Insulin and leptin acutely modulate the energy metabolism of primary hypothalamic and cortical astrocytes.

Astrocytes constitute a heterogeneous cell population within the brain, contributing crucially to brain homeostasis and playing an important role in overall brain function. Their function and metabolism are not only regulated by local signals, for example, from nearby neurons, but also by long-range signals such as hormones. Thus, two prominent hormones primarily known for regulating the energy balance of the whole organism, insulin, and leptin, have been reported to also impact astrocytes within the brain. In this study, we investigated the acute regulation of astrocytic metabolism by these hormones in cultured astrocytes prepared from the mouse cortex and hypothalamus, a pivotal region in the context of nutritional regulation. Utilizing genetically encoded, fluorescent nanosensors, the cytosolic concentrations of glucose, lactate, and ATP, along with glycolytic rate and the NADH/NAD+ redox state were measured. Under basal conditions, differences between the two populations of astrocytes were observed for glucose and lactate concentrations as well as the glycolytic rate. Additionally, astrocytic metabolism responded to insulin and leptin in both brain regions, with some unique characteristics for each cell population. Finally, both hormones influenced how cells responded to elevated extracellular levels of potassium ions, a common indicator of neuronal activity. In summary, our study provides evidence that insulin and leptin acutely regulate astrocytic metabolism within minutes. Additionally, while astrocytes from the hypothalamus and cortex share similarities in their metabolism, they also exhibit distinct properties, further underscoring the growing recognition of astrocyte heterogeneity.

New horizons in the role of digital data in the healthcare of older people.

There are national and global moves to improve effective digital data design and application in healthcare. This New Horizons commentary describes the role of digital data in healthcare of the ageing population. We outline how health and social care professionals can engage in the proactive design of digital systems that appropriately serve people as they age, carers and the workforce that supports them. KEY POINTS: Healthcare improvements have resulted in increased population longevity and hence multimorbidity. Shared care records to improve communication and information continuity across care settings hold potential for older people. Data structure and coding are key considerations. A workforce with expertise in caring for older people with relevant knowledge and skills in digital healthcare is important.

A wrinkle in time: circadian biology in pulmonary vascular health and disease.

An often overlooked element of pulmonary vascular disease is time. Cellular responses to time, which are regulated directly by the core circadian clock, have only recently been elucidated. Despite an extensive collection of data regarding the role of rhythmic contribution to disease pathogenesis (such as systemic hypertension, coronary artery, and renal disease), the roles of key circadian transcription factors in pulmonary hypertension remain understudied. This is despite a large degree of overlap in the pulmonary hypertension and circadian rhythm fields, not only including shared signaling pathways, but also cell-specific effects of the core clock that are known to result in both protective and adverse lung vessel changes. Therefore, the goal of this review is to summarize the current dialogue regarding common pathways in circadian biology, with a specific emphasis on its implications in the progression of pulmonary hypertension. In this work, we emphasize specific proteins involved in the regulation of the core molecular clock while noting the circadian cell-specific changes relevant to vascular remodeling. Finally, we apply this knowledge to the optimization of medical therapy, with a focus on sleep hygiene and the role of chronopharmacology in patients with this disease. In dissecting the unique relationship between time and cellular biology, we aim to provide valuable insight into the practical implications of considering time as a therapeutic variable. Armed with this information, physicians will be positioned to more efficiently use the full four dimensions of patient care, resulting in improved morbidity and mortality of pulmonary hypertension patients.

Routine platelet transfusion in patients with traumatic intracranial hemorrhage taking antiplatelet medication: Is it warranted?

