Capillary rarefaction during bed rest is proportionally less than fibre atrophy and loss of oxidative capacity

Background Muscle disuse from bed rest or spaceflight results in losses in muscle mass, strength and oxidative capacity. Capillary rarefaction may contribute to muscle atrophy and the reduction in oxidative capacity during bed rest. Artificial gravity may attenuate the negative effects of long-term space missions or bed rest. The aim of the present study was to assess (1) the effects of bed rest on muscle fibre size, fibre type composition, capillarization and oxidative capacity in the vastus lateralis and soleus muscles after 6 and 55 days of bed rest and (2) the effectiveness of artificial gravity in mitigating bed-rest-induced detriments to these parameters. Methods Nineteen participants were assigned to a control group (control, n = 6) or an intervention group undergoing 30 min of centrifugation (n = 13). All underwent 55 days of head-down tilt bed rest. Vastus lateralis and soleus biopsies were taken at baseline and after 6 and 55 days of bed rest. Fibre type composition, fibre cross-sectional area, capillarization indices and oxidative capacity were determined. Results After just 6 days of bed rest, fibre atrophy ( 23.2 ± 12.4%, P < 0.001) and reductions in capillary-to-fibre ratio (C:F; 1.97 ± 0.57 vs. 1.56 ± 0.41, P < 0.001) were proportional in both muscles as reflected by a maintained capillary density. Fibre atrophy proceeded at a much slower rate between 6 and 55 days of bed rest ( 11.6 ± 12.1% of 6 days, P = 0.032) and was accompanied by a 19.1% reduction in succinate dehydrogenase stain optical density (P < 0.001), without any further significant decrements in C:F (1.56 ± 0.41 vs. 1.49 ± 0.37, P = 0.459). Consequently, after 55 days of bed rest, the capillary supply–oxidative capacity ratio of a fibre had increased by 41.9% (P < 0.001), indicating a capillarization in relative excess of oxidative capacity. Even though the heterogeneity of capillary spacing (LogRSD) was increased after 55 days by 12.7% (P = 0.004), tissue oxygenation at maximal oxygen consumption of the fibres was improved after 55 days bed rest. Daily centrifugation failed to blunt the bed-rest-induced reductions in fibre size and oxidative capacity and capillary rarefaction. Conclusions The relationship between fibre size and oxidative capacity with the capillary supply of a fibre is uncoupled during prolonged bed rest as reflected by a rapid loss of muscle mass and capillaries, followed at later stages by a more than proportional loss of mitochondria without further capillary loss. The resulting excessive capillary supply of the muscle after prolonged bed rest is advantageous for the delivery of substrates needed for subsequent muscle recovery

Skeletal muscle properties and fatigue resistance in relation to smoking history

Although smoking-related diseases, such as chronic obstructive pulmonary disease (COPD), are often accompanied by increased peripheral muscle fatigability, the extent to which this is a feature of the disease or a direct effect of smoking per se is not known. Skeletal muscle function was investigated in terms of maximal voluntary isometric torque, activation, contractile properties and fatigability, using electrically evoked contractions of the quadriceps muscle of 40 smokers [19 men and 21 women; mean (SD) cigarette pack years: 9.9 (10.7)] and age- and physical activity level matched non-smokers (22 men and 23 women). Maximal strength and isometric contractile speed did not differ significantly between smokers and non-smokers. Muscle fatigue (measured as torque decline during a series of repetitive contractions) was greater in smokers (P = 0.014), but did not correlate with cigarette pack years (r = 0.094, P = 0.615), cigarettes smoked per day (r = 10.092, P = 0.628), respiratory function (%FEV1pred) (r = −0.187, P = 0.416), or physical activity level (r = −0.029, P = 0.877). While muscle mass and contractile properties are similar in smokers and non-smokers, smokers do suffer from greater peripheral muscle fatigue. The observation that the cigarette smoking history did not correlate with fatigability suggests that the effect is either acute and/or reaches a ceiling, rather than being cumulative. An acute and reversible effect of smoking could be caused by carbon monoxide and/or other substances in smoke hampering oxygen delivery and mitochondrial function

