Age-Associated Impairments in Mitochondrial ADP Sensitivity Contribute to Redox Stress in Senescent Human Skeletal Muscle.

This is the final version of the article. Available from Elsevier (Cell Press) via the DOI in this record.It remains unknown if mitochondrial bioenergetics are altered with aging in humans. We established an in vitro method to simultaneously determine mitochondrial respiration and H2O2emission in skeletal muscle tissue across a range of biologically relevant ADP concentrations. Using this approach, we provide evidence that, although the capacity for mitochondrial H2O2emission is not increased with aging, mitochondrial ADP sensitivity is impaired. This resulted in an increase in mitochondrial H2O2and the fraction of electron leak to H2O2, in the presence of virtually all ADP concentrations examined. Moreover, although prolonged resistance training in older individuals increased muscle mass, strength, and maximal mitochondrial respiration, exercise training did not alter H2O2emission rates in the presence of ADP, the fraction of electron leak to H2O2, or the redox state of the muscle. These data establish that a reduction in mitochondrial ADP sensitivity increases mitochondrial H2O2emission and contributes to age-associated redox stress.This work was funded by the Natural Sciences and Engineering Research Council of Canada (03656) and TI Food and Nutrition, a public-private partnership on precompetitive research in food and nutrition

Endurance-Type Exercise Increases Bulk and Individual Mitochondrial Protein Synthesis Rates in Rats.

Physical activity increases muscle protein synthesis rates. However, the impact of exercise on the coordinated up- and/or downregulation of individual protein synthesis rates in skeletal muscle tissue remains unclear. The authors assessed the impact of exercise on mixed muscle, myofibrillar, and mitochondrial protein synthesis rates as well as individual protein synthesis rates in vivo in rats. Adult Lewis rats either remained sedentary (n = 3) or had access to a running wheel (n = 3) for the last 2 weeks of a 3-week experimental period. Deuterated water was injected and subsequently administered in drinking water over the experimental period. Blood and soleus muscle were collected and used to assess bulk mixed muscle, myofibrillar, and mitochondrial protein synthesis rates using gas chromatography-mass spectrometry and individual muscle protein synthesis rates using liquid chromatography-mass spectrometry (i.e., dynamic proteomic profiling). Wheel running resulted in greater myofibrillar (3.94 ± 0.26 vs. 3.03 ± 0.15%/day; p < .01) and mitochondrial (4.64 ± 0.24 vs. 3.97 ± 0.26%/day; p < .05), but not mixed muscle (2.64 ± 0.96 vs. 2.38 ± 0.62%/day; p = .71) protein synthesis rates, when compared with the sedentary condition. Exercise impacted the synthesis rates of 80 proteins, with the difference from the sedentary condition ranging between -64% and +420%. Significantly greater synthesis rates were detected for F1-ATP synthase, ATP synthase subunit alpha, hemoglobin, myosin light chain-6, and synaptopodin-2 (p < .05). The skeletal muscle protein adaptive response to endurance-type exercise involves upregulation of mitochondrial protein synthesis rates, but it is highly coordinated as reflected by the up- and downregulation of various individual proteins across different bulk subcellular protein fractions

Intermittent versus continuous enteral nutrition attenuates increases in insulin and leptin during short-term bed rest

This is the final version. Available on open access from Springer via the DOI in this recordPurpose: To compare endocrine responses to intermittent vs continuous enteral nutrition provision during short-term bed rest. Methods: Twenty healthy men underwent 7 days of bed rest, during which they were randomized to receive enteral nutrition (47%E as carbohydrate, 34%E as fat, 16%E as protein and 3%E as fibre) in a continuous (CONTINUOUS; n = 10; 24 h day−1 at a constant rate) or intermittent (INTERMITTENT; n = 10; as 4 meals per day separated by 5 h) pattern. Daily plasma samples were taken every morning to assess metabolite/hormone concentrations. Results: During bed rest, plasma leptin concentrations were elevated to a lesser extent with INTERMITTENT vs CONTINUOUS (iAUC: 0.42 ± 0.38 vs 0.95 ± 0.48 nmol L−1, respectively; P = 0.014) as were insulin concentrations (interaction effect, P < 0.001) which reached a peak of 369 ± 225 pmol L−1 in CONTINUOUS, compared to 94 ± 38 pmol L−1 in INTERMITTENT (P = 0.001). Changes in glucose infusion rate were positively correlated with changes in fasting plasma GLP-1 concentrations (r = 0.44, P = 0.049). Conclusion: Intermittent enteral nutrition attenuates the progressive rise in plasma leptin and insulinemia seen with continuous feeding during bed rest, suggesting that continuous feeding increases insulin requirements to maintain euglycemia. This raises the possibility that hepatic insulin sensitivity is impaired to a greater extent with continuous versus intermittent feeding during bed rest. To attenuate endocrine and metabolic changes with enteral feeding, an intermittent feeding strategy may, therefore, be preferable to continuous provision of nutrition. This trial was registered on clinicaltrials.gov as NCT02521025.University of Bat

