Search

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]

Aim: This study mapped the spatiotemporal positions and connectivity of Onecut3+ neuronal populations in the developing and adult mouse brain. Methods: We generated fluorescent reporter mice to chart Onecut3+ neurons for brain‐wide analysis. Moreover, we crossed Onecut3‐iCre and Mapt‐mGFP (Tau‐mGFP) mice to visualize axonal projections. A dual Cre/Flp‐dependent AAV construct in Onecut3‐iCre cross‐bred with Slc17a6‐FLPo mice was used in an intersectional strategy to map the connectivity of glutamatergic lateral hypothalamic neurons in the adult mouse. Results: We first found that Onecut3 marks a hitherto undescribed Slc17a6+/Vglut2+ neuronal cohort in the lateral hypothalamus, with the majority expressing thyrotropin‐releasing hormone. In the adult, Onecut3+/Vglut2+ neurons of the lateral hypothalamus had both intra‐ and extrahypothalamic efferents, particularly to the septal complex and habenula, where they targeted other cohorts of Onecut3+ neurons and additionally to the neocortex and hippocampus. This arrangement suggests that intrinsic reinforcement loops could exist for Onecut3+ neurons to coordinate their activity along the brain's midline axis. Conclusion: We present both a toolbox to manipulate novel subtypes of hypothalamic neurons and an anatomical arrangement by which extrahypothalamic targets can be simultaneously entrained. [ABSTRACT FROM AUTHOR]

Aim: Accurate evaluation of glomerular filtration rate (GFR) is crucial in Oncology as drug eligibility and dosing depend on estimates of GFR. However, there are no clear guidelines on the optimal method of determining kidney function in patients with cancer. We aimed to summarize the evidence on estimation of kidney function in patients with cancer. Methods: We searched PubMed for literature discussing the performance of GFR estimating equations in patients with malignancy to create a table of the evidence for creatinine‐ and cystatin c‐based equations. We further reviewed novel estimation techniques such as panel eGFR, real‐time measured GFR, and functional magnetic resonance imaging. Results: The commonly used GFR estimating equations were derived from populations of patients without cancer. These equations may be less applicable in Oncology due to severe sarcopenia, inflammation, and other physiologic changes in patients with cancer. The Cockcroft‐Gault equation currently dominates in clinical Oncology despite significant limitations and accumulating evidence for use of the CKD‐EPICr formula. Additional considerations in the practice of Oncology include a recently developed equation (CamGFRv2, also called the Janowitz formula) and the use of cystatin c‐based equations to overcome some of the barriers to accurate GFR estimation based on creatinine alone. Conclusion: Overall, we suggest using the CKD‐EPI equations (either cystatin c or creatinine‐based) among patients with cancer in routine clinical practice and measured GFR for patients at a critical threshold for treatment decisions. [ABSTRACT FROM AUTHOR]

The author reflects on ageing. The author mentions that the basis of ageing is still unidentified despite the papers published about the topic particularly in the journal "Acta Physiologica." He also explores the concept of change and its role on ageing. Moreover, he adds that people cannot change the fact that they are ageing.

The global north is facing an unprecedented rise in the prevalence of neurodegenerative diseases. The increasing incidence of Parkinson's disease is being referred to as a pandemic. The reason for the enormous increase is only partly understood. Lifestyle factors are known to play a role, but they alone cannot account for the surge. One factor that—although being recognized as important—has not been explored in detail so far is the influence of circadian rhythms. Sleep and circadian rhythm disruption are known as key factors in neurodegeneration, and their occurrence during early disease stages suggests a causal role in the pathogenesis. Isolated rapid eye movement (REM) sleep behavior disorder (iRBD) has been identified as a prodromal state of α‐synucleinopathies, such as Parkinson's disease, Lewy body dementia, and multiple system atrophy offering a window for insights into the early development of these diseases. Even though REM sleep is the sleep state most pronounced, driven and modulated by the circadian timing system, specific circadian abnormalities have not been described in iRBD. Novel experimental and clinical approaches exploiting the molecular circuitry underlying circadian timekeeping hold promise to disentangle some of the pathophysiologic mechanisms of α‐synucleinopathies. In this review, we summarize current knowledge on sleep and circadian rhythm disruptions in α‐synucleinopathies with an emphasis on molecular aspects and therapeutic potentials. These insights might contribute to our understanding of the pathogenesis of neurodegenerative diseases and may allow therapeutic interventions addressing the disturbed circadian system at the early stage of disease. [ABSTRACT FROM AUTHOR]

Extreme environments are powerful drivers of physiological adaptation. Naked mole‐rats offer an informative example of this relationship as they putatively encounter intermittent hypoxia and hypercapnia in their subterranean habitat. This has presumably driven the evolution of a suite of cellular and physiological adaptations that enable life in these conditions. Recently, my laboratory and others have begun to examine physiological responses to environmental hypoxia and hypercapnia in naked mole‐rats, and the underlying cellular and molecular mechanisms that differentiate the responses of this species from those of other small mammals. Prominent among these adaptations are a robust hypoxic metabolic response and blunted ventilatory responses to hypoxia and hypercapnia. These responses are mediated in part by modifications to the central nervous system signaling pathways that sense and communicate changes in environmental gas levels and initiate and maintain downstream physiological responses. For example, naked mole‐rats retain the signaling architecture necessary for "normal" ventilatory responses to hypoxia and hypercapnia; however, the underlying signaling pathways are muted, resulting in reduced, or even the absence of, sensitivity to otherwise powerful environmental stimuli. Herein, I discuss what we have learned about the manifestation and control of ventilatory and metabolic responses to hypoxia and hypercapnia in naked mole‐rats. I also highlight areas where additional work is warranted and consider the implications of what we have learned for the ecophysiology of a species that thrives in conditions that are deleterious or lethal to most adult mammals. [ABSTRACT FROM AUTHOR]