BACKGROUND: After a traumatic intracranial hemorrhage (tICH), patients often receive a platelet transfusion to reverse the effects of antiplatelet medication and to reduce neurologic complications. As platelet transfusions have their own risks, this study evaluated their effects on tICH progression, need for operations and mortality. METHODS: In this retrospective study, we identified patients admitted to a level 1 trauma centre with a tICH from 2011 to 2015 who were taking acetylsalicylic acid (ASA) or clopidogrel, or both. We categorized patients into 2 groups: platelet transfusion recipients and nonrecipients. We collected data on demographic characteristics, changes in brain computed tomography findings, neurosurgical interventions, in-hospital death and intensive care unit (ICU) length of stay (LOS). We used multivariable logistic regression to compare outcomes between the 2 groups. RESULTS: We identified 224 patients with tICH, 156 (69.6%) in the platelet transfusion group and 68 (30.4%) in the no transfusion group. There were no between-group differences in progression of bleeds or rates of neurosurgical interventions. In the transfusion recipients, there was a trend toward increased ICU LOS (adjusted odds ratio [OR] 1.59, 95% confidence interval [CI] 0.74-3.40) and in-hospital death (adjusted OR 3.23, 95% CI 0.48-21.74). CONCLUSION: There were no differences in outcomes between patients who received platelet transfusions and those who did not; however, the results suggest a worse clinical course, as indicated by greater ICU LOS and mortality, in the transfusion recipients. Routine platelet transfusion may not be warranted in patients taking ASA or clopidogrel who experience a tICH, as it may increase ICU LOS and mortality risk.

Binge alcohol disrupts skeletal muscle core molecular clock independent of glucocorticoids.

Circadian rhythms are central to optimal physiological function, as disruption contributes to the development of several chronic diseases. Alcohol (EtOH) intoxication disrupts circadian rhythms within liver, brain, and intestines, but it is unknown whether alcohol also disrupts components of the core clock in skeletal muscle. Female C57BL/6Hsd mice were randomized to receive either saline (control) or alcohol (EtOH) (5 g/kg) via intraperitoneal injection at the start of the dark cycle [Zeitgeber time (ZT12)], and gastrocnemius was collected every 4 h from control and EtOH-treated mice for the next 48 h following isoflurane anesthetization. In addition, metyrapone was administered before alcohol intoxication in separate mice to determine whether the alcohol-induced increase in serum corticosterone contributed to circadian gene regulation. Finally, synchronized C2C12 myotubes were treated with alcohol (100 mM) to assess the influence of centrally or peripherally mediated effects of alcohol on the muscle clock. Alcohol significantly disrupted mRNA expression of Bmal1, Per1/2, and Cry1/2 in addition to perturbing the circadian pattern of clock-controlled genes, Myod1, Dbp, Tef, and Bhlhe40 (P < 0.05), in muscle. Alcohol increased serum corticosterone levels and glucocorticoid target gene, Redd1, in muscle. Metyrapone prevented the EtOH-mediated increase in serum corticosterone but did not normalize the EtOH-induced change in Per1, Cry1 and Cry2, and Myod1 mRNA expression. Core clock gene expression (Bmal, Per1/2, and Cry1/2) was not changed following 4, 8, or 12 h of alcohol treatment on synchronized C2C12 myotubes. Therefore, binge alcohol disrupted genes of the core molecular clock independently of elevated serum corticosterone or direct effects of EtOH on the muscle.NEW & NOTEWORTHY Alcohol is a myotoxin that impairs skeletal muscle metabolism and function following either chronic consumption or acute binge drinking; however, mechanisms underlying alcohol-related myotoxicity have not been fully elucidated. Herein, we demonstrate that alcohol acutely interrupts oscillation of skeletal muscle core clock genes, and this is neither a direct effect of ethanol on the skeletal muscle, nor an effect of elevated serum corticosterone, a major clock regulator.

Time-of-day dependent effects of contractile activity on the phase of the skeletal muscle clock.