Dietary feeding pattern does not modulate the loss of muscle mass or the decline in metabolic health during short-term bed rest

This is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this record.Short periods of bed rest lead to the loss of muscle mass and quality. It has been speculated that dietary feeding pattern may impact upon muscle protein synthesis rates and, therefore, modulate the loss of muscle mass and quality. We subjected 20 healthy men (age: 25±1 y, BMI: 23.8±0.8 kg·m-2) to one week of strict bed rest with intermittent (4 meals/day) or continuous (24 h/day) enteral tube feeding. Participants consumed deuterium oxide for 7 days prior to bed rest and throughout the 7-day bed rest period. Prior to and immediately after bed rest, lean body mass (DXA), quadriceps cross-sectional area (CSA; CT), maximal oxygen uptake capacity (VO2peak), and whole-body insulin sensitivity (hyperinsulinaemic-euglycaemic clamp) were assessed. Muscle biopsies were collected 7 days prior to, 1 day prior to, and immediately after bed rest to assess muscle tracer incorporation. Bed rest resulted in 0.3±0.3 vs 0.7±0.4 kg lean tissue loss and a 1.1±0.6 vs 0.8±0.5% decline in quadriceps CSA in the intermittent vs continuous feeding group, respectively (both P0.05). Moreover, feeding pattern did not modulate the bed rest-induced decline in insulin sensitivity (-46±3% vs 39±3%; P0.05). Myofibrillar protein synthesis rates during bed rest did not differ between the intermittent and continuous feeding group (1.33±0.07 vs 1.50±0.13%·d−1, respectively; P>0.05). In conclusion, dietary feeding pattern does not modulate the loss of muscle mass or the decline in metabolic health during one week of bed rest in healthy men

Evidence of the Generation of Isosaccharinic Acids and Their Subsequent Degradation by Local Microbial Consortia within Hyper-Alkaline Contaminated Soils, with Relevance to Intermediate Level Radioactive Waste Disposal

The contamination of surface environments with hydroxide rich wastes leads to the formation of high pH (>11.0) soil profiles. One such site is a legacy lime works at Harpur Hill, Derbyshire where soil profile indicated in-situ pH values up to pH 12. Soil and porewater profiles around the site indicated clear evidence of the presence of the α and β stereoisomers of isosaccharinic acid (ISA) resulting from the anoxic, alkaline degradation of cellulosic material. ISAs are of particular interest with regards to the disposal of cellulosic materials contained within the intermediate level waste (ILW) inventory of the United Kingdom, where they may influence radionuclide mobility via complexation events occurring within a geological disposal facility (GDF) concept. The mixing of uncontaminated soils with the alkaline leachate of the site resulted in ISA generation, where the rate of generation in-situ is likely to be dependent upon the prevailing temperature of the soil. Microbial consortia present in the uncontaminated soil were capable of surviving conditions imposed by the alkaline leachate and demonstrated the ability to utilise ISAs as a carbon source. Leachate-contaminated soil was sub-cultured in a cellulose degradation product driven microcosm operating at pH 11, the consortia present were capable of the degradation of ISAs and the generation of methane from the resultant H2/CO2 produced from fermentation processes. Following microbial community analysis, fermentation processes appear to be predominated by Clostridia from the genus Alkaliphilus sp, with methanogenesis being attributed to Methanobacterium and Methanomassiliicoccus sp. The study is the first to identify the generation of ISA within an anthropogenic environment and advocates the notion that microbial activity within an ILW-GDF is likely to influence the impact of ISAs upon radionuclide migration

Unravelling the spatial dependency of the complex solid-state chemistry of Pb in a paint micro-sample from Rembrandt's Homer using XRD-CT

The surface of many Old Master paintings has been affected by the appearance of whitish lead-rich deposits, which are often difficult to fully characterise, thereby hindering conservation. A paint micro-sample from Rembrandt's Homer was imaged using X-ray Diffraction Computed Tomography (XRD-CT) in order to understand the evolving solid-state Pb chemistry from the painting surface and beneath. The surface crust was identified as a complex mixture of lead sulfates. From the S : Pb ratios throughout the paint layer, we can conclude that S is from an external source in the form of SO2, and that the nature of Pb-SO4 product is dependent on the degree of diffusion/absorption of SO2 into the paint layers

Mitochondrial bioenergetics are not associated with myofibrillar protein synthesis rates

