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Long chain fatty acids (LCFAs) are an important substrate for ATP production within the skeletal muscle. The process of LCFA delivery from adipose tissue to muscle mitochondria involves many regulatory steps. Recently, it has been recognized that LCFA oxidation is not only dependent on LCFA delivery to the muscle, but also on regulatory steps within the muscle. Increasing selected fatty acid binding proteins/transporters on the plasma membrane facilitates a very rapid LCFA increase into the muscle, independent of any changes in LCFA delivery to the muscle. Such a mechanism of LCFA transporter translocation is activated by muscle contraction. Intramuscular triacylglycerols may also be hydrolysed to provide fatty acids for mitochondrial oxidation, particularly during exercise, when hormone-sensitive lipase and other enzymes are activated. Mitochondrial LCFA entry is also highly regulated. This however does not involve only the malonyl CoA carnitine palmitoyltransferase-I (CPTI) axis. Exercise-induced fatty acid entry into mitochondria is also regulated by at least one of the proteins (FAT/CD36) that also regulates plasma membrane fatty acid transport. Among individuals, differences in mitochondrial fatty acid oxidation appear to be correlated with the content of mitochondrial CPTI and FAT/CD36. This paper provides a brief overview of mechanisms that regulate LCFA uptake and oxidation in skeletal muscle during exercise and in obesity. We focus largely on our own work on FAT/CD36, which contributes to regulating, in a coordinated fashion, LCFA uptake across the plasma membrane and the mitochondrial membrane. Very little is known about the roles of FATP1-6 on fatty acid transport in skeletal muscle. [ABSTRACT FROM AUTHOR]

Aim: The purpose of this study was to 1. investigate if glucose tolerance is affected after one acute bout of different types of exercise; 2. assess if potential differences between two exercise paradigms are related to changes in mitochondrial function; and 3. determine if endurance athletes differ from nonendurance‐trained controls in their metabolic responses to the exercise paradigms. Methods: Nine endurance athletes (END) and eight healthy nonendurance‐trained controls (CON) were studied. Oral glucose tolerance tests (OGTT) and mitochondrial function were assessed on three occasions: in the morning, 14 h after an overnight fast without prior exercise (RE), as well as after 3 h of prolonged continuous exercise at 65% of VO2max (PE) or 5 × 4 min at ~95% of VO2max (HIIT) on a cycle ergometer. Results: Glucose tolerance was markedly reduced in END after PE compared with RE. END also exhibited elevated fasting serum FFA and ketones levels, reduced insulin sensitivity and glucose oxidation, and increased fat oxidation during the OGTT. CON showed insignificant changes in glucose tolerance and the aforementioned measurements compared with RE. HIIT did not alter glucose tolerance in either group. Neither PE nor HIIT affected mitochondrial function in either group. END also exhibited increased activity of 3‐hydroxyacyl‐CoA dehydrogenase activity in muscle extracts vs. CON. Conclusion: Prolonged exercise reduces glucose tolerance and increases insulin resistance in endurance athletes the following day. These findings are associated with an increased lipid load, a high capacity to oxidize lipids, and increased fat oxidation. [ABSTRACT FROM AUTHOR]

Exactly 50 years ago, I was a post‐doc in the laboratory of Olov Lindberg in Stockholm measuring fatty acid oxidation by mitochondria isolated from thermogenic brown adipose tissue, when we noticed a curious nonlinearity in the respiration rate. This initiated a convoluted chain of experiments revealing that the mitochondria were textbook demonstrations of the then novel and highly controversial "chemiosmotic hypothesis" of Peter Mitchell and that thermogenesis was regulated by a proton short‐circuit, mediated by a 32 kDa "uncoupling protein," UCP1, activated by fatty acid. This review is a personal account of the research into the bioenergetics of isolated brown adipocytes and isolated mitochondria, which led, after fifteen years of investigation, to what is still accepted as the "canonical" UCP1‐mediated mechanism of nonshivering thermogenesis, uniting whole animal physiology with mitochondrial bioenergetics. [ABSTRACT FROM AUTHOR]