Data integration, data sharing, and standardized analyses are important enablers for data‐driven medical research. Circadian medicine is an emerging field with a particularly high need for coordinated and systematic collaboration between researchers from different disciplines. Datasets in circadian medicine are multimodal, ranging from molecular circadian profiles and clinical parameters to physiological measurements and data obtained from (wearable) sensors or reported by patients. Uniquely, data spanning both the time dimension and the spatial dimension (across tissues) are needed to obtain a holistic view of the circadian system. The study of human rhythms in the context of circadian medicine has to confront the heterogeneity of clock properties within and across subjects and our inability to repeatedly obtain relevant biosamples from one subject. This requires informatics solutions for integrating and visualizing relevant data types at various temporal resolutions ranging from milliseconds and seconds to minutes and several hours. Associated challenges range from a lack of standards that can be used to represent all required data in a common interoperable form, to challenges related to data storage, to the need to perform transformations for integrated visualizations, and to privacy issues. The downstream analysis of circadian rhythms requires specialized approaches for the identification, characterization, and discrimination of rhythms. We conclude that circadian medicine research provides an ideal environment for developing innovative methods to address challenges related to the collection, integration, visualization, and analysis of multimodal multidimensional biomedical data. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study is to investigate associations between the physical activity (PA) spectrum (sedentary behavior to exercise) and tissue‐specific insulin resistance (IR). Methods: We included 219 participants for analysis (median [IQR]: 61 [55; 67] years, BMI 29.6 [26.9; 32.0] kg/m2; 60% female) with predominant muscle or liver IR, as determined using a 7‐point oral glucose tolerance test (OGTT). PA and sedentary behavior were measured objectively (ActivPAL) across 7 days. Context‐specific PA was assessed with the Baecke questionnaire. Multiple linear regression models (adjustments include age, sex, BMI, site, season, retirement, and dietary intake) were used to determine associations between the PA spectrum and hepatic insulin resistance index (HIRI), muscle insulin sensitivity index (MISI) and whole‐body IR (HOMA‐IR, Matsuda index). Results: In fully adjusted models, objectively measured total PA (standardized regression coefficient β = 0.17, p = 0.020), light‐intensity PA (β = 0.15, p = 0.045) and moderate‐to‐vigorous intensity PA (β = 0.13, p = 0.048) were independently associated with Matsuda index, but not HOMA‐IR (p > 0.05). A higher questionnaire‐derived sport index and leisure index were associated with significantly lower whole‐body IR (Matsuda, HOMA‐IR) in men but not in women. Results varied across tissues: more time spent sedentary (β = −0.24, p = 0.045) and a higher leisure index (β = 0.14, p = 0.034) were respectively negatively and positively associated with MISI, but not HIRI. A higher sport index was associated with lower HIRI (β = −0.30, p = 0.007, in men only). Conclusion: While we confirm a beneficial association between PA and whole‐body IR, our findings indicate that associations between the PA spectrum and IR seem distinct depending on the primary site of insulin resistance (muscle or liver). [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: Although calcium‐sensing receptor (CaSR) and transient receptor potential vanilloid 4 (TRPV4) channels are functionally expressed on macrophages, it is unclear if they work coordinately to mediate macrophage function. The present study investigates whether CaSR couples to TRPV4 channels and mediates macrophage polarization via Ca2+ signaling. Methods: The role of CaSR/TRPV4/Ca2+ signaling was assessed in lipopolysaccharide (LPS)‐treated peritoneal macrophages (PMs) from wild‐type (WT) and TRPV4 knockout (TRPV4 KO) mice. The expression and function of CaSR and TRPV4 in PMs were analyzed by immunofluorescence and digital Ca2+ imaging. The correlation factors of M1 polarization, CCR7, IL‐1β, and TNFα were detected using q‐PCR, western blot, and ELISA. Results: We found that PMs expressed CaSR and TRPV4, and CaSR activation‐induced marked Ca2+ signaling predominately through extracellular Ca2+ entry, which was inhibited by selective pharmacological blockers of CaSR and TRPV4 channels. The CaSR activation‐induced Ca2+ signaling was significantly attenuated in PMs from TRPV4 KO mice compared to those from WT mice. Moreover, the CaSR activation‐induced Ca2+ entry via TRPV4 channels was inhibited by blocking phospholipases A2 (PLA2)/cytochromeP450 (CYP450) and phospholipase C (PLC)/Protein kinase C (PKC) pathways. Finally, CaSR activation promoted the expression and release of M1‐associated cytokines IL‐1β and TNFɑ, which were attenuated in PMs from TRPV4 KO mice. Conclusion: We reveal a novel coupling of the CaSR and TRPV4 channels via PLA2/CYP450 and PLC/PKC pathways, promoting a Ca2+‐dependent M1 macrophage polarization. Modulation of this coupling and downstream pathways may become a potential strategy for the prevention/treatment of immune‐related disease. [ABSTRACT FROM AUTHOR]

Arterial hypertension is a serious medical condition that significantly increases the risks of heart, brain, kidney, and other diseases affecting 1.28 billion adults worldwide. The authors employed an animal model with wild-type (Floxed) and CD-specific deletion of renin (CD renin KO) mice. In animals, immunofluorescence analysis of renal sections from mice after 5 days of acute pyelonephritis revealed apical plasma membrane targeting of AQP2 and pS256-AQP2 in inner medullary collecting ducts. CD renin KO mice had blunted HK-induced intrarenal renin response and developed impaired kaliuresis and elevated plasma potassium level. [Extracted from the article]

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]