KEY POINTS: Disruptions in circadian rhythms across an organism are associated with negative health outcomes, such as cardiometabolic and neurodegenerative diseases. Exercise has been proposed as a time cue for the circadian clock in rodents and humans. In this study, we assessed the effect of a single bout of endurance exercise on the skeletal muscle clock in vivo and a bout of muscle contractions in vitro. Timing of exercise or contractions influences the directional response of the muscle clock phase in vivo and in vitro. Our findings demonstrate that muscle contractions, as a component of exercise, can directly modulate the expression of muscle clock components in a time-of-day dependent manner. ABSTRACT: Exercise has been proposed to be a zeitgeber for the muscle circadian clock mechanism. However, this is not well defined and it is unknown if exercise timing induces directional shifts of the muscle clock. Our purpose herein was to assess the effect of one bout of treadmill exercise on skeletal muscle clock phase changes. We subjected PERIOD2::LUCIFERASE mice (n = 30F) to one 60 min treadmill exercise bout at three times of day. Exercise at ZT5, 5 h after lights on, induced a phase advance (100.2 ± 25.8 min; P = 0.0002), whereas exercise at ZT11, 1 h before lights off, induced a phase delay (62.1 ± 21.1 min; P = 0.0003). Exercise at ZT17, middle of the dark phase, did not alter the muscle clock phase. Exercise induces diverse systemic changes so we developed an in vitro model system to examine the effects of contractile activity on muscle clock phase. Contractions applied at peak or trough Bmal1 expression induced significant phase delays (applied at peak: 27.2 ± 10.2 min; P = 0.0017; applied at trough: 64.6 ± 6.5 min, P < 0.0001). Contractions applied during the transition from peak to trough Bmal1 expression induced a phase advance (49.8 ± 23.1 min; P = 0.0051). Lastly, contractions at different times of day resulted in differential changes of core clock gene expression, demonstrating an exercise and clock interaction, providing insight into potential mechanisms of exercise-induced phase shifts. These data demonstrate that muscle contractions, as part of exercise, are sufficient to shift the muscle circadian clock phase, likely through changes in core clock gene expression. Additionally, our findings that exercise induces directional muscle clock phase changes confirms that exercise is a bona fide environmental time cue for skeletal muscle.

Relationship between intermuscular adipose tissue infiltration and myostatin before and after aerobic exercise training.

Intermuscular adipose tissue (IMAT) is associated with impaired skeletal muscle contractile and metabolic function. Myostatin and downstream signaling proteins such as cyclin-dependent kinase 2 (CDK2) contribute to the regulation of adipose and skeletal muscle mass in cell culture and animals models, but this relationship remains incompletely understood in humans. The purpose of this study was to determine if the infiltration of IMAT was associated with skeletal muscle myostatin and downstream proteins before and after 12 wk of aerobic exercise training (AET) in healthy older women (OW; 69 ± 2 yr), older men (OM; 74 ± 3 yr), and young men (YM; 20 ± 1 yr). We found that the infiltration of IMAT was correlated with myostatin and phosphorylated CDK2 at tyrosine 15 [P-CDK2(Tyr15)]. IMAT infiltration was greater in the older subjects and was associated with lower skeletal muscle function and exercise capacity. After 12 wk of AET, there was no change in body weight. Myostatin and P-CDK2(Tyr15) were both decreased after AET, and the reduction in myostatin was associated with decreased IMAT infiltration. The decrease in myostatin and IMAT occurred concomitantly with increased exercise capacity, skeletal muscle size, and function after AET. These findings demonstrate that the reduction in IMAT infiltration after AET in weight stable individuals was accompanied by improvements in skeletal muscle function and exercise capacity. Moreover, the association between myostatin and IMAT was present in the untrained state and in response to exercise training, strengthening the potential regulatory role of myostatin on IMAT.

Ultrastructural and Molecular Analysis of Ribose-Induced Glycated Reconstructed Human Skin.

Aging depicts one of the major challenges in pharmacology owing to its complexity and heterogeneity. Thereby, advanced glycated end-products modify extracellular matrix proteins, but the consequences on the skin barrier function remain heavily understudied. Herein, we utilized transmission electron microscopy for the ultrastructural analysis of ribose-induced glycated reconstructed human skin (RHS). Molecular and functional insights substantiated the ultrastructural characterization and proved the relevance of glycated RHS beyond skin aging. In particular, electron microscopy mapped the accumulation and altered spatial orientation of fibrils and filaments in the dermal compartment of glycated RHS. Moreover, the epidermal basement membrane appeared thicker in glycated than in non-glycated RHS, but electron microscopy identified longitudinal clusters of the finest collagen fibrils instead of real thickening. The stratum granulosum contained more cell layers, the morphology of keratohyalin granules decidedly differed, and the stratum corneum lipid order increased in ribose-induced glycated RHS, while the skin barrier function was almost not affected. In conclusion, dermal advanced glycated end-products markedly changed the epidermal morphology, underlining the importance of matrix⁻cell interactions. The phenotype of ribose-induced glycated RHS emulated aged skin in the dermis, while the two to three times increased thickness of the stratum granulosum resembled poorer cornification.