Aim: Nonalcoholic steatohepatitis (NASH) is a severe form of nonalcoholic fatty liver disease (NAFLD) and lacks effective treatment options. Heme oxygenase‐1 (HO‐1) is a critical defense against oxidative stress and inflammation in the liver injury. This study aims to investigate the protective role and underlying mechanisms of HO‐1 in NASH pathogenesis. Methods: The hepatocyte‐specific HO‐1 knockout (HO‐1HEPKO) mice on a C57BL/6J background (HO‐1fl/fl/Alb‐Cre) were generated and fed a high‐fat/western‐style diet (HFD) or methionine‐choline‐deficient diet (MCD). Changes in mitochondrial ultrastructure were observed by transmission electron microscopy and confocal microscopy. A mitochondrial PCR array was used to identify the crucial genes associated with mitochondrial dysfunction. Results: Hepatocyte‐specific HO‐1HEPKO mice developed steatohepatitis with severe steatosis, ballooning, and necroinflammation. Dysregulated hepatic expression of mitochondria‐related proteins, including DRP1, Tomm20, MFN1 and MFN2 were detected in NASH animals. Ultrastructural mitochondrial damage was observed in HO‐1HEPKO mice. Mitochondrial dysfunction was recapitulated in HO‐1‐knockdown cells in vitro, as evidenced by decreased membrane potential, reduced ATP content, and mtDNA damage. Conversely, HO‐1 overexpression restored these changes in vitro. Mechanistically, HO‐1 deficiency reduced the inhibitory effect on Tomm20, leading to mitochondrial dysfunction, and thereby causing steatohepatitis. Conclusions: HO‐1 attenuates diet‐induced steatohepatitis by preventing mitochondrial dysfunction, indicating that HO‐1 may constitute a potential therapeutic target for NASH. [ABSTRACT FROM AUTHOR]

Aim: The current study investigated the impact of maternal obesity on placental phenotype in relation to fetal growth and sex. Methods: Female C57BL6/J mice were fed either a diet high in fat and sugar or a standard chow diet, for 6 weeks prior to, and during, pregnancy. At day 19 of gestation, placental morphology and mitochondrial respiration and dynamics were assessed using high‐resolution respirometry, stereology, and molecular analyses. Results: Diet‐induced maternal obesity increased the rate of small for gestational age fetuses in both sexes, and increased blood glucose concentrations in offspring. Placental weight, surface area, and maternal blood spaces were decreased in both sexes, with reductions in placental trophoblast volume, oxygen diffusing capacity, and an increased barrier to transfer in males only. Despite these morphological changes, placental mitochondrial respiration was unaffected by maternal obesity, although the influence of fetal sex on placental respiratory capacity varied between dietary groups. Moreover, in males, but not females, maternal obesity increased mitochondrial complexes (II and ATP synthase) and fission protein DRP1 abundance. It also reduced phosphorylated AMPK and capacity for lipid synthesis, while increasing indices of oxidative stress, specifically in males. In females only, placental mitochondrial biogenesis and capacity for lipid synthesis, were both enhanced. The abundance of uncoupling protein‐2 was decreased by maternal obesity in both fetal sexes. Conclusion: Maternal obesity exerts sex‐dependent changes in placental phenotype in association with alterations in fetal growth and substrate supply. These findings may inform the design of personalized lifestyle interventions or therapies for obese pregnant women. [ABSTRACT FROM AUTHOR]

Aim: Assessments of mitochondrial respiration and mitochondrial content are common in skeletal muscle research and exercise science. However, many sources of technical and biological variation render these analyses susceptible to error. This study aimed to better quantify the reliability of different experimental designs and/or techniques so as to assist researchers to obtain more reliable data. Methods: We examined the repeatability of maximal mitochondrial oxidative phosphorylation in permeabilized muscle fibres via high‐resolution respirometry, and citrate synthase activity (a biomarker for mitochondrial content) in a microplate with spectrophotometery. Results: For mitochondrial respiration using permeabilized skeletal muscle fibres, the variability was reduced using three chambers and removing outliers compared to two chambers (CV reduced from 12.7% to 11.0%), and the minimal change that can be detected with 10 participants reduced from 17% to 13% according to modelling. For citrate synthase activity, the within‐plate CV (3.5%) increased when the assay was repeated after 4 hours (CV = 10.2%) and 4 weeks (CV = 30.5%). The readings were correlated, but significantly different after 4 hours and 4 weeks. Conclusion: This research provides evidence for important technical considerations when measuring mitochondrial respiration and content using citrate synthase activity as a biomarker. When assessing mitochondrial respiration in human skeletal muscle, the technical variability of high‐resolution respirometry can be reduced by increasing technical repeats and excluding outliers, practices which are not currently common. When analysing citrate synthase activity, our results highlight the importance of analysing all samples from the same study at the same time. [ABSTRACT FROM AUTHOR]

