Circadian Rhythms in Sudden Cardiac Arrest: A Review.

BACKGROUND: Sudden cardiac arrest (SCA) is a serious public health issue caused by the cessation of cardiac electrical and mechanical activity. Despite advances in pedestrian lifesaving technologies like defibrillators, the SCA mortality rate remains high, and survivors are at risk of suffering ischemic injury to various organs. Understanding the contributing factors for SCA is essential for improving morbidity and mortality. One factor capable of influencing SCA incidence and survival is the time of day at which SCA occurs. OBJECTIVES: This review focused on the effect of time of day on SCA incidence, survival rate, and survival to discharge over the past 30 years and the role of age, sex, and SCA location in modulating the timing of SCA. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews criteria guided this review. Four databases (PubMed, Cochrane Libraries, Scopus, and Cumulative Index to Nursing and Allied Health Literature) were queried for research reports or articles addressing time of day and cardiac arrest, which were subsequently screened by the authors for inclusion in this analysis. RESULTS: A total of 48 articles were included in the final analysis. This analysis showed a bimodal SCA distribution with a primary peak in the morning and a secondary peak in the afternoon; these peaks were dependent on age (older persons), sex (more frequent in males), and the location of occurrence (out-of-hospital cardiac arrest vs. in-hospital cardiac rest). Survival following SCA was lowest between midnight and 06:00 a.m. DISCUSSION: The circadian rhythm likely plays an important role in the time-of-day-dependent pattern that is evident in both the incidence of and survival following SCA. There is a renewed call for nursing research to examine or address circadian rhythm as an element in studies involving older adults and activities affecting cardiovascular or respiratory parameters.

Genetic disruption of the cardiomyocyte circadian clock differentially influences insulin-mediated processes in the heart.

Cardiovascular physiology exhibits time-of-day-dependent oscillations, which are mediated by both extrinsic (e.g., environment/behavior) and intrinsic (e.g., circadian clock) factors. Disruption of circadian rhythms negatively affects multiple cardiometabolic parameters. Recent studies suggest that the cardiomyocyte circadian clock directly modulates responsiveness of the heart to metabolic stimuli (e.g., fatty acids) and stresses (e.g., ischemia/reperfusion). The aim of this study was to determine whether genetic disruption of the cardiomyocyte circadian clock impacts insulin-regulated pathways in the heart. Genetic disruption of the circadian clock in cardiomyocyte-specific Bmal1 knockout (CBK) and cardiomyocyte-specific Clock mutant (CCM) mice altered expression (gene and protein) of multiple insulin signaling components in the heart, including p85α and Akt. Both baseline and insulin-mediated Akt activation was augmented in CBK and CCM hearts (relative to littermate controls). However, insulin-mediated glucose utilization (both oxidative and non-oxidative) and AS160 phosphorylation were attenuated in CBK hearts, potentially secondary to decreased Inhibitor-1. Consistent with increased Akt activation in CBK hearts, mTOR signaling was persistently increased, which was associated with attenuation of autophagy, augmented rates of protein synthesis, and hypertrophy. Importantly, pharmacological inhibition of mTOR (rapamycin; 10days) normalized cardiac size in CBK mice. These data suggest that disruption of cardiomyocyte circadian clock differentially influences insulin-regulated processes, and provide new insights into potential pathologic mediators following circadian disruption.

Biotinylation: a novel posttranslational modification linking cell autonomous circadian clocks with metabolism.