Aims: We aimed to investigate the tolerability, safety, and effectiveness of enhanced external counterpulsation therapy (EECP) versus individual shear rate therapy (ISRT) in patients with lower extremity atherosclerotic disease (LEAD). Methods: Eighteen patients (age: 73.1 ± 6 years) underwent EECP and ISRT, each daily over five consecutive days in a cross‐over design with a 1 week resting period in between the two regimens. A quality‐of‐life questionnaire was used to assess the therapy experience. Oxygen saturation (SO2), relative hemoglobin amount (rHb) and blood flow (Flow) in the capillary‐venous‐system (microcirculation) of the skin were monitored continuously during all therapy sessions using the micro‐lightguide spectrophotometer, also known as oxygen to see (O2C). The effects of EECP and ISRT on the renal function and skeletal muscles were evaluated using serial blood and urine tests. Results: EECP therapy had to be terminated early before the end of the 5th session in 10 patients (55.6%) because of discomfort. Four patients (22.2%) experienced signs of critical limb ischaemia under EECP. The total score of the quality‐of‐life questionnaire was significantly higher (= better tolerated) post‐ISRT compared with EECP. Microcirculation monitoring revealed that ISRT significantly increased the SO2, blood flow and rHb during the therapy. All three parameters remained significantly increased in the observation period after ISRT. The serum levels of creatin kinase and myoglobin increased significantly under EECP. Conclusions: ISRT significantly improves tolerability, safety, and effectiveness over EECP in patients with LEAD. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article "The discovery of a new class of synaptic transmitters in smooth muscle fifty years ago and amelioration of coronary artery thrombosis" by Max R. Bennett in the February 2013 issue of the periodical.

Aim: Tissue hypoxia is an early key feature of acute kidney injury. Assessment of renal oxygenation using magnetic resonance imaging (MRI) markers T2 and T2* enables insights into renal pathophysiology. This assessment can be confounded by changes in the blood and tubular volume fractions, occurring upon pathological insults. These changes are mirrored by changes in kidney size (KS). Here, we used dynamic MRI to monitor KS for physiological interpretation of T2* and T2 changes in acute pathophysiological scenarios. Methods: KS was determined from T2*, T2 mapping in rats. Six interventions that acutely alter renal tissue oxygenation were performed directly within the scanner, including interventions that change the blood and/or tubular volume. A biophysical model was used to estimate changes in O2 saturation of hemoglobin from changes in T2* and KS. Results: Upon aortic occlusion KS decreased; this correlated with a decrease in T2*, T2. Upon renal vein occlusion KS increased; this negatively correlated with a decrease in T2*, T2. Upon simultaneous occlusion of both vessels KS remained unchanged; there was no correlation with decreased T2*, T2. Hypoxemia induced mild reductions in KS and T2*, T2. Administration of an X‐ray contrast medium induced sustained KS increase, with an initial increase in T2*, T2 followed by a decrease. Furosemide caused T2*, T2 elevation and a minor increase in KS. Model calculations yielded physiologically plausible calibration ratios for T2*. Conclusion: Monitoring KS allows physiological interpretation of acute renal oxygenation changes obtained by T2*, T2. KS monitoring should accompany MRI‐oximetry, for new insights into renal pathophysiology and swift translation into human studies. [ABSTRACT FROM AUTHOR]

The attained 30-fold coverage allowed for direct estimation of Denisovan heterozygosity, which showed that genetic diversity among the Denisovans was surprisingly low.[6] The application of a single-stranded DNA library also enabled the high-coverage genome sequencing of a Neanderthal woman from Siberia in 2014. Further studies involving other available archaic genomes and 25 modern genomes detected several gene flow events among Neanderthals, Denisovans and anatomically modern humans, thus giving evidence for possible common ancestry between hominins in the Late Pleistocene. The full mitochondrial genome was sequenced in 2008, while in 2010 appeared the first draft of the Neanderthal genome, followed by high coverage Neanderthal genome in 2014. [Extracted from the article]

Aim: Investigate whether juvenile exercise could induce a long‐term muscle memory, boosting the effects of exercise in adults. Methods: We devised a 5‐week climbing exercise scheme with food reward administered to male juvenile rats (post‐natal week 4–9). Subsequently, the animals were subjected to 10 weeks of detraining (week 9–19) without climbing and finally retraining during week 19–21. Results: The juvenile exercise increased fiber cross‐sectional area (fCSA) by 21% (p = 0.0035), boosted nuclear accretion by 13% (p = 0.057), and reduced intraperitoneal fat content by 28% (p = 0.007) and body weight by 9% (p = 0.001). During detraining, the fCSA became similar in the animals that had been climbing compared to naive controls, but the elevated number of myonuclei induced by the climbing were maintained (15%, p = 0.033). When the naive rats were subjected to 2 weeks of adult exercise there was little effect on fCSA, while the previously trained rats displayed an increase of 19% (p = 0.0007). Similarly, when the rats were subjected to unilateral surgical overload in lieu of the adult climbing exercise, the increase in fCSA was 20% (p = 0.0039) in the climbing group, while there was no significant increase in naive rats when comparing to the contralateral leg. Conclusion: This demonstrates that juvenile exercise can establish a muscle memory boosting the effects of adult exercise. The juvenile climbing exercise with food reward also led to leaner animals with lower body weight. These differences were to some extent maintained throughout the adult detraining period in spite of all animals being fed ad libitum, indicating a form of body weight memory. [ABSTRACT FROM AUTHOR]

Aims: Diets containing high‐fat and high sugar (HFHS) lead to overweight/obesity. Overweight/obesity increases the risk of infertility, and of the pregnant mother and her child for developing metabolic conditions. Overweight/obesity has been recreated in mice, but most studies focus on the effects of chronic, long‐term HFHS diet exposure. Here, we exposed mice to HFHS from 3 weeks prior to pregnancy with the aim of determining impacts on fertility, and gestational and neonatal outcomes. Methods: Time‐domain NMR scanning was used to assess adiposity, glucose, and insulin tolerance tests were employed to examine metabolic physiology, and morphological and proteomic analyses conducted to assess structure and nutrient levels of maternal organs and placenta. Results: Fertility measures of HFHS dams were largely the same as controls. HFHS dams had increased adiposity pre‐pregnancy, however, exhibited exacerbated lipolysis/hyper‐mobilization of adipose stores in late pregnancy. While there were no differences in glucose or insulin tolerance, HFHS dams were hyperglycemic and hyperinsulinemic in pregnancy. HFHS dams had fatty livers and altered pancreatic islet morphology. Although fetuses were hyperglycemic and hyperinsulinemic, there was no change in fetal growth in HFHS dams. There were also reductions in placenta formation. Moreover, there was increased offspring loss during lactation, which was related to aberrant mammary gland development and milk protein composition in HFHS dams. Conclusions: These findings are relevant given current dietary habits and the development of maternal and offspring alterations in the absence of an increase in maternal weight and adiposity during pregnancy, which are the current clinical markers to determine risk across gestation. [ABSTRACT FROM AUTHOR]