The role of older children and adults in wild poliovirus transmission.

As polio eradication inches closer, the absence of poliovirus circulation in most of the world and imperfect vaccination coverage are resulting in immunity gaps and polio outbreaks affecting adults. Furthermore, imperfect, waning intestinal immunity among older children and adults permits reinfection and poliovirus shedding, prompting calls to extend the age range of vaccination campaigns even in the absence of cases in these age groups. The success of such a strategy depends on the contribution to poliovirus transmission by older ages, which has not previously been estimated. We fit a mathematical model of poliovirus transmission to time series data from two large outbreaks that affected adults (Tajikistan 2010, Republic of Congo 2010) using maximum-likelihood estimation based on iterated particle-filtering methods. In Tajikistan, the contribution of unvaccinated older children and adults to transmission was minimal despite a significant number of cases in these age groups [reproduction number, R = 0.46 (95% confidence interval, 0.42-0.52) for >5-y-olds compared to 2.18 (2.06-2.45) for 0- to 5-y-olds]. In contrast, in the Republic of Congo, the contribution of older children and adults was significant [R = 1.85 (1.83-4.00)], perhaps reflecting sanitary and socioeconomic variables favoring efficient virus transmission. In neither setting was there evidence for a significant role of imperfect intestinal immunity in the transmission of poliovirus. Bringing the immunization response to the Tajikistan outbreak forward by 2 wk would have prevented an additional 130 cases (21%), highlighting the importance of early outbreak detection and response.

A Discussion on the Regulation of Blood Flow and Pressure.

This paper discusses two kinds of regulation essential to the circulatory system: namely the regulation of blood flow and that of (systemic) arterial blood pressure. It is pointed out that blood flow requirements sub-serve the nutritional needs of the tissues, adequately catered for by keeping blood flow sufficient for the individual oxygen needs. Individual tissue oxygen requirements vary between tissue types, while highly specific for a given individual tissue. Hence, blood flows are distributed between multiple tissues, each with a specific optimum relationship between the rate of oxygen delivery (DO2) and oxygen consumption (VO2). Previous work has illustrated that the individual tissue blood flows are adjusted proportionately, where there are variations in metabolic rate and where arterial oxygen content (CaO2) varies. While arterial blood pressure is essential for the provision of a sufficient pressure gradient to drive blood flow, it is applicable throughout the arterial system at any one time. Furthermore, It is regulated independently of the input resistance to individual tissues (local arterioles), since they are regulated locally, that being the means by which the highly specific adequate local requirement for DO2 is ensured. Since total blood flow is the summation of all the individually regulated tissue blood flows cardiac inflow (venous return) amounts to total tissue blood flow and as the heart puts out what it receives cardiac output is therefore determined at the tissues. Hence, regulation of arterial blood pressure is independent of the distributed independent regulation of individual tissues. It is proposed here that mechanical features of arterial blood pressure regulation will depend rather on the balance between blood volume and venous wall tension, determinants of venous pressure. The potential for this explanation is treated in some detail.

Progress toward laboratory containment of poliovirus after polio eradication.

BACKGROUND: The first steps (phase 1) toward laboratory containment of poliovirus after eradication are a national survey of biomedical facilities and a global inventory of such facilities retaining wild poliovirus (WPV) infectious and potentially infectious materials. METHODS: We reviewed published reports on national laboratory surveys and inventories of WPV materials from each of the 3 polio-free World Health Organization (WHO) regions (the European Region, completed in 2006; the Western Pacific Region, completed in 2008; and the Region of the Americas, completed in 2010), as well as reports on progress in polio-free countries of the remaining 3 regions (the African Region, the Eastern Mediterranean Region, and the WHO South-East Asia Region). RESULTS: Containment phase 1 activities are complete in 154 of 194 WHO Member States (79%), including all countries and areas of the polio-free regions and most polio-free countries in the remaining 3 regions. A reported 227 209 biomedical facilities were surveyed, with 532 facilities in 45 countries identified as retaining WPV-associated infectious or potentially infectious materials. CONCLUSIONS: Completion of containment phase 1 global activities is achievable within the time frame set by the Polio Eradication and Endgame Strategic Plan 2013-2018.