Coordinated action among various organelles maintains cellular functions. For instance, mitochondria and lysosomes are the main organelles contributing to cellular metabolism and provide energy for cardiomyocyte contraction. They also provide essential signalling platforms in the cell that regulate many key processes such as autophagy, apoptosis, oxidative stress, inflammation and cell death. Often, abnormalities in mitochondrial or lysosomal structures and functions bring about cardiovascular diseases (CVDs). Although the communication between mitochondria and lysosomes throughout the cardiovascular system is intensely studied, the regulatory mechanisms have not been completely understood. Thus, we summarize the most recent studies related to mitochondria and lysosomes' role in CVDs and their potential connections and communications under cardiac pathophysiological conditions. Further, we discuss limitations and future perspectives regarding diagnosis, therapeutic strategies and drug discovery in CVDs. [ABSTRACT FROM AUTHOR]

Aim: This study sought to provide a statistically robust reference for measures of mitochondrial function from standardized high‐resolution respirometry with permeabilized human skeletal muscle (ex vivo), compare analogous values obtained via indirect calorimetry, arterial‐venous O2 differences and 31P magnetic resonance spectroscopy (in vivo) and attempt to resolve differences across complementary methodologies as necessary. Methods: Data derived from 831 study participants across research published throughout March 2009 to November 2019 were amassed to examine the biological relevance of ex vivo assessments under standard conditions, ie physiological temperatures of 37°C and respiratory chamber oxygen concentrations of ~250 to 500 μmol/L. Results: Standard ex vivo‐derived measures are lower (Z ≥ 3.01, P ≤.0258) en masse than corresponding in vivo‐derived values. Correcting respiratory values to account for mitochondrial temperatures 10°C higher than skeletal muscle temperatures at maximal exercise (~50°C): (i) transforms data to resemble (Z ≤ 0.8, P >.9999) analogous yet context‐specific in vivo measures, eg data collected during maximal 1‐leg knee extension exercise; and (ii) supports the position that maximal skeletal muscle respiratory rates exceed (Z ≥ 13.2, P <.0001) those achieved during maximal whole‐body exercise, e.g. maximal cycling efforts. Conclusion: This study outlines and demonstrates necessary considerations when actualizing the biological relevance of human skeletal muscle respiratory control, metabolic flexibility and bioenergetics from standard ex vivo‐derived assessments using permeabilized human muscle. These findings detail how cross‐procedural comparisons of human skeletal muscle mitochondrial function may be collectively scrutinized in their relationship to human health and lifespan. [ABSTRACT FROM AUTHOR]

Aim: To investigate the role of zinc finger homeobox 3 gene (ZFHX3) in tachypacing‐induced mitochondrial dysfunction and explore its molecular mechanisms and potential as a therapeutic target in atrial fibrillation (AF). Methods: Through a bioluminescent assay, a patch clamp, confocal fluorescence and fluorescence microscopy, microplate enzyme activity assays and Western blotting, we studied ATP and ADP production, mitochondrial electron transfer chain complex activities, ATP‐sensitive potassium channels (IKATP), mitochondrial oxidative stress, Ca2+ content, and protein expression in control and ZFHX3 knockdown (KD) HL‐1 cells subjected to 1 and 5‐Hz pacing for 24 hours. Results: Compared with 1‐Hz pacing, 5‐Hz pacing increased ATP and ADP production, IKATP, phosphorylated adenosine monophosphate‐activated protein kinase and inositol 1,4,5‐triphosphate (IP3) receptor (IP3R) protein expression. Tachypacing induced mitochondrial oxidative stress and Ca2+ overload in both cell types. Furthermore, under 1‐ and 5‐Hz pacing, ZFHX3 KD cells showed higher IKATP, ATP and ADP production, mitochondrial oxidative stress and Ca2+ content than control cells. Under 5‐Hz pacing, 2‐aminoethoxydiphenyl borate (2‐APB; 3 μmol/L, an IP3R inhibitor) and MitoTEMPO (10 µmol/L, a mitochondria‐targeted antioxidant) reduced ADP and increased ATP production in both cell types; however, only 2‐APB significantly reduced mitochondrial Ca2+ overload in control cells. Under 5‐Hz pacing, mitochondrial oxidative stress was significantly reduced by both MitoTEMPO and 2‐APB and only by 2‐APB in control and ZFHX3 KD cells respectively. Conclusion: ZFHX3 KD cells modulate mitochondrial adaptations to tachypacing in HL‐1 cardiomyocytes through Ca2+ overload, oxidative stress and metabolic disorder. Targeting IP3R signalling or oxidative stress could reduce AF. [ABSTRACT FROM AUTHOR]