A Defective Pentose Phosphate Pathway Reduces Inflammatory Macrophage Responses during Hypercholesterolemia

Metabolic reprogramming has emerged as a crucial regulator of immune cell activation, but how systemic metabolism influences immune cell metabolism and function remains to be investigated. To investigate the effect of dyslipidemia on immune cell metabolism, we performed in-depth transcriptional, metabolic, and functional characterization of macrophages isolated from hypercholesterolemic mice. Systemic metabolic changes in such mice alter cellular macrophage metabolism and attenuate inflammatory macrophage responses. In addition to diminished maximal mitochondrial respiration, hypercholesterolemia reduces the LPS-mediated induction of the pentose phosphate pathway (PPP) and the Nrf2-mediated oxidative stress response. Our observation that suppression of the PPP diminishes LPS-induced cytokine secretion supports the notion that this pathway contributes to inflammatory macrophage responses. Overall, this study reveals that systemic and cellular metabolism are strongly interconnected, together dictating macrophage phenotype and function

The effect of ambient temperature on gross-efficiency in cycling

Time-trial performance deteriorates in the heat. This might potentially be the result of a temperature-induced decrease in gross-efficiency (GE). The effect of high ambient temperature on GE during cycling will be studied, with the intent of determining if a heat-induced change in GE could account for the performance decrements in time trial exercise found in literature. Ten well-trained male cyclists performed 20-min cycle ergometer exercise at 60% \documentclass[12pt]{minimal} \usepackage{amsmath} \usepackage{wasysym} \usepackage{amsfonts} \usepackage{amssymb} \usepackage{amsbsy} \usepackage{mathrsfs} \usepackage{upgreek} \setlength{\oddsidemargin}{-69pt} \begin{document}$$P_{V{\text{O}}_{{\text{2max}}} }$$\end{document} (power output at which VO2max was attained) in a thermo-neutral climate (N) of 15.6 ± 0.3°C, 20.0 ± 10.3% RH and a hot climate (H) of 35.5 ± 0.5°C, 15.5 ± 3.2% RH. GE was calculated based on VO2 and RER. Skin temperature (Tsk), rectal temperature (Tre) and muscle temperature (Tm) (only in H) were measured. GE was 0.9% lower in H compared to N (19.6 ± 1.1% vs. 20.5 ± 1.4%) (P < 0.05). Tsk (33.4 ± 0.6°C vs. 27.7 ± 0.7°C) and Tre (37.4 ± 0.6°C vs. 37.0 ± 0.6°C) were significantly higher in H. Tm was 38.7 ± 1.1°C in H. GE was lower in heat. Tm was not high enough to make mitochondrial leakage a likely explanation for the observed reduced GE. Neither was the increased Tre. Increased skin blood flow might have had a stealing effect on muscular blood flow, and thus impacted GE. Cycling model simulations showed, that the decrease in GE could account for half of the performance decrement. GE decreased in heat to a degree that could explain at least part of the well-established performance decrements in the heat

Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement

The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Gottingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitrosoredox balance, increased superoxide production-principally due to endothelial nitric oxide synthase (eNOS) uncoupling-reduced nitric oxide (NO) production, alterations in myocardial gene- expressionparticularly genes related to glucose and fatty acid metabolism- and mitochondrial dysfunction. These abnormalities were accompanied by increased passive force of isolated cardiomyocytes, and impaired LV diastolic function, evidenced by reduced LV peak untwist velocity and increased E/e'. However, LV weight, volume, collagen content, and cardiomyocyte cross-sectional area were unchanged at this stage of DMetD. In conclusion, DMetD, in a clinically relevant large-animal model results in myocardial oxidative stress, eNOS uncoupling and reduced NO production, together with an altered metabolic gene expression profile and mitochondrial dysfunction. These molecular alterations are associated with stiffening of the cardiomyocytes and early diastolic dysfunction before any structural cardiac remodeling occurs. Therapies should be directed to ameliorate these early DMetD-induced myocardial changes to prevent the development of overt cardiac failure