This is the final version. Available on open access from Wiley via the DOI in this recordData availability statement: The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.BACKGROUND: Mitochondria represent key organelles influencing cellular homeostasis and have been implicated in the signalling events regulating protein synthesis. METHODS: We examined whether mitochondrial bioenergetics (oxidative phosphorylation and reactive oxygen species (H2O2) emission, ROS) measured in vitro in permeabilized muscle fibres represent regulatory factors for integrated daily muscle protein synthesis rates and skeletal muscle mass changes across the spectrum of physical activity, including free-living and bed-rest conditions: n = 19 healthy, young men (26 ± 4 years, 23.4 ± 3.3 kg/m2) and following 12 weeks of resistance-type exercise training: n = 10 healthy older men (70 ± 3 years, 25.2 ± 2.1 kg/m2). Additionally, we evaluated the direct relationship between attenuated mitochondrial ROS emission and integrated daily myofibrillar and sarcoplasmic protein synthesis rates in genetically modified mice (mitochondrial-targeted catalase, MCAT). RESULTS: Neither oxidative phosphorylation nor H2O2 emission were associated with muscle protein synthesis rates in healthy young men under free-living conditions or following 1 week of bed rest (both P > 0.05). Greater increases in GSSG concentration were associated with greater skeletal muscle mass loss following bed rest (r = -0.49, P  0.05). Additionally, MCAT mice displayed no differences in myofibrillar (2.62 ± 0.22 vs. 2.75 ± 0.15%/day) and sarcoplasmic (3.68 ± 0.35 vs. 3.54 ± 0.35%/day) protein synthesis rates when compared with wild-type mice (both P > 0.05). CONCLUSIONS: Mitochondrial oxidative phosphorylation and reactive oxygen emission do not seem to represent key factors regulating muscle protein synthesis or muscle mass regulation across the spectrum of physical activity.Natural Sciences and Engineering Research Council of Canada (NSERC)TI Food and Nutritio

Short-term muscle disuse induces a rapid and sustained decline in daily myofibrillar protein synthesis rates

This is the author accepted manuscript. The final version is available from the American Physiological Society via the DOI in this recordIntroduction: Short-term muscle disuse has been reported to lower both post-absorptive and post-prandial myofibrillar protein synthesis rates. This study assessed the impact of disuse on daily myofibrillar protein synthesis rates following acute (2 days) and more prolonged (7 days) muscle disuse under free living conditions. Methods: Thirteen healthy young men (age, 20±1 y; BMI, 23±1 kg·m-2) underwent 7 days of unilateral leg immobilization via a knee brace with the non-immobilized leg acting as a control. Four days prior to immobilization participants ingested 400 mL 70% deuterated water, with 50 mL doses consumed daily thereafter. Upper leg bilateral MRI scans and muscle biopsies were collected before, and after 2 and 7 days of immobilization to determine quadriceps volume and daily myofibrillar protein synthesis rates. Results: Immobilization reduced quadriceps volume in the immobilized leg by 1.7±0.3 and 6.7±0.6 % after 2 and 7 days, respectively, with no changes in the control leg. Over the one week immobilization period myofibrillar protein synthesis rates were 36±4% lower in the immobilized (0.81±0.04%·d-1) compared with the control (1.26±0.04%·d-1) leg (P<0.001). Myofibrillar protein synthesis rates in the control leg did not change over time (P=0.775), but in the immobilized leg were numerically lower during the 0-2 day period (16±6%, 1.11±0.09%·d-1, P=0.153) and were significantly lower during the 2-7 day period (44±5%, 0.70±0.06%·d-1, P<0.001) when compared with the control leg. Conclusion: One week of muscle disuse induces a rapid and sustained decline in daily myofibrillar protein synthesis rates in healthy young men.University of MaastrichtRoyal SocietyUniversity of ExeterNational Institute for Health Research (NIHR

Fluid-structure interaction simulation of prosthetic aortic valves : comparison between immersed boundary and arbitrary Lagrangian-Eulerian techniques for the mesh representation

In recent years the role of FSI (fluid-structure interaction) simulations in the analysis of the fluid-mechanics of heart valves is becoming more and more important, being able to capture the interaction between the blood and both the surrounding biological tissues and the valve itself. When setting up an FSI simulation, several choices have to be made to select the most suitable approach for the case of interest: in particular, to simulate flexible leaflet cardiac valves, the type of discretization of the fluid domain is crucial, which can be described with an ALE (Arbitrary Lagrangian-Eulerian) or an Eulerian formulation. The majority of the reported 3D heart valve FSI simulations are performed with the Eulerian formulation, allowing for large deformations of the domains without compromising the quality of the fluid grid. Nevertheless, it is known that the ALE-FSI approach guarantees more accurate results at the interface between the solid and the fluid. The goal of this paper is to describe the same aortic valve model in the two cases, comparing the performances of an ALE-based FSI solution and an Eulerian-based FSI approach. After a first simplified 2D case, the aortic geometry was considered in a full 3D set-up. The model was kept as similar as possible in the two settings, to better compare the simulations' outcomes. Although for the 2D case the differences were unsubstantial, in our experience the performance of a full 3D ALE-FSI simulation was significantly limited by the technical problems and requirements inherent to the ALE formulation, mainly related to the mesh motion and deformation of the fluid domain. As a secondary outcome of this work, it is important to point out that the choice of the solver also influenced the reliability of the final results