In this case, Southern was not a direction, but a scientist: Edwin M. Southern. I Acta Physiologica i caters to a wide variety of research efforts related to physiology - itself one of if not the most diverse discipline of biomedical research. He established a method to split up DNA via electrophoresis and detect specific sequences by hybridization - the Southern blot.4 Methods for detecting specific proteins5 and RNA sequences6 were established soon after, based on the same principle. Subsequently, searching recent I Acta Physiologica i publications for references to "blotting" should provide a reliable and lower bound estimate of the prominence of "blotting" in biomedicine. [Extracted from the article]

The author comments on a study conducted by researcher M. Venturelli and others, which focused on mechanism for in vivo loss of skeletal muscle mass and function, known as sarcopenia, in elderly women. It mentions how exercise can help prevent sarcopenia and reflects on the in vivo loss of absolute muscle contraction in old women. It informs that the study concluded that myofibres' intrinsic contractile properties in vitro may be unaffected by age.

The author discusses the study on the increase in the levels of hypothalamic paraventricular nucleus (PVH) glucose and insulin in insulin resistant (IR) rats. Topics covered include the effects of the sympathetic nervous system (SNS) innervation of the white adipose tissue (WAT), role of the spinal afferents in the sensory nerve circuits, and impressions of the level of obesity to SNS outflows. Results of circulating norepinephrine induced by the adipose afferent reflex are also mentioned.

Aim: Erythropoietin (EPO) is regulated by hypoxia‐inducible factor (HIF)‐2. In the kidney, it is produced by cortico‐medullary perivascular interstitial cells, which transdifferentiate into collagen‐producing myofibroblasts in response to injury. Inhibitors of prolyl hydroxylase domain (PHD) dioxygenases (HIF‐PHIs) activate HIF‐2 and stimulate kidney and liver EPO synthesis in patients with anemia of chronic kidney disease (CKD). We examined whether HIF‐PHIs can reactivate EPO synthesis in interstitial cells that have undergone myofibroblast transdifferentiation in established kidney fibrosis. Methods: We investigated Epo transcription in myofibroblasts and characterized the histological distribution of kidney Epo transcripts by RNA in situ hybridization combined with immunofluorescence in mice with adenine nephropathy (AN) treated with HIF‐PHI molidustat. Lectin absorption chromatography was used to assess liver‐derived EPO. In addition, we examined kidney Epo transcription in Phd2 knockout mice with obstructive nephropathy. Results: In AN, molidustat‐induced Epo transcripts were not found in areas of fibrosis and did not colocalize with interstitial cells that expressed α‐smooth muscle actin, a marker of myofibroblast transdifferentiation. Epo transcription was associated with megalin‐expressing, kidney injury molecule 1‐negative nephron segments and contingent on residual renal function. Liver‐derived EPO did not contribute to serum EPO in molidustat‐treated mice. Epo transcription was not associated with myofibroblasts in Phd2 knockout mice with obstructive nephropathy. Conclusions: Our studies suggest that HIF‐PHIs do not reactivate Epo transcription in interstitial myofibroblasts and that their efficacy in inducing kidney EPO in CKD is dependent on the degree of myofibroblast formation, the preservation of renal parenchyma and the level of residual renal function. [ABSTRACT FROM AUTHOR]

Aim & Methods: Extreme endurance exercise provides a valuable research model for understanding the adaptive metabolic response of older and younger individuals to intense physical activity. Here, we compare a wide range of metabolic and physiologic parameters in two cohorts of seven trained men, age 30 ± 5 years or age 65 ± 6 years, before and after the participants travelled ≈3000 km by bicycle over 15 days. Results: Over the 15‐day exercise intervention, participants lost 2–3 kg fat mass with no significant change in body weight. V̇O2max did not change in younger cyclists, but decreased (p = 0.06) in the older cohort. The resting plasma FFA concentration decreased markedly in both groups, and plasma glucose increased in the younger group. In the older cohort, plasma LDL‐cholesterol and plasma triglyceride decreased. In skeletal muscle, fat transporters CD36 and FABPm remained unchanged. The glucose handling proteins GLUT4 and SNAP23 increased in both groups. Mitochondrial ROS production decreased in both groups, and ADP sensitivity increased in skeletal muscle in the older but not in the younger cohort. Conclusion: In summary, these data suggest that older but not younger individuals experience a negative adaptive response affecting cardiovascular function in response to extreme endurance exercise, while a positive response to the same exercise intervention is observed in peripheral tissues in younger and older men. The results also suggest that the adaptive thresholds differ in younger and old men, and this difference primarily affects central cardiovascular functions in older men after extreme endurance exercise. [ABSTRACT FROM AUTHOR]