Circadian clocks are critical modulators of metabolism. However, mechanistic links between cell autonomous clocks and metabolic processes remain largely unknown. Here, we report that expression of the biotin transporter slc5a6 gene is decreased in hearts of two distinct genetic mouse models of cardiomyocyte-specific circadian clock disruption [i.e., cardiomyocyte-specific CLOCK mutant (CCM) and cardiomyocyte-specific BMAL1 knockout (CBK) mice]. Biotinylation is an obligate posttranslational modification for five mammalian carboxylases: acetyl-CoA carboxylase α (ACCα), ACCß, pyruvate carboxylase (PC), methylcrotonyl-CoA carboxylase (MCC), and propionyl-CoA carboxylase (PCC). We therefore hypothesized that the cardiomyocyte circadian clock impacts metabolism through biotinylation. Consistent with decreased slc5a6 expression, biotinylation of all carboxylases is significantly decreased (10-46%) in CCM and CBK hearts. In association with decreased biotinylated ACC, oleate oxidation rates are increased in both CCM and CBK hearts. Consistent with decreased biotinylated MCC, leucine oxidation rates are significantly decreased in both CCM and CBK hearts, whereas rates of protein synthesis are increased. Importantly, feeding CBK mice with a biotin-enriched diet for 6 wk normalized myocardial 1) ACC biotinylation and oleate oxidation rates; 2) PCC/MCC biotinylation (and partially restored leucine oxidation rates); and 3) net protein synthesis rates. Furthermore, data suggest that the RRAGD/mTOR/4E-BP1 signaling axis is chronically activated in CBK and CCM hearts. Finally we report that the hepatocyte circadian clock also regulates both slc5a6 expression and protein biotinylation in the liver. Collectively, these findings suggest that biotinylation is a novel mechanism by which cell autonomous circadian clocks influence metabolic pathways.

Involvement of the δ-opioid receptor in exercise-induced cardioprotection.

NEW FINDINGS: What is the central question of this study? Does the δ-opioid receptor trigger exercise-induced cardioprotection against ischaemia-reperfusion injury? What is the main finding and its importance? In exercised hearts, the δ-opioid receptor appears to trigger cardioprotection against ischaemia-reperfusion-induced tissue necrosis but not apoptosis. ABSTRACT: Endogenous opioids mediate exercise-induced cardioprotection against ischaemia-reperfusion (IR) injury, although the opioid receptor subtype mediating this effect is unknown. We investigated whether the δ-opioid receptor mediates exercise-induced cardioprotection against IR injury. Endogenous opioids are produced in various tissues, including the heart and skeletal muscle; therefore, we also sought to identify the effect of exercise on circulating endogenous opioid as well as transcript, protein and receptor expression in heart and skeletal muscle. Male Sprague-Dawley rats (n = 73) were assigned randomly to treadmill exercise or sedentary treatments. Cardiac tissue and serum were harvested 0, 20 and 120 min following exercise and from sedentary animals (n = 32) to quantify effects on proenkephalin and δ-opioid receptor mRNA and protein levels, as well as serum enkephalin. Skeletal muscle (soleus) was harvested at identical time points for determination of proenkephalin protein and mRNA. A separate group of rats (n = 41) were randomly assigned to sham operation (Sham; surgical control), sedentary (Sed), exercise (Ex) or exercise + Î´-opioid receptor antagonist (ExD; naltrindole, 5 mg kg(-1) i.p.) and received IR by left anterior descending coronary artery ligation in vivo. After IR, tissues were harvested to quantify treatment effects on necrosis and apoptosis. Cardiac proenkephalin mRNA expression increased following exercise (0 min, P = 0.03; 120 min, P = 0.021), while soleus expression was unaffected. Exercise-induced changes in serum enkephalin were undetectable. After IR, tissue necrosis was elevated in Sed and ExD hearts (P < 0.001 and P = 0.003, respectively) compared with the Sham group, while the Ex group was partly protected. After IR, apoptosis was evident in Sed hearts (P = 0.016), while Ex and ExD hearts were protected. Data suggest that cardioprotective opioids are produced by the heart, but not by the soleus. After IR, the δ-opioid receptor may mediate, in part, cardioprotection against necrosis but not apoptosis.

Exercise in a natural environment increases program compliance in people with chronic migraine: A pilot cross-over randomized trial.