Skeletal muscle BMAL1 is necessary for transcriptional adaptation of local and peripheral tissues in response to endurance exercise training.

OBJECTIVE: In this investigation, we addressed the contribution of the core circadian clock factor, BMAL1, in skeletal muscle to both acute transcriptional responses to exercise and transcriptional remodeling in response to exercise training. Additionally, we adopted a systems biology approach to investigate how loss of skeletal muscle BMAL1 altered peripheral tissue homeostasis as well as exercise training adaptations in iWAT, liver, heart, and lung of male mice. METHODS: Combining inducible skeletal muscle specific BMAL1 knockout mice, physiological testing and standardized exercise protocols, we performed a multi-omic analysis (transcriptomics, chromatin accessibility and metabolomics) to explore loss of muscle BMAL1 on muscle and peripheral tissue responses to exercise. RESULTS: Muscle-specific BMAL1 knockout mice demonstrated a blunted transcriptional response to acute exercise, characterized by the lack of upregulation of well-established exercise responsive transcription factors including Nr4a3 and Ppargc1a. Six weeks of exercise training in muscle-specific BMAL1 knockout mice induced significantly greater and divergent transcriptomic and metabolomic changes in muscle. Surprisingly, liver, lung, inguinal white adipose and heart showed divergent exercise training transcriptomes with less than 5% of 'exercise-training' responsive genes shared for each tissue between genotypes. CONCLUSIONS: Our investigation has uncovered the critical role that BMAL1 plays in skeletal muscle as a key regulator of gene expression programs for both acute exercise and training adaptations. In addition, our work has uncovered the significant impact that altered exercise response in muscle and its likely impact on the system plays in the peripheral tissue adaptations to exercise training. Our work also demonstrates that if the muscle adaptations diverge to a more maladaptive state this is linked to increased gene expression signatures of inflammation across many tissues. Understanding the molecular targets and pathways contributing to health vs. maladaptive exercise adaptations will be critical for the next stage of therapeutic design for exercise mimetics.

Autophagy gene expression in skeletal muscle of older individuals is associated with physical performance, muscle volume and mitochondrial function in the study of muscle, mobility and aging (SOMMA).

Autophagy is essential for proteostasis, energetic balance, and cell defense and is a key pathway in aging. Identifying associations between autophagy gene expression patterns in skeletal muscle and physical performance outcomes would further our knowledge of mechanisms related with proteostasis and healthy aging. Muscle biopsies were obtained from participants in the Study of Muscle, Mobility, and Aging (SOMMA). For 575 participants, RNA was sequenced and expression of 281 genes related to autophagy regulation, mitophagy, and mTOR/upstream pathways was determined. Associations between gene expression and outcomes including mitochondrial respiration in muscle fiber bundles (MAX OXPHOS), physical performance (VO2 peak, 400 m walking speed, and leg power), and thigh muscle volume, were determined using negative binomial regression models. For autophagy, key transcriptional regulators including TFE3 and NFKB-related genes (RELA, RELB, and NFKB1) were negatively associated with outcomes. On the contrary, regulators of oxidative metabolism that also promote overall autophagy, mitophagy, and pexophagy (PPARGC1A, PPARA, and EPAS1) were positively associated with multiple outcomes. In line with this, several mitophagy, fusion, and fission-related genes (NIPSNAP2, DNM1L, and OPA1) were also positively associated with outcomes. For mTOR pathway and related genes, expression of WDR59 and WDR24, both subunits of GATOR2 complex (an indirect inhibitor of mTORC1), and PRKAG3, which is a regulatory subunit of AMPK, were negatively correlated with multiple outcomes. Our study identifies autophagy and selective autophagy such as mitophagy gene expression patterns in human skeletal muscle related to physical performance, muscle volume, and mitochondrial function in older persons which may lead to target identification to preserve mobility and independence.

Expression of mitochondrial oxidative stress response genes in muscle is associated with mitochondrial respiration, physical performance, and muscle mass in the Study of Muscle, Mobility, and Aging.