Aims: Dietary inorganic phosphate (Pi) modulates renal Pi reabsorption by regulating the expression of the NaPi‐IIa and NaPi‐IIc Pi transporters. Here, we aimed to clarify the role of several Pi‐regulatory mechanisms including parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23) and inositol hexakisphosphate kinases (IP6‐kinases) in the acute regulation of NaPi‐IIa and NaPi‐IIc. Methods: Wildtype (WT) and PTH‐deficient mice (PTH‐KO) with/without inhibition of FGF23 signalling were gavaged with Pi/saline and examined at 1, 4 and 12 h. Results: Pi‐gavage elevated plasma Pi and decreased plasma Ca2+ in both genotypes after 1 h Within 1 h, Pi‐gavage decreased NaPi‐IIa abundance in WT and PTH‐KO mice. NaPi‐IIc was downregulated 1 h post‐administration in WT and after 4 h in PTH‐KO. PTH increased after 1 h in WT animals. After 4 h Pi‐gavage, FGF23 increased in both genotypes being higher in the KO group. PTHrp and dopamine were not altered by Pi‐gavage. Blocking FGF23 signalling blunted PTH upregulation in WT mice and reduced NaPi‐IIa downregulation in PTH‐KO mice 4 h after Pi‐gavage. Inhibition of IP6‐kinases had no effect. Conclusions: (1) Acute downregulation of renal Pi transporters in response to Pi intake occurs also in the absence of PTH and FGF23 signalling, (2) when FGF23 signalling is blocked, a partial contribution of PTH is revealed, (3) IP6 kinases, intracellular Pi‐sensors in yeast and bacteria, are not involved, and (4) Acute Pi does not alter PTHrp and dopamine. Thus, signals other than PTH, PTHrp, FGF23 and dopamine contribute to renal adaption. [ABSTRACT FROM AUTHOR]

A letter to the editor in response to the article "Depolarization vs. repolarization: what is the mechanism of ventricular arrhythmogenesis underlying sodium channel haploinsufficiency in mouse hearts?" by K. Jeevaratnam and colleagues that was published in a previous issue is presented.

Applications of Artificial Intelligence (AI) have become part of our life. The reason for the success here was the tremendously improved computing power and the availability of graphics processing units (GPUs) that have an intrinsic architecture ideally suited for artificial neuronal network applications. [Extracted from the article]

Aim: To describe ribosome biogenesis during resistance training, its relation to training volume and muscle growth. Methods: A training group (n = 11) performed 12 sessions (3‐4 sessions per week) of unilateral knee extension with constant and variable volume (6 and 3‐9 sets per session respectively) allocated to either leg. Ribosome abundance and biogenesis markers were assessed from vastus lateralis biopsies obtained at baseline, 48 hours after sessions 1, 4, 5, 8, 9 and 12, and after eight days of de‐training, and from a control group (n = 8). Muscle thickness was measured before and after the intervention. Results: Training led to muscle growth (3.9% over baseline values, 95% CrI: [0.2, 7.5] vs. control) with concomitant increases in total RNA, ribosomal RNA, upstream binding factor (UBF) and ribosomal protein S6 with no differences between volume conditions. Total RNA increased rapidly in response to the first four sessions (8.6% [5.6, 11.7] per session), followed by a plateau and peak values after session 8 (49.5% [34.5, 66.5] above baseline). Total RNA abundance was associated with UBF protein levels (5.0% [0.2, 10.2] per unit UBF), and the rate of increase in total RNA levels predicted hypertrophy (0.3 mm [0.1, 0.4] per %‐point increase in total RNA per session). After de‐training, total RNA decreased (−19.3% [−29.0, −8.1]) without muscle mass changes indicating halted biosynthesis of ribosomes. Conclusion: Ribosomes accumulate in the initial phase of resistance training with abundances sensitive to training cessation and associated with UBF protein levels. The average accumulation rate predicts muscle training‐induced hypertrophy. [ABSTRACT FROM AUTHOR]

Aim: Defects in hepatic glycogen synthesis contribute to post‐prandial hyperglycaemia in type 2 diabetic patients. Chromogranin A (CgA) peptide Catestatin (CST: hCgA352‐372) improves glucose tolerance in insulin‐resistant mice. Here, we seek to determine whether CST induces hepatic glycogen synthesis. Methods: We determined liver glycogen, glucose‐6‐phosphate (G6P), uridine diphosphate glucose (UDPG) and glycogen synthase (GYS2) activities; plasma insulin, glucagon, noradrenaline and adrenaline levels in wild‐type (WT) as well as in CST knockout (CST‐KO) mice; glycogen synthesis and glycogenolysis in primary hepatocytes. We also analysed phosphorylation signals of insulin receptor (IR), insulin receptor substrate‐1 (IRS‐1), phosphatidylinositol‐dependent kinase‐1 (PDK‐1), GYS2, glycogen synthase kinase‐3β (GSK‐3β), AKT (a kinase in AKR mouse that produces Thymoma)/PKB (protein kinase B) and mammalian/mechanistic target of rapamycin (mTOR) by immunoblotting. Results: CST stimulated glycogen accumulation in fed and fasted liver and in primary hepatocytes. CST reduced plasma noradrenaline and adrenaline levels. CST also directly stimulated glycogenesis and inhibited noradrenaline and adrenaline‐induced glycogenolysis in hepatocytes. In addition, CST elevated the levels of UDPG and increased GYS2 activity. CST‐KO mice had decreased liver glycogen that was restored by treatment with CST, reinforcing the crucial role of CST in hepatic glycogenesis. CST improved insulin signals downstream of IR and IRS‐1 by enhancing phospho‐AKT signals through the stimulation of PDK‐1 and mTORC2 (mTOR Complex 2, rapamycin‐insensitive complex) activities. Conclusions: CST directly promotes the glycogenic pathway by (a) reducing glucose production, (b) increasing glycogen synthesis from UDPG, (c) reducing glycogenolysis and (d) enhancing downstream insulin signalling. [ABSTRACT FROM AUTHOR]

Using this technique, discrete electrically-evoked Ca SP 2+ sp release events termed Ca SP 2+ sp spikes were recorded, supporting the notion that propagation of these events leads to the Ca SP 2+ sp transient. The cardiomyocyte firestarter - RyR clusters ignite their neighbours after augmentation of Ca2+ release by -stimulation Adrenergic stimuli augment cardiomyocyte contraction through modulation of intracellular Ca SP 2+ sp transient properties. Ca SP 2+ sp release at RyR clusters gives rise to Ca SP 2+ sp sparks, which summate in space and time to produce the cell-wide Ca SP 2+ sp transient. [Extracted from the article]