Nicotinamide adenine dinucleotide (NAD) is an abundant cofactor that plays crucial roles in several cellular processes. NAD can be synthesized de novo starting with tryptophan, or from salvage pathways starting with NAD precursors like nicotinic acid (NA), nicotinamide (NAM) or nicotinamide riboside (NR), referred to as niacin/B3 vitamins, arising from dietary supply or from cellular NAD catabolism. Given the interconversion between its oxidized (NAD+) and reduced form (NADH), NAD participates in a wide range of reactions: regulation of cellular redox status, energy metabolism and mitochondrial biogenesis. Plus, NAD acts as a signalling molecule, being a cosubstrate for several enzymes such as sirtuins, poly‐ADP‐ribose‐polymerases (PARPs) and some ectoenzymes like CD38, regulating critical biological processes like gene expression, DNA repair, calcium signalling and circadian rhythms. Given the large number of mitochondria present in cardiac tissue, the heart has the highest NAD levels and is one of the most metabolically demanding organs. In several models of heart failure, myocardial NAD levels are depressed and this depression is caused by mitochondrial dysfunction, metabolic remodelling and inflammation. Emerging evidence suggests that regulating NAD homeostasis by NAD precursor supplementation has therapeutic efficiency in improving myocardial bioenergetics and function. This review provides an overview of the latest understanding of the different NAD biosynthesis pathways, as well as its role as a signalling molecule particularly in cardiac tissue. We highlight the significance of preserving NAD equilibrium in various models of heart diseases and shed light on the potential pharmacological interventions aiming to use NAD boosters as therapeutic agents. [ABSTRACT FROM AUTHOR]

Aims: The body responds to exercise training by profound adaptations throughout the cardiorespiratory and muscular systems, which may result in improvements in maximal oxygen consumption (VO2peak) and mitochondrial capacity. By convenience, mitochondrial respiration is often measured at supra‐physiological oxygen levels, an approach that ignores any potential regulatory role of mitochondrial affinity for oxygen (p50mito) at physiological oxygen levels. Methods: In this study, we examined the p50mito of mitochondria isolated from the Vastus lateralis and Triceps brachii in 12 healthy volunteers before and after a training intervention with seven sessions of sprint interval training using both leg cycling and arm cranking. The changes in p50mito were compared to changes in whole‐body VO2peak. Results: We here show that p50mito is similar in isolated mitochondria from the Vastus (40 ± 3.8 Pa) compared to Triceps (39 ± 3.3) but decreases (mitochondrial oxygen affinity increases) after seven sessions of sprint interval training (to 26 ± 2.2 Pa in Vastus and 22 ± 2.7 Pa in Triceps, both P <.01). The change in VO2peak modelled from changes in p50mito was correlated to actual measured changes in VO2peak (R2 =.41, P =.002). Conclusion: Together with mitochondrial respiratory capacity, p50mito is a critical factor when measuring mitochondrial function, it can decrease with sprint interval training and should be considered in the integrative analysis of the oxygen cascade from lung to mitochondria. [ABSTRACT FROM AUTHOR]

The article discusses whether the increased mitochondrial content during endurance training can be explained by mitochondrial remodelling (hypertrophy) pr by a distinct biogenesis of new organelle structures. Also cited are the effects of aerobic exercise training in the body like increased whole-body maximal oxygen uptake, as well as higher mitochondrial content, enzyme capacity, and ATP production within the muscles.