Adverse side effects from pharmacological treatments cause people with migraine to delay or avoid taking medication. Exercise is effective, but the effect of environment is unknown. The purpose was to determine if a natural environment affects monthly migraine load. Sedentary individuals (8 female, 1 non-binary) who experienced migraines participated. Participants completed one month of exercise (3 x week, 30-min, 60-70% estimated HRmax) indoors as well as in a natural outdoor environment in a randomized counterbalanced order. Migraine load was determined using the Headache Impact Test (HIT-6) and Migraine Disability Assessment (MIDAS) at the beginning and end of each month. Data were analyzed using repeated measures ANOVA. No interactions were evident for HIT-6 (p = 0.80), MIDAS (p = 0.72), migraine days (p = 0.508), or pain intensity (p = 0.66). No main effects were noted. Compliance was greater in the outdoor environment, with more exercise sessions completed in nature (Indoor = 72%, Outdoor = 90%, p < 0.001). Exercise environment did not impact MIDAS or HIT-6 questionnaire results, number of migraine days, or pain intensity. While there was no reduction in migraine load, it is possible that other health benefits were experienced due to greater compliance in a natural environment.

Effects of Acute Sleep Deprivation on the Physiological Response to Woodsmoke and Exercise.

OBJECTIVE: To evaluate sleep deprivation effects on the acute physiological response to a combined stressor of woodsmoke and exercise. METHODS: Ten participants completed two exercise trials (8 hours of sleep vs 4 hours) with woodsmoke. Trials were conducted in a crossover design. Key measures examined before and after each trial included heart rate variability, pulse wave velocity, blood pressure, pulmonary function testing, and oxidative stress. RESULTS: Acute sleep deprivation experienced before exercise and woodsmoke exposure did not impact metrics of heart rate variability, pulse wave velocity, pulmonary function testing, blood pressure, or oxidative stress. CONCLUSIONS: Acute sleep deprivation did not amplify physiologic metrics in response to moderate-intensity aerobic exercise with inhaled woodsmoke. Although findings do not eliminate the negative impacts of inhaling woodsmoke, more research is needed to understand the acute effects of woodsmoke exposure on the cardiovascular system. 1.

Social jet lag impairs exercise volume and attenuates physiological and metabolic adaptations to voluntary exercise training.

Social jet lag (SJL) is a misalignment between sleep and wake times on workdays and free days. SJL leads to chronic circadian rhythm disruption and may affect nearly 70% of the general population, leading to increased risk for cardiometabolic diseases. This study investigated the effects of SJL on metabolic health, exercise performance, and exercise-induced skeletal muscle adaptations in mice. Ten-week-old C57BL/6J mice (n = 40) were allocated to four groups: control sedentary (CON-SED), control exercise (CON-EX), social jet lag sedentary (SJL-SED), and social jet lag exercise (SJL-EX). CON mice were housed under a 12:12-h light-dark cycle. SJL was simulated by implementing a 4-h phase delay for 3 days to simulate "weekends," followed by a 4-h phase advance back to "weekdays," for 6 wk. EX mice had free access to a running wheel. Graded exercise tests (GXTs) and glucose tolerance tests (GTTs) were performed at baseline and after intervention to monitor the effects of exercise and social jet lag on cardiorespiratory and metabolic health, respectively. SJL led to alterations in activity and running patterns and clock gene expression in skeletal muscle and decreased average running distance (P < 0.05). SJL-SED mice gained significantly more weight compared with CON-SED and SJL-EX mice (P < 0.01). SJL impaired fasting blood glucose and glucose tolerance compared with CON mice (P < 0.05), which was partially restored by exercise in SJL-EX mice. SJL also blunted improvements in exercise performance and mitochondrial content in the quadriceps. These data suggest that SJL blunted some cardiometabolic adaptations to exercise and that proper circadian hygiene is necessary for maintaining health and performance.NEW & NOTEWORTHY In mice, disrupting circadian rhythms with social jet lag for 6 wk caused significant weight gain, higher fasting blood glucose, and impaired glucose tolerance compared with control. Voluntary exercise in mice experiencing social jet lag prevented weight gain, though the mice still experienced increased fasting blood glucose and impaired exercise performance compared with trained mice not experiencing social jet lag. Social jet lag seems to be a potent circadian rhythm disruptor that impacts exercise-induced training adaptations.