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: In the mammalian circadian clock, the CLOCK/BMAL1 heterodimer binds to E‐box enhancer elements in the promoters of its target genes to activate transcription. The classical Clock mice, the first circadian mouse mutant discovered, are behaviourally arrhythmic. In this mutant, CLOCK lacks a 51 amino acid domain corresponding to exon 19 (CLOCKΔ19), which is required for normal transactivation. While the importance of this CLOCK domain for circadian rhythms is well established, the exact molecular mechanism is still unclear. Methods: Using CRISPR/Cas9 technology, we created a CLOCK knockout – CLOCK rescue system in human circadian reporter cells and performed systematic mutational scanning to assess the functionality of individual amino acids within the CLOCK exon 19‐domain. Results: CLOCK knockout cells were arrhythmic, and circadian rhythms could be rescued by introducing wild‐type CLOCK, but not CLOCKΔ19. In addition, we identified several residues, whose mutation failed to rescue rhythms in CLOCK knockout cells. Many of these are part of the hydrophobic binding interface of the predicted dimer of the CLOCK exon 19‐domain. Conclusion: Our data not only indicate that CLOCK/BMAL1 oligomerization mediated by the exon 19‐domain is important for circadian dynamics but also suggest that the exon 19‐domain provides a platform for binding coactivators and repressors, which in turn is required for normal circadian rhythms. [ABSTRACT FROM AUTHOR]

Aim: To develop a method for direct measurement of the fluorescent d‐glucose analogue 2‐NBDG transport across the plasma membrane of single skeletal muscle fibres and derive the theoretical framework for determining the kinetic parameters for d‐glucose transport under basal conditions. Methods: A novel method is described for measuring free 2‐NBDG transport across plasma membrane of single rat muscle fibres at rest. The 2‐NBDG uptake was >90% suppressed by 100 µM cytochalasin B in both fast‐twitch and slow‐twitch fibres, indicating that the 2‐NBDG transport is GLUT‐mediated. Fibres were identified as fast‐twitch or slow‐twitch based on the differential sensitivity of their contractile apparatus to Sr2+. Results: The time course of 2‐NBDG uptake in the presence of 50 µM 2‐NBDG follows a one‐phase exponential plateau curve and is faster in fast‐twitch (rate constant 0.053 ± 0.0024 s‐1) than in slow‐twitch fibres (rate constant 0.031 ± 0.0021 s‐1). The rate constants were markedly reduced in the presence of 20 mM d‐glucose to 0.0082 ± 0.0004 s‐1 and 0.0056 ± 0.0002 s‐1 in fast‐twitch and slow‐twitch fibres respectively. 2‐NBDG transport was asymmetric, consistent with GLUT1 being the major functional GLUT isoform transporting 2‐NBDG in muscle fibres at rest. The parameters describing the transport kinetics for both 2‐NBDG and d‐glucose (dissociation constants, Michaelis–Menten constants, maximal rates of uptake and outflow) were calculated from the measurements made with 2‐NBDG. Conclusion: Free 2‐NBDG and d‐glucose transport across the plasma membrane of single rat muscle fibres at rest is fast, conclusively showing that the rate‐limiting step in d‐glucose uptake in skeletal muscle is not necessarily the GLUT‐mediated transport of d‐glucose. [ABSTRACT FROM AUTHOR]

Aims: It is unknown how β‐adrenergic stimulation affects calcium dynamics in individual RyR2 clusters and leads to the induction of spontaneous calcium waves. To address this, we analysed spontaneous calcium release events in green fluorescent protein (GFP)‐tagged RyR2 clusters. Methods: Cardiomyocytes from mice with GFP‐tagged RyR2 or human right atrial tissue were subjected to immunofluorescent labelling or confocal calcium imaging. Results: Spontaneous calcium release from single RyR2 clusters induced 91.4% ± 2.0% of all calcium sparks while 8.0% ± 1.6% were caused by release from two neighbouring clusters. Sparks with two RyR2 clusters had 40% bigger amplitude, were 26% wider, and lasted 35% longer at half maximum. Consequently, the spark mass was larger in two‐ than one‐cluster sparks with a median and interquartile range for the cumulative distribution of 15.7 ± 20.1 vs 7.6 ± 5.7 a.u. (P <.01). β2‐adrenergic stimulation increased RyR2 phosphorylation at s2809 and s2815, tripled the fraction of two‐ and three‐cluster sparks, and significantly increased the spark mass. Interestingly, the amplitude and mass of the calcium released from a RyR2 cluster were proportional to the SR calcium load, but the firing rate was not. The spark mass was also higher in 33 patients with atrial fibrillation than in 36 without (22.9 ± 23.4 a.u. vs 10.7 ± 10.9; P =.015). Conclusions: Most sparks are caused by activation of a single RyR2 cluster at baseline while β‐adrenergic stimulation doubles the mass and the number of clusters per spark. This mimics the shift in the cumulative spark mass distribution observed in myocytes from patients with atrial fibrillation. [ABSTRACT FROM AUTHOR]

Aim: Adaptive mechanisms in spinal circuits are likely involved in homeostatic responses to maintain motor output in amyotrophic lateral sclerosis. Given the role of Renshaw cells in regulating the motoneuron input/output gain, we investigated the modulation of heteronymous recurrent inhibition. Methods: Electrical stimulations were used to activate recurrent collaterals resulting in the Hoffmann reflex depression. Inhibitions from soleus motor axons to quadriceps motoneurons, and vice versa, were tested in 38 patients and matched group of 42 controls. Results: Compared with controls, the mean depression of quadriceps reflex was larger in patients, while that of soleus was smaller, suggesting that heteronymous recurrent inhibition was enhanced in quadriceps but reduced in soleus. The modulation of recurrent inhibition was linked to the size of maximal direct motor response and lower limb dysfunctions, suggesting a significant relationship with the integrity of the target motoneuron pool and functional abilities. No significant link was found between the integrity of motor axons activating Renshaw cells and the level of inhibition. Enhanced inhibition was particularly observed in patients within the first year after symptom onset and with slow progression of lower limb dysfunctions. Normal or reduced inhibitions were mainly observed in patients with motor weakness first in lower limbs and greater dysfunctions in lower limbs. Conclusion: We provide the first evidence for enhanced recurrent inhibition and speculate that Renshaw cells might have transient protective role on motoneuron by counteracting hyperexcitability at early stages. Several mechanisms likely participate including cortical influence on Renshaw cell and reinnervation by slow motoneurons. [ABSTRACT FROM AUTHOR]