In this review, we argue that several key features of maximal oxygen uptake (VO2max) should underpin discussions about the biological and reductionist determinants of its interindividual variability: (i) training-induced increases in VO2max are largely facilitated by expansion of red blood cell volume and an associated improvement in stroke volume, which also adapts independent of changes in red blood cell volume. These general concepts are also informed by cross-sectional studies in athletes that have very high values for VO2max. Therefore, (ii) variations in VO2max improvements with exercise training are also likely related to variations in these physiological determinants. (iii) All previously untrained individuals will respond to endurance exercise training in terms of improvements in VO2max provided the stimulus exceeds a certain volume and/or intensity. Thus, genetic analysis and/or reductionist studies performed to understand or predict such variations might focus specifically on DNA variants or other molecular phenomena of relevance to these physiological pathways. [ABSTRACT FROM AUTHOR]

To meet high cellular demands, the energy metabolism of cardiac muscles is organized by precise and coordinated functioning of intracellular energetic units ( ICEUs). ICEUs represent structural and functional modules integrating multiple fluxes at sites of ATP generation in mitochondria and ATP utilization by myofibrillar, sarcoplasmic reticulum and sarcolemma ion-pump ATPases. The role of ICEUs is to enhance the efficiency of vectorial intracellular energy transfer and fine tuning of oxidative ATP synthesis maintaining stable metabolite levels to adjust to intracellular energy needs through the dynamic system of compartmentalized phosphoryl transfer networks. One of the key elements in regulation of energy flux distribution and feedback communication is the selective permeability of mitochondrial outer membrane ( MOM) which represents a bottleneck in adenine nucleotide and other energy metabolite transfer and microcompartmentalization. Based on the experimental and theoretical (mathematical modelling) arguments, we describe regulation of mitochondrial ATP synthesis within ICEUs allowing heart workload to be linearly correlated with oxygen consumption ensuring conditions of metabolic stability, signal communication and synchronization. Particular attention was paid to the structure-function relationship in the development of ICEU, and the role of mitochondria interaction with cytoskeletal proteins, like tubulin, in the regulation of MOM permeability in response to energy metabolic signals providing regulation of mitochondrial respiration. Emphasis was given to the importance of creatine metabolism for the cardiac energy homoeostasis. [ABSTRACT FROM AUTHOR]

Aim Mitochondria undergo continuous changes in shape as result of complex fusion and fission processes. The physiological relevance of mitochondrial dynamics is still unclear. In the field of mitochondria bioenergetics, there is a need of tools to assess cell mitochondrial content. To develop a method to visualize mitochondrial networks in high resolution and assess mitochondrial volume. Methods Confocal fluorescence microscopy imaging of mitochondrial network stains in human vastus lateralis single muscle fibres and focused ion beam/ scanning electron microscopy (FIB/SEM) imaging, combined with 3D reconstruction was used as a tool to analyse mitochondrial morphology and measure mitochondrial fractional volume. Results Most type I and type II muscle fibres have tubular highly interconnected profusion mitochondria, which are thicker and more structured in type I muscle fibres (Fig. 1). In some muscle fibres, profission-isolated ellipsoid-shaped mitochondria were observed. Mitochondrial volume was significantly higher in type I muscle fibres and showed no correlation with any of the investigated molecular and biochemical mitochondrial measurements (Fig. 2). Three-dimensional reconstruction of FIB/SEM data sets shows that some subsarcolemmal mitochondria are physically interconnected with some intermyofibrillar mitochondria (Fig. 3). Conclusion Two microscopy methods to visualize skeletal muscle mitochondrial networks in 3D are described and can be used as tools to investigate mitochondrial dynamics in response to life-style interventions and/or in certain pathologies. Our results question the classification of mitochondria into subsarcolemmal and intermyofibrillar pools, as they are physically interconnected. [ABSTRACT FROM AUTHOR]