Effects of time-restricted exercise on activity rhythms and exercise-induced adaptations in the heart.

Circadian rhythms play a crucial role in the regulation of various physiological processes, including cardiovascular function and metabolism. Exercise provokes numerous beneficial adaptations in heart, including physiological hypertrophy, and serves to shift circadian rhythms. This study investigated the impact of time-restricted exercise training on exercise-induced adaptations in the heart and locomotor activity rhythms. Male mice (n = 45) were allocated to perform voluntary, time-restricted exercise in the early active phase (EAP), late active phase (LAP), or remain sedentary (SED) for 6 weeks. Subsequently, mice were allowed 24-h ad libitum access to the running wheel to assess diurnal rhythms in locomotor activity. Heart weight and cross-sectional area were measured at sacrifice, and cardiac protein and gene expression levels were assessed for markers of mitochondrial abundance and circadian clock gene expression. Mice rapidly adapted to wheel running, with EAP mice exhibiting a significantly greater running distance compared to LAP mice. Time-restricted exercise induced a shift in voluntary wheel activity during the 24-h free access period, with the acrophase in activity being significantly earlier in EAP mice compared to LAP mice. Gene expression analysis revealed a higher expression of Per1 in LAP mice. EAP exercise elicited greater cardiac hypertrophy compared to LAP exercise. These findings suggest that the timing of exercise affects myocardial adaptations, with exercise in the early active phase inducing hypertrophy in the heart. Understanding the time-of-day dependent response to exercise in the heart may have implications for optimizing exercise interventions for cardiovascular health.

Blood oxidative-stress markers during a high-altitude trek.

UNLABELLED: Oxidative stress occurs as a result of altitude-induced hypobaric hypoxia and physical exercise. The effect of exercise on oxidative stress under hypobaric hypoxia is not well understood. PURPOSE: To determine the effect of high-altitude exercise on blood oxidative stress. Nine male participants completed a 2-d trek up and down Mt Rainer, in North America, at a peak altitude of 4,393 m. Day 1 consisted of steady-pace climbing for 6.25 hr to a final elevation of 3,000 m. The 4,393-m summit was reached on Day 2 in approximately 5 hr. Climb-rest intervals varied but were consistent between participants, with approximately 14 hr of total time including rest periods. Blood samples were assayed for biomarkers of oxidative stress and antioxidant potential at the following time points: Pre (before the trek), 3Kup (at ascent to 3,000 m), 3Kdown (at 3,000 m on the descent), and Post (posttrek at base elevation). Blood serum variables included ferric-reducing antioxidant potential (FRAP), Trolox equivalent antioxidant capacity (TEAC), protein carbonyls (PC), and lipid hydroperoxides. Serum FRAP was elevated at 3Kup and 3Kdown compared with Pre and Post values (p = .004, 8% and 11% increase from Pre). Serum TEAC values were increased at 3Kdown and Post (p = .032, 10% and 18% increase from Pre). Serum PC were elevated at 3Kup and 3Kdown time points (p = .034, 194% and 138% increase from Pre), while lipid hydroperoxides were elevated Post only (p = .004, 257% increase from Pre). CONCLUSIONS: Findings indicate that high-altitude trekking is associated with increased blood oxidative stress.

Time of Day and Chronotype-Dependent Synchrony Effects Exercise-Induced Reduction in Migraine Load: A Pilot Cross-Over Randomized Trial.

Migraines are the most common cause of chronic pain. Effective, non-pharmacological strategies to reduce migraine load, like exercise, are needed, but it is unclear how exercise timing and chronotype modulate the effects. We sought to determine the effects of time-of-day of exercise, and synchrony with one's chronotype, on migraine load. We performed a pilot cross-over randomized trial where participants with chronic migraine completed two one-month exercise interventions, consisting of either morning exercise (before 09:00 a.m.) or evening exercise (after 7:00 p.m.) in a randomized repeated measures cross-over design (Clinical Trial #NCT04553445). Synchrony was determined by exercise time and chronotype (i.e., a morning type participant exercising in the morning is 'in-sync,' while an evening type participant exercising in the morning is 'out-of-sync'). Migraine burden, and anthropometric assessment occurred before and after each month of exercise. Data was analyzed using repeated measures ANOVA with significance accepted at p < 0.05. When comparing morning and evening exercise, there was no significant improvements in any migraine-related parameters. However, when comparing in-sync and out-of-sync exercise, we found that migraine burden was only improved following in-sync exercise, while no benefits were seen in out-of-sync exercise. Our data suggests that exercise timing has limited impact, but synchrony with chronotype may be essential to decrease migraine load in chronic migraineurs.