Protein kinase C and casein kinase substrate in neurons (PACSINs), or syndapins (synaptic dynamin‐associated proteins), are a family of proteins involved in the regulation of cell cytoskeleton, intracellular trafficking and signalling. Over the last twenty years, PACSINs have been mostly studied in the in vitro and ex vivo settings, and only in the last decade reports on their function in vivo have emerged. We first summarize the identification, structure and cellular functions of PACSINs, and then focus on the relevance of PACSINs in vivo. During development in various model organisms, PACSINs participate in diverse processes, such as neural crest cell development, gastrulation, laterality development and neuromuscular junction formation. In mouse, PACSIN2 regulates angiogenesis during retinal development and in human, PACSIN2 associates with monosomy and embryonic implantation. In adulthood, PACSIN1 has been extensively studied in the brain and shown to regulate neuromorphogenesis, receptor trafficking and synaptic plasticity. Several genetic studies suggest a role for PACSIN1 in the development of schizophrenia, which is also supported by the phenotype of mice depleted of PACSIN1. PACSIN2 plays an essential role in the maintenance of intestinal homeostasis and participates in kidney repair processes after injury. PACSIN3 is abundant in muscle tissue and necessary for caveolar biogenesis to create membrane reservoirs, thus controlling muscle function, and has been linked to certain genetic muscular disorders. The above examples illustrate the importance of PACSINs in diverse physiological or tissue repair processes in various organs, and associations to diseases when their functions are disturbed. [ABSTRACT FROM AUTHOR]

Acute exposure to low oxygen (hypoxia) places conflicting demands on the heart. Whilst an increase in heart rate (tachycardia) may compensate systemic oxygen delivery as arterial oxygenation falls, the heart itself is an energetically expensive organ that may benefit from slowing (bradycardia) to reduce work when oxygen is limited. Both strategies are apparent in vertebrates, with tetrapods (mammals, birds, reptiles, and amphibians) classically exhibiting hypoxic tachycardia and fishes displaying characteristic hypoxic bradycardia. With a richer understanding of the ontogeny and evolution of the responses, however, we see similarities in the underlying mechanisms between vertebrate groups. For example, in adult mammals, primary bradycardia results from the hypoxic stimulation of carotid body chemoreceptors that are overwhelmed by mechano‐sensory feedback from the lung associated with hyperpnoea. Fish‐like bradycardia prevails in the mammalian foetus (which, at this stage, is incapable of pulmonary ventilation), and in fish and foetus alike, the bradycardia ensues despite an elevation of circulating catecholamines. In both cases, the reduced heart rate may primarily serve to protect the heart. Thus, the comparative perspective offers fundamental insight into how and why different vertebrates regulate heart rate in different ways during periods of hypoxia. [ABSTRACT FROM AUTHOR]

Aim: The sodium/hydrogen exchanger 2 (NHE2) is an intestinal acid extruder with crypt‐predominant localization and unresolved physiological significance. Our aim was to decipher its role in colonic epithelial cell proliferation, differentiation and electrolyte transport. Methods: Alterations induced by NHE2‐deficiency were addressed in murine nhe2−/− and nhe2+/+ colonic crypts and colonoids, and NHE2‐knockdown and control Caco2Bbe cells using pH‐fluorometry, gene expression analysis and immunofluorescence. Results: pHi‐measurements along the colonic cryptal axis revealed significantly decreased intracellular pH (pHi) in the middle segment of nhe2−/− compared to nhe2+/+ crypts. Increased Nhe2 mRNA expression was detected in murine colonoids in the transiently amplifying/progenitor cell stage (TA/PE). Lack of Nhe2 altered the differentiation programme of colonic epithelial cells with reduced expression of absorptive lineage markers alkaline phosphatase (iAlp), Slc26a3 and transcription factor hairy and enhancer‐of‐split 1 (Hes1), but increased expression of secretory lineage markers Mucin 2, trefoil factor 3 (Tff3), enteroendocrine marker chromogranin A and murine atonal homolog 1 (Math1). Enterocyte differentiation was found to be pHi dependent with acidic pHi reducing, and alkaline pHi stimulating the expression of enterocyte differentiation markers in Caco2Bbe cells. A thicker mucus layer, longer crypts and an expanded brush border membrane zone of sodium/hydrogen exchanger 3 (NHE3) abundance may explain the lack of inflammation and the normal fluid absorptive rate in nhe2−/− colon. Conclusions: The results suggest that NHE2 expression is activated when colonocytes emerge from the stem cell niche. Its activity increases progenitor cell pHi and thereby supports absorptive enterocyte differentiation. [ABSTRACT FROM AUTHOR]

The article provides information on the award "Ulf von Euler Award for Neurohumoral Control" to be launched by the periodical. The award is named after Ulf Svante von Euler-Chelpin, a scientist and will be granted to the authors of a seminal study published in this periodical in the field of neurohumoral control, including areas such as cardiovascular, gastrointestinal and metabolism. A biography of Ulf Svante von Euler-Chelpin is also presented.

An introduction is presented in which the editor discusses various article within the issue on dystonia, a syndrome featured by involuntary muscle contraction.