Magnetic resonance spectroscopy ( MRS) can give information about cellular metabolism in vivo which is difficult to obtain in other ways. In skeletal muscle, non-invasive 31 P MRS measurements of the post-exercise recovery kinetics of p H, [ PCr], [ Pi] and [ ADP] contain valuable information about muscle mitochondrial function and cellular p H homeostasis in vivo, but quantitative interpretation depends on understanding the underlying physiology. Here, by giving examples of the analysis of 31 P MRS recovery data, by some simple computational simulation, and by extensively comparing data from published studies using both 31 P MRS and invasive direct measurements of muscle O2 consumption in a common analytical framework, we consider what can be learnt quantitatively about mitochondrial metabolism in skeletal muscle using MRS-based methodology. We explore some technical and conceptual limitations of current methods, and point out some aspects of the physiology which are still incompletely understood. [ABSTRACT FROM AUTHOR]

In 1937, August Krogh discovered a powerful active Cl uptake mechanism in frog skin. After WWII, Hans Ussing continued the studies on the isolated skin and discovered the passive nature of the chloride uptake. The review concludes that the two modes of transport are associated with a minority cell type denoted as the γ-type mitochondria-rich (MR) cell, which is highly specialized for epithelial Cl uptake whether the frog is in the pond of low [NaCl] or the skin is isolated and studied by Ussing chamber technique. One type of apical Cl channels of the γ-MR cell is activated by binding of Cl to an external binding site and by membrane depolarization. This results in a tight coupling of the uptake of Na by principal cells and Cl by MR cells. Another type of Cl channels (probably CFTR) is involved in isotonic fluid uptake. It is suggested that the Cl channels serve passive uptake of Cl from the thin epidermal film of fluid produced by mucosal glands. The hypothesis is evaluated by discussing the turnover of water and ions of the epidermal surface fluid under terrestrial conditions. The apical Cl channels close when the electrodiffusion force is outwardly directed as it is when the animal is in the pond. With the passive fluxes eliminated, the Cl flux is governed by active transport and evidence is discussed that this is brought about by an exchange of cellular HCO with Cl of the outside bath driven by an apical H V-ATPase. [ABSTRACT FROM AUTHOR]

Aim: Platelet-activating factor (PAF) triggers cardiac pre-conditioning against ischemia/reperfusion injury. The actual protection of ischaemic pre-conditioning occurs in the reperfusion phase. Therefore, we studied in this phase the kinases involved in PAF-induced pre-conditioning. Methods: Langendorff-perfused rat hearts underwent 30 min of ischaemia and 2 h of reperfusion (group 1, control). Before ischaemia, group 2 hearts were perfused for 19 min with PAF (2 × 10−11 m); groups 3–5 hearts were co-infused during the initial 20 min of reperfusion, with the protein kinase C (PKC) inhibitor chelerythrine (5 × 10−6 m) or the phosphoinositide 3-kinase (PI3K) inhibitor LY294002 (5 × 10−5 m) and atractyloside (2 × 10−5 m), a mitochondrial permeability transition pore (mPTP) opener respectively. Phosphorylation of PKCε, PKB/Aκt, GSK-3β and ERK1/2 at the beginning of reperfusion was also checked. Left ventricular pressure and infarct size were determined. Results: PAF pre-treatment reduced infarct size (33 ± 4% vs. 64 ± 5% of the area at risk of control hearts) and improved pressure recovery. PAF pre-treatment enhanced the phosphorylation/activation of PKCε, PKB/Aκt and the phosphorylation/inactivation of GSK-3β at reperfusion. Effects on ERK1/2 phosphorylation were not consistent. Infarct-sparing effect and post-ischaemic functional improvement induced by PAF pre-treatment were abolished by post-ischaemic infusion of either chelerythrine, LY294002 or atractyloside. Conclusions: The cardioprotective effect exerted by PAF pre-treatment involves activation of PKC and PI3K in post-ischaemic phases and might be mediated by the prevention of mPTP opening in reperfusion via GSK-3β inactivation. [ABSTRACT FROM AUTHOR]