Assessing the Validity of Several Heart Rate Monitors in Wearable Technology While Mountain Biking.

Purpose: This study sought to assess the validity of several heart rate (HR) monitors in wearable technology during mountain biking (MTB), compared to the Polar H7® HR monitor, used as the criterion device. Methods: A total of 20 participants completed two MTB trials while wearing six HR monitors (5 test devices, 1 criterion). HR was recorded on a second-by-second basis for all devices analyzed. After data processing, validity measures were calculated, including 1. error analysis: mean absolute percentage errors (MAPE), mean absolute error (MAE), and mean error (ME), and 2. Correlation analysis: Lin's concordance correlation coefficient (CCC) and Pearson's correlation coefficient (r). Thresholds for validity were set at MAPE < 10% and CCC > 0.7. Results: The only device that was found to be valid during mountain biking was the Suunto Spartan Sport watch with accompanying HR monitor, with a MAPE of 0.66% and a CCC of 0.99 for the overall, combined data. Conclusion: If a person would like to track their HR during mountain biking, for pacing, training, or other reasons, the devices best able to produce valid results are chest-based, wireless electrocardiogram (ECG) monitors, secured by elastic straps to minimize the movement of the device, such as the Suunto chest-based HR monitor.

Chronotype and Social Jetlag Influence Performance and Injury during Reserve Officers' Training Corps Physical Training.

Sleep and circadian rhythms are critically important for optimal physical performance and maintaining health during training. Chronotype and altered sleep may modulate the response to exercise training, especially when performed at specific times/days, which may contribute to musculoskeletal injury. The purpose of this study was to determine if cadet characteristics (chronotype, sleep duration, and social jetlag) were associated with injury incidence and inflammation during physical training. Reserve Officers' Training Corps (ROTC) cadets (n = 42) completed the Morningness/Eveningness Questionnaire to determine chronotype, and 1-week sleep logs to determine sleep duration and social jetlag. Salivary IL-6 was measured before and after the first and fourth exercise sessions during training. Prospective injury incidence was monitored over 14 weeks of training, and Army Physical Fitness Test scores were recorded at the conclusion. Chronotype, sleep duration, and social jetlag were assessed as independent factors impacting IL-6, injury incidence, and APFT scores using ANOVAs, chi-squared tests, and the t-test where appropriate, with significance accepted at p < 0.05. Evening chronotypes performed worse on the APFT (evening = 103.8 ± 59.8 vs. intermediate = 221.9 ± 40.3 vs. morning = 216.6 ± 43.6; p < 0.05), with no difference in injury incidence. Sleep duration did not significantly impact APFT score or injury incidence. Social jetlag was significantly higher in injured vs. uninjured cadets (2:40 ± 1:03 vs. 1:32 ± 55, p < 0.05). Exercise increased salivary IL-6, with no significant effects of chronotype, sleep duration, or social jetlag. Evening chronotypes and cadets with social jetlag display hampered performance during morning APFT. Social jetlag may be a behavioral biomarker for musculoskeletal injury risk, which requires further investigation.

Impact of Nutrition-Based Interventions on Athletic Performance during Menstrual Cycle Phases: A Review.

Despite the steady increase in female participation in sport over the last two decades, comprehensive research on interventions attenuating the influence of female menstrual physiology on performance remains scarce. Studies involving eumenorrheic women often only test in one menstrual phase to limit sex hormone variance, which may restrict the application of these findings to the rest of the menstrual cycle. The impacts