Gene expression in skeletal muscle of older individuals may reflect compensatory adaptations in response to oxidative damage that preserve tissue integrity and maintain function. Identifying associations between oxidative stress response gene expression patterns and mitochondrial function, physical performance, and muscle mass in older individuals would further our knowledge of mechanisms related to managing molecular damage that may be targeted to preserve physical resilience. To characterize expression patterns of genes responsible for the oxidative stress response, RNA was extracted and sequenced from skeletal muscle biopsies collected from 575 participants (≥70 years old) from the Study of Muscle, Mobility, and Aging. Expression levels of 21 protein-coding RNAs related to the oxidative stress response were analyzed in relation to six phenotypic measures, including maximal mitochondrial respiration from muscle biopsies (Max OXPHOS), physical performance (VO2 peak, 400-m walking speed, and leg strength), and muscle size (thigh muscle volume and whole-body D3Cr muscle mass). The mRNA level of the oxidative stress response genes most consistently associated across outcomes are preferentially expressed within the mitochondria. Higher expression of mRNAs that encode generally mitochondria located proteins SOD2, TRX2, PRX3, PRX5, and GRX2 were associated with higher levels of mitochondrial respiration and VO2 peak. In addition, greater SOD2, PRX3, and GRX2 expression was associated with higher physical performance and muscle size. Identifying specific mechanisms associated with high functioning across multiple performance and physical domains may lead to targeted antioxidant interventions with greater impacts on mobility and independence.

Higher expression of denervation-responsive genes is negatively associated with muscle volume and performance traits in the study of muscle, mobility, and aging (SOMMA).

With aging skeletal muscle fibers undergo repeating cycles of denervation and reinnervation. In approximately the 8th decade of life reinnervation no longer keeps pace, resulting in the accumulation of persistently denervated muscle fibers that in turn cause an acceleration of muscle dysfunction. The significance of denervation in important clinical outcomes with aging is poorly studied. The Study of Muscle, Mobility, and Aging (SOMMA) is a large cohort study with the primary objective to assess how aging muscle biology impacts clinically important traits. Using transcriptomics data from vastus lateralis muscle biopsies in 575 participants we have selected 49 denervation-responsive genes to provide insights to the burden of denervation in SOMMA, to test the hypothesis that greater expression of denervation-responsive genes negatively associates with SOMMA participant traits that included time to walk 400 meters, fitness (VO2peak), maximal mitochondrial respiration, muscle mass and volume, and leg muscle strength and power. Consistent with our hypothesis, increased transcript levels of: a calciumdependent intercellular adhesion glycoprotein (CDH15), acetylcholine receptor subunits (CHRNA1, CHRND, CHRNE), a glycoprotein promoting reinnervation (NCAM1), a transcription factor regulating aspects of muscle organization (RUNX1), and a sodium channel (SCN5A) were each negatively associated with at least 3 of these traits. VO2peak and maximal respiration had the strongest negative associations with 15 and 19 denervation-responsive genes, respectively. In conclusion, the abundance of denervationresponsive gene transcripts is a significant determinant of muscle and mobility outcomes in aging humans, supporting the imperative to identify new treatment strategies to restore innervation in advanced age.

Oxygen delivery: the principal role of the circulation.

Autoregulation of blood flow to most individual organs is well known. The balance of oxygen supply relative to the rate of oxygen consumption ensures normal function. There is less reserve as regards oxygen supply than for any other necessary metabolite or waste product so oxygen supply is flow dependent. Reduced rate of supply compromises tissue oxygenation long before any other substance. The present report reiterates evidence from earlier studies demonstrating that the rate of oxygen delivery (DO2), for most individual tissues, is well sustained at a value bearing a ratio to oxygen consumption (VO2) which is specific for the organ concerned. For the brain DO2 is sustained at approximately three times the rate of oxygen consumption and for exercising skeletal muscle (below the anaerobic threshold), a ratio close to 1.5. The tissue-specific ratios are sustained in the face of alterations in local VO2 and lowered arterial oxygen content (CaO2). Tolerance varies between different organs. Hence, the role of the circulation is predominantly one of ensuring an adequate supply of oxygen. The precise values of the individual tissue DO2:VO2 ratios apply within physiological ranges which require further investigation.

Oxygen delivery deficit in exercise with rapid ascent to high altitude.