Aim: The swimming capacity of wild and reared fish differs. Whether the differences are associated with metabolic, contractile or structural variation in swimming musculature is unknown. In the present study, some aspects of contractile machinery in swimming muscles of wild and reared salmon are compared. Methods: Several morphological parameters and key enzyme activities were measured using electron microscopy and histochemical methods. Results: The density and size of the mitochondria was significantly higher in the muscle samples from wild fish when compared with the reared ones. Similar variability was also seen in the density of triads. Conversely, the size and density of lipid droplets was significantly lower in the red muscle of wild vs. reared salmon. The densities of two excitation contraction coupling components, dihydropyridine and ryanodine receptor, were considerably higher in swimming muscles of wild salmon than in reared fish. A similar difference was observed in the activities of aerobic enzymes. Moreover, oxygen consumption followed the same pattern, being significantly higher in the samples of wild salmon. Phosphorylase activity was, on the other hand, significantly lower in the muscles of wild fish. Conclusions: There are significant differences in morphology, Ca2+-regulating capacity and enzyme activities in swimming muscles between wild and reared salmon. These results provide evidence that the prerequisites for efficient contraction of the swimming muscles are better met in wild than in reared salmon. Importantly, the results also suggest that the observed variation is a major contributing factor to the difference in the swimming capacity between wild and hatchery-reared salmon. [ABSTRACT FROM AUTHOR]

Despite considerable progress during recent years our understanding of how lipid oxidation (LOx) is controlled during exercise remains incomplete. This review focuses on the role of mitochondria and energy state in the control of LOx. LOx increases in parallel with increased energy demand up to an exercise intensity of about 50–60% of VO2max after which the contribution of lipid decreases. The switch from lipid to carbohydrate (CHO) is of energetic advantage due to the increased ATP/O2 yield. In the low-intensity domain (<50% VO2max) a moderate reduction in energy state will stimulate both LOx and CHO oxidation and relative fuel utilization is mainly controlled by substrate availability and the capacity of the metabolic pathways. In the high-intensity domain (>60% VO2max) there is a pronounced decrease in energy state, which will stimulate glycolysis in excess of the substrate requirements of the oxidative processes. This will lead to acidosis, reduced levels of free Coenzyme A (CoASH) and reduced levels of free carnitine. Acidosis and reduced carnitine may limit the carnitine-mediated transfer of long-chain fatty acids (LCFA) into mitochondria and may thus explain the observed reduction in LOx during high-intensity exercise. Another potential mechanism, suggested in this review, is that Acyl-CoA synthetase (ACS), an initial step in LCFA catabolism, functions as a regulator of LOx. ACS activity is suggested to be under control of CoASH and energy state. Furthermore, evidence exists that additional control points exist beyond mitochondrial FA influx. The nature and site of this control remain to be investigated. [ABSTRACT FROM AUTHOR]

Aim: The effect of long-term endurance training on skeletal muscle and myocardial uptake of 99mTc-sestamibi, a radiopharmaceutical accumulating in the mitochondria, was investigated. Methods: Twenty-six Wistar rats were divided into a trained (5 days week−1 endurance running for 14 weeks) and an untrained group. On completion of training, 99mTc-sestamibi was administered and, 2 h post-injection, the myocardium and the soleus, extensor digitorum longus (EDL) and medial gastrocnemius (MG) muscles were removed for the measurement of cytochrome c oxidase (CCO) activity and 99mTc-sestamibi uptake. Tissue 99mTc-sestamibi kinetics was preliminarily studied in 16 other rats for up to 2 h post-injection. Results: Two hours post-injection 99mTc-sestamibi uptake was either stable (myocardium) or still rising (skeletal muscles). Both CCO activity and 99mTc-sestamibi uptake decreased in the same order (myocardium, soleus, EDL, MG) in the tissues examined. The CCO activity of the EDL and MG muscles was higher ( P < 0.05) in the trained compared to the untrained group. 99mTc-sestamibi uptake in the soleus and EDL muscles was higher ( P < 0.05) in the trained compared to the untrained rats, whereas the difference in MG was marginally significant ( P = 0.06) in favour of the trained group. Conclusions: Long-term endurance training, resulting in elevated skeletal muscle CCO activity, is also associated with a similar increase in 99mTc-sestamibi uptake. This finding suggests that 99mTc-sestamibi could be used in imaging assessment of skeletal muscle metabolism with possible applications in both clinical and sports medicine settings. [ABSTRACT FROM AUTHOR]

