confidence interval 14-62, P = .003). Ex vivo oxidized low-density lipoprotein was significantly lowered in the bilberry group compared to control, geometric mean ratio 0.80 (95% confidence interval 0.66-0.96, P = .017), whereas total cholesterol and low-density lipoprotein cholesterol did not differ significantly between groups. Anthocyanin-derived metabolites in blood increased significantly in the bilberry group during the intervention and were different after 8 weeks between the bilberry group and control. Findings in the present study suggest that bilberries may have clinically relevant beneficial effects following AMI; a larger, double-blind clinical trial is warranted to confirm this.

A nutrient cocktail prevents lipid metabolism alterations induced by 20 days of daily steps reduction and fructose overfeeding: result from a randomized study.

Physical inactivity and sedentary behaviors are independent risk factors for numerous diseases. We examined the ability of a nutrient cocktail composed of polyphenols, omega-3 fatty acids, vitamin E, and selenium to prevent the expected metabolic alterations induced by physical inactivity and sedentary behaviors. Healthy trained men ( n = 20) (averaging ∼14,000 steps/day and engaged in sports) were randomly divided into a control group (no supplementation) and a cocktail group for a 20-day free-living intervention during which they stopped exercise and decreased their daily steps (averaging ∼3,000 steps/day). During the last 10 days, metabolic changes were further triggered by fructose overfeeding. On days 0, 10, and 20, body composition (dual energy X-ray), blood chemistry, glucose tolerance [oral glucose tolerance test (OGTT)], and substrate oxidation (indirect calorimetry) were measured. OGTT included 1% fructose labeled with (U-13C) fructose to assess liver de novo lipogenesis. Histological changes and related cellular markers were assessed from muscle biopsies collected on days 0 and 20. While the cocktail did not prevent the decrease in insulin sensitivity and its muscular correlates induced by the intervention, it fully prevented the hypertriglyceridemia, the drop in fasting HDL and total fat oxidation, and the increase in de novo lipogenesis. The cocktail further prevented the decrease in the type-IIa muscle fiber cross-sectional area and was associated with lower protein ubiquitination content. The circulating antioxidant capacity was improved by the cocktail following the OGTT. In conclusion, a cocktail of nutrient compounds from dietary origin protects against the alterations in lipid metabolism induced by physical inactivity and fructose overfeeding. NEW & NOTEWORTHY This is the first study to test the efficacy of a novel dietary nutrient cocktail on the metabolic and physiological changes occurring during 20 days of physical inactivity along with fructose overfeeding. The main findings of this study are that 1) reduction in daily steps leads to decreased insulin sensitivity and total fat oxidation, resulting in hyperlipemia and increased de novo lipogenesis and 2) a cocktail supplement prevents the alterations on lipid metabolism.

Effects of chronic calorie restriction or dietary resveratrol supplementation on insulin sensitivity markers in a primate, Microcebus murinus.

The prevalence of diabetes and hyperinsulinemia increases with age, inducing metabolic failure and limiting lifespan. Calorie restriction (CR) without malnutrition delays the aging process, but its long-term application to humans seems difficult. Resveratrol (RSV), a dietary polyphenol, appears to be a promising CR mimetic that can be easily administered in humans. In this work, we hypothesized that both CR and RSV impact insulin sensitivity in a non-human primate compared to standard-fed control (CTL) animals. Four- to five-year-old male grey mouse lemurs (Microcebus murinus) were assigned to three dietary groups: a CTL group, a CR group receiving 30% fewer calories than the CTL and a RSV group receiving the CTL diet supplemented with RSV (200 mg·day(-1)·kg(-1)). Insulin sensitivity and glycemia were assessed using an oral glucose tolerance test (OGTT) and the homeostasis model assessment of insulin resistance (HOMA-IR index) evaluation after 21 or 33 months of chronic treatment. Resting metabolic rate was also measured to assess the potential relationships between this energy expenditure parameter and insulin sensitivity markers. No differences were found after a 21-month period of treatment, except for lower glucose levels 30 min after glucose loading in CR animals. After 33 months, CR and RSV decreased glycemia after the oral glucose loading without decreasing fasting blood insulin. A general effect of treatment was observed on the HOMA-IR index, with an 81% reduction in CR animals and 53% in RSV animals after 33 months of treatment compared to CTL. Chronic CR and dietary supplementation with RSV affected insulin sensitivity by improving the glucose tolerance of animals without disturbing their baseline insulin secretion. These results suggest that both CR and RSV have beneficial effects on metabolic alterations, although these effects are different in amplitude between the two anti-aging treatments and potentially rely on different metabolic changes.

Does protein supplementation prevent muscle disuse atrophy and loss of strength?

Recently there has been much interest in the use of dietary amino acids supplements to decrease the losses in muscle mass and strength observed after space flight or during aging using bed rest analogs. This interest persists even if the results have been mixed. Of the six published amino acid supplementation studies, three showed benefit, three did not. A recent study re-evaluating protein requirements in humans suggests that the official RDA is 41% underestimated. Interestingly, the three studies that showed benefits fed their test subjects a baseline protein level around the old RDA for protein. The three that did not show benefit gave the subjects a baseline protein intake higher than the new RDA. We suggest that the positive effects observed on protein metabolism might just reflect the benefits of adequate protein intake achieved during bed rest rather than a protective effect against bed-rest induced disuse. In conclusion, the efficiency of amino acid countermeasures for preventing the loss in protein mass during space flight or bed rest needs to be seriously questioned. These results extend to clinical situations such as serious illness and progress of aging in which physical inactivity is a significant component of the loss in muscle function.

Resveratrol prevents the wasting disorders of mechanical unloading by acting as a physical exercise mimetic in the rat.

Long-term spaceflight induces hypokinesia and hypodynamia, which, along microgravity per se, result in a number of significant physiological alterations, such as muscle atrophy, force reduction, insulin resistance, substrate use shift from fats to carbohydrates, and bone loss. Each of these adaptations could turn to serious health deterioration during the long-term spaceflight needed for planetary exploration. We hypothesized that resveratrol (RES), a natural polyphenol, could be used as a nutritional countermeasure to prevent muscle metabolic and bone adaptations to 15 d of rat hindlimb unloading. RES treatment maintained a net protein balance, soleus muscle mass, and soleus muscle maximal force contraction. RES also fully maintained soleus mitochondrial capacity to oxidize palmitoyl-carnitine and reversed the decrease of the glutathione vs. glutathione disulfide ratio, a biomarker of oxidative stress. At the molecular level, the protein content of Sirt-1 and COXIV in soleus muscle was also preserved. RES further protected whole-body insulin sensitivity and lipid trafficking and oxidation, and this was likely associated with the maintained expression of FAT/CD36, CPT-1, and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) in muscle. Finally, chronic RES supplementation maintained the bone mineral density and strength of the femur. For the first time, we report a simple countermeasure that prevents the deleterious adaptations of the major physiological functions affected by mechanical unloading. RES could thus be envisaged as a nutritional countermeasure for spaceflight but remains to be tested in humans.