Some publishers have open access strategies where the publisher requires the assignment of the copyright and where it is unclear that the data in publications can be truly regarded as open data. "When research is widely available to other researchers and the public, it can save lives, provide policymakers with the tools to make critical decisions, and drive more equitable outcomes across every sector of society", Dr. Alondra Nelson, head of White House Office of Science and Technology Policy, Washington DC, USA. One issue for open data by scientists is the great afford to provide data to the public. There is an extensive discussion of how the idea of open data should be integrated into the publication guidelines.6 Some open-access publishers do not require the authors to assign copyright and the data associated with these publications can be regarded as open data. [Extracted from the article]

Aim: Sex differences are evident in human skeletal muscle as the cross-sectional area of individual muscle fibres is greater in men than in women. We have recently shown that resistance exercise stimulates mammalian target of rapamycin (mTOR) signalling and muscle protein synthesis in humans during early post-exercise recovery. Therefore, the aim of this study was to determine if sex influences the muscle protein synthesis response during recovery from resistance exercise. Methods: Seventeen subjects, nine male and eight female, were studied in the fasted state before, during and for 2 h following a bout of high-intensity leg resistance exercise. Mixed muscle protein fractional synthetic rate was measured using stable isotope techniques and mTOR signalling was assessed by immunoblotting from repeated vastus lateralis muscle biopsy samples. Results: Post-exercise muscle protein synthesis increased by 52% in the men and by 47% in the women ( P < 0.05) and was not different between groups ( P > 0.05). Akt phosphorylation increased in both groups at 1 h post-exercise ( P < 0.05) and returned to baseline during 2 h post-exercise with no differences between groups ( P > 0.05). Phosphorylation of mTOR and its downstream effector S6K1 increased significantly and similarly between groups during post-exercise recovery ( P < 0.05). eEF2 phosphorylation decreased at 1- and 2 h post-exercise ( P < 0.05) to a similar extent in both groups. Conclusion: The contraction-induced increase in early post-exercise mTOR signalling and muscle protein synthesis is independent of sex and appears to not play a role in the sexual dimorphism of leg skeletal muscle in young men and women. [ABSTRACT FROM AUTHOR]

A letter to the editor is presented in response to the article about work-independent assessment of efficiency in ex vivo working rodent hearts published in the previous issue.

The article discusses the report "Niere und Kreislauf," by R. Tigerstedt and P. G. Bergman. The authors in this study had injected extracts from rabbit kidneys and found that cortical, but not medulary injections, caused prolonged blood pressure elevations. The study has been remarkable in many respects and sustained surge of enthusiasm, particularly in hypertension research.

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]

Aim: This study examined whether aerobic‐interval exercise with blood flow restriction (BFR) potentiates early markers of metabolic health compared to exercise with systemic hypoxia or normoxia in man. Methods: In a randomized‐crossover fashion, eight healthy men completed nine 2‐minute running bouts at 105% of their lactate threshold on three occasions separated by one week, either with BFR (BFR‐trial), systemic hypoxia (HYP‐trial) or normoxia (control; CON‐trial). Near‐infrared spectroscopy was used to assess the muscle level of hypoxia. A muscle biopsy was collected at rest and 3 hours after exercise to quantify genes involved in cholesterol synthesis (PGC‐1α2), glucose disposal (GLUT4) and capillary growth (HIF‐1α; VEGFA), as well as mitochondrial respiration (PGC‐1α2/3), uncoupling (UCP3) and expansion (p53; COXIV‐1/2; CS; AMPKα1/2). Results: The muscle level of hypoxia was matched between the BFR‐trial and HYP‐trial (~90%; P >.05), which was greater than the CON‐trial (~70%; P <.05). PGC‐1α2 increased most in the BFR‐trial (16‐fold vs CON‐trial; 11‐fold vs HYP‐trial; P <.05). GLUT4 and VEGFA selectively increased by 2.0 and 3.4‐fold, respectively in BFR‐trial (P <.05), which was greater than CON‐trial (1.2 and 1.3 fold) and HYP‐trial (1.2 and 1.8 fold; P <.05). UCP3 increased more in BFR‐trial than the HYP‐trial (4.3 vs 1.6 fold), but was not different between BFR‐trial and CON‐trial (2.1 fold) or between CON‐trial and HYP‐trial (P >.05). No trial differences were evident for other genes (P >.05). Conclusion: Independent of the muscle level of hypoxia, BFR‐exercise potentiates early markers of metabolic health associated with the regulation of cholesterol production and glucose homeostasis in man. [ABSTRACT FROM AUTHOR]

Aim: MicroRNAs (miRNAs) are abundantly expressed in vasoactive intestinal peptide expressing (VIP+) interneurons and are indispensable for their functional maintenance and survival. Here, we blocked miRNA biogenesis in postmitotic VIP+ interneurons in mice by selectively ablating Dicer, an enzyme essential for miRNA maturation, to study whether ablation of VIP+ miRNA affects olfactory function and neural activity in olfactory centres such as the olfactory bulb, which contains a large number of VIP+ interneurons. Methods: A go/no‐go odour discrimination task and a food‐seeking test were used to assess olfactory discrimination and olfactory detection. In vivo electrophysiological techniques were used to record single units and local field potentials. Results: Olfactory detection and olfactory discrimination behaviours were impaired in VIP+‐specific Dicer‐knockout mice. In vivo electrophysiological recordings in awake, head‐fixed mice showed that both spontaneous and odour‐evoked firing rates were decreased in mitral/tufted cells in knockout mice. The power of ongoing and odour‐evoked beta local field potentials response of the olfactory bulb and anterior piriform cortex were dramatically decreased. Furthermore, the coherence of theta oscillations between the olfactory bulb and anterior piriform cortex was decreased. Importantly, Dicer knockout restricted to olfactory bulb VIP+ interneurons recapitulated the behavioural and electrophysiological results of the global knockout. Conclusions: VIP+ miRNAs are an important factor in sensory processing, affecting olfactory function and olfactory neural activity. [ABSTRACT FROM AUTHOR]