Synergisitic role of ADP and Ca2+ in diastolic myocardial stiffness

Heart failure (HF) with diastolic dysfunction has been attributed to increased myocardial stiffness that limits proper filling of the ventricle. Altered cross-bridge interaction may significantly contribute to high diastolic stiffness, but this has not been shown thus far. Cross-bridge interactions are dependent on cytosolic [Ca2+] and the regeneration of ATP from ADP. Depletion of myocardial energy reserve is a hallmark of HF leading to ADP accumulation and disturbed Ca2+-handling. Here, we investigated if ADP elevation in concert with increased diastolic [Ca2+] promotes diastolic cross-bridge formation and force generation and thereby increases diastolic stiffness. ADP dose-dependently increased force production in the absence of Ca2+ in membrane-permeabilized cardiomyocytes from human hearts. Moreover, physiological levels of ADP increased actomyosin force generation in the presence of Ca2+ both in human and rat membrane-permeabilized cardiomyocytes. Diastolic stress measured at physiological lattice spacing and 37°C in the presence of pathologicallevels of ADP and diastolic [Ca2+] revealed a 76±1% contribution of cross-bridge interaction to total diastolic stress in rat membrane-permeabilized cardiomyocytes. Inhibition of creatine kinase (CK), which increases cytosolic ADP, in enzyme-isolated intact rat cardiomyocytes impaired diastolic re-lengthening associated with diastolic Ca2+- overload. In isolated Langendorff-perfused rat hearts, CK-inhibition increased ventricular stiffness only in the presence of diastolic [Ca2+]. We propose that elevations of intracellular ADP in specific types of cardiac disease, including those where myocardial energy reserve is limited, contribute to diastolic dysfunction by recruiting cross-bridges even at low Ca2+ and thereby increase myocardial stiffness

Cellular, mitochondrial and molecular alterations associate with early left ventricular diastolic dysfunction in a porcine model of diabetic metabolic derangement

The prevalence of diabetic metabolic derangement (DMetD) has increased dramatically over the last decades. Although there is increasing evidence that DMetD is associated with cardiac dysfunction, the early DMetD-induced myocardial alterations remain incompletely understood. Here, we studied early DMetD-related cardiac changes in a clinically relevant large animal model. DMetD was established in adult male Göttingen miniswine by streptozotocin injections and a high-fat, high-sugar diet, while control animals remained on normal pig chow. Five months later left ventricular (LV) function was assessed by echocardiography and hemodynamic measurements, followed by comprehensive biochemical, molecular and histological analyses. Robust DMetD developed, evidenced by hyperglycemia, hypercholesterolemia and hypertriglyceridemia. DMetD resulted in altered LV nitroso-redox balance

Fiber capillary supply related to fiber size and oxidative capacity in human and rat skeletal muscle

The capillary supply of a muscle fiber is thought to be determined by its type, oxidative capacity, size and metabolic surrounding. Size and oxidative capacity, however, differ between fiber types. To investigate which of these factors determines the capillary supply of a myofiber most we analysed in sections from human vastus lateralis (n = 11) and rat plantaris muscle (n = 8) the type, succinate dehydrogenase activity (SDH), reflecting oxidative capacity, and capillary supply of individual fibers. Capillary fiber density differed between fiber types in rat (P < 0.03) but not in human muscle. In human muscle only, the local capillary to fiber ratio (LCFR) correlated with the integrated SDH (fiber cross-sectional area x SDH) of a fiber (R = 0.62; P < 0.001). Backward multiple regression revealed, however, that the LCFR was primarily determined by fiber size, type (R = 0.71, human) and surrounding of the fiber (R = 0.62; rat plantaris muscle), i.e. whether it came from the deep or superficial region of the muscle (all P < 0.001) and not SDH. In conclusion, size, type and metabolic surrounding rather than mitochondrial activity determine the capillary supply to a muscle fiber