In the vertebrate brain, neural stem cells (NSCs) generate both neuronal and glial cells throughout life. However, their neuro‐ and gliogenic capacity changes as a function of the developmental context. Despite the growing body of evidence on the variety of intrinsic and extrinsic factors regulating NSC physiology, their precise cellular and molecular actions are not fully determined. Our review focuses on thyroid hormone (TH), a vital component for both development and adult brain function that regulates NSC biology at all stages. First, we review comparative data to analyse how TH modulates neuro‐ and gliogenesis during vertebrate brain development. Second, as the mammalian brain is the most studied, we highlight the molecular mechanisms underlying TH action in this context. Lastly, we explore how the interplay between TH signalling and cell metabolism governs both neurodevelopmental and adult neurogenesis. We conclude that, together, TH and cellular metabolism regulate optimal brain formation, maturation and function from early foetal life to adult in vertebrate species. [ABSTRACT FROM AUTHOR]

Aims: Patients with renovascular hypertension (RVH) exhibit elevated urinary mtDNA copy numbers, considered to constitute surrogate markers of renal mitochondrial injury. The modest success of percutaneous transluminal renal angioplasty (PTRA) in restoring renal function in RVH has been postulated to be partly attributable to acute reperfusion injury. We hypothesized that mitoprotection during revascularization would ameliorate PTRA–induced renal mitochondrial injury, reflected in elevated urinary mtDNA copy numbers and improve blood pressure and functional outcomes 3 months later. Methods: We prospectively measured urinary copy number of the mtDNA genes COX3 and ND1 using qPCR in RVH patients before and 24 hrs after PTRA, performed during IV infusion of vehicle (n = 8) or the mitoprotective drug elamipretide (ELAM, 0.05 mg/kg/h, n = 6). Five healthy volunteers (HV) served as controls. Urinary mtDNA levels were also assessed in RVH and normal pigs (n = 7 each), in which renal mitochondrial structure and density were studied ex‐vivo. Results: Baseline urinary mtDNA levels were elevated in all RVH patients vs HV and directly correlated with serum creatinine levels. An increase in urinary mtDNA 24 hours after PTRA was blunted in PTRA+ELAM vs PTRA+Placebo. Furthermore, 3‐months after PTRA, systolic blood pressure decreased and estimated glomerular filtration rate increased only in ELAM–treated subjects. In RVH pigs, mitochondrial damage was observed using electron microscopy in tubular cells and elevated urinary mtDNA levels correlated inversely with renal mitochondrial density. Conclusions: PTRA leads to an acute rise in urinary mtDNA, reflecting renal mitochondrial injury that in turn inhibits renal recovery. Mitoprotection might minimize PTRA–associated mitochondrial injury and improve renal outcomes after revascularization. [ABSTRACT FROM AUTHOR]

Aim: We examined the Fick components together with mitochondrial O2 affinity (p50mito) in defining O2 extraction and O2 uptake during exercise with large and small muscle mass during normoxia (NORM) and hyperoxia (HYPER). Methods: Seven individuals performed 2 incremental exercise tests to exhaustion on a bicycle ergometer (BIKE) and 2 on a 1‐legged knee extension ergometer (KE) in NORM or HYPER. Leg blood flow and VO2 were determined by thermodilution and the Fick method. Maximal ADP‐stimulated mitochondrial respiration (OXPHOS) and p50mito were measured ex vivo in isolated mitochondria. Mitochondrial excess capacity in the leg was determined from OXPHOS in permeabilized fibres and muscle mass measured with magnetic resonance imaging in relation to peak leg O2 delivery. Results: The ex vivo p50mito increased from 0.06 ± 0.02 to 0.17 ± 0.04 kPa with varying substrate supply and O2 flux rates from 9.84 ± 2.91 to 16.34 ± 4.07 pmol O2·s−1·μg−1 respectively. O2 extraction decreased from 83% in BIKE to 67% in KE as a function of a higher O2 delivery and lower mitochondrial excess capacity. There was a significant relationship between O2 extraction and mitochondrial excess capacity and p50mito that was unrelated to blood flow and mean transit time. Conclusion: O2 extraction varies with mitochondrial respiration rate, p50mito and O2 delivery. Mitochondrial excess capacity maintains a low p50mito which enhances O2 diffusion from microvessels to mitochondria during exercise. [ABSTRACT FROM AUTHOR]