This study of high altitude physiology was undertaken during an 11-day expedition to the Himalaya with ascent to Annapurna base camp (4,130 m) reaching it on the sixth day. Fourteen male UK residents (13 aged 16-17 years; 1 adult) measured arterial oxygen saturation (SaO(2)) and heart rate (HR) at rest and at 2 min exercise (30 cm step), daily, after arrival at each altitude. Precision was limited by availability of only one oximeter (CMS50-DLP model, Contec Medical Systems, Qinhuangdao, P.R. China). Mean HR correlated (negatively) with SaO(2) both for rest (HR = -1.7974 × SaO(2)% + 236.33, r = 0.841, p = 0.001) and exercise (HR = -0.8834 × SaO(2)% + 226.14, r = 0.711 p < 0.02). Four subjects individually showed significant HR/SaO(2) correlations at rest (nos. 10, 11, 12 and 13) and one, subject 11, in exercise. SaO2 in exercise was lower than at rest (SaO(2), exercise = 1.5835 × SaO(2), rest - 59.177, r = 0.987, p < 0.001). The product, HR × SaO(2), calculated as a surrogate for oxygen delivery (DO(2), Brierley et al., Adv Exp Med Biol 737:207-212, 2012), from mean values was approximately constant for rest, suggesting good cardiac output (CO) compensation for de-saturation. The HR × SaO(2) for exercise, however, showed a dramatic fall at the highest altitude. Since this deficit occurred at the highest altitude, following 2 days of rapid ascent, there was probably impairment of adequate oxygen delivery (DO(2)) at this point. Correlation, HR versus SaO(2) for exercise, was highly significant, with greater significance (HR = -1.798 × SaO(2) + 281.83, r = 0.769, p = 0.01) on omission of the values for the highest ascent point (4,130 m), where the reduced HR × SaO(2) occurred. In conclusion, oxygen delivery is sustained well here except where there are the extra stresses of rapid ascent and exercise.

Early morning run-training results in enhanced endurance performance adaptations in mice.

Time-of-day differences in acute exercise performance in mice are well established with late active phase (afternoon) runners exhibiting significantly greater endurance performance compared to early active phase (morning) runners. In this study, we asked if performance adaptations would be different when training for 6 weeks at two different times of day, and if this corresponds to steady state changes in the phase of peripheral tissue clocks. To address these questions, we endurance trained female PER2::Luciferase mice, at the same relative workload, either in the morning, at ZT13, or in the afternoon, at ZT22. Then, after training, we recorded luminescence from tissues of PER2::Luciferase mice to report timing of tissue clocks in several peripheral tissues. After 6 weeks, we found that both groups exhibited significant improvements in maximal endurance capacity (total treadmill work)(p < 0.0001), but the morning runners exhibited an enhanced rate of adaptation as there was no detectable difference in maximal endurance capacity (p = 0.2182) between the morning and afternoon runners. In addition, morning and afternoon runners exhibited divergent clock phase shifts with a significant 5-hour phase advance in the EDL (p < 0.0001) and soleus (p < 0.0001) of morning runners, but a phase delay in the EDL (p < 0.0001) and Soleus (p < 0.0001) of afternoon runners. Therefore, our data demonstrate that morning training enhances endurance adaptations compared to afternoon training in mice, and we suggest this is due to phase advancement of muscle clocks to better align metabolism with exercise performance.

Defining the age-dependent and tissue-specific circadian transcriptome in male mice.

Cellular circadian clocks direct a daily transcriptional program that supports homeostasis and resilience. Emerging evidence has demonstrated age-associated changes in circadian functions. To define age-dependent changes at the systems level, we profile the circadian transcriptome in the hypothalamus, lung, heart, kidney, skeletal muscle, and adrenal gland in three age groups. We find age-dependent and tissue-specific clock output changes. Aging reduces the number of rhythmically expressed genes (REGs), indicative of weakened circadian control. REGs are enriched for the hallmarks of aging, adding another dimension to our understanding of aging. Analyzing differential gene expression within a tissue at four different times of day identifies distinct clusters of differentially expressed genes (DEGs). Increased variability of gene expression across the day is a common feature of aged tissues. This analysis extends the landscape for understanding aging and highlights the impact of aging on circadian clock function and temporal changes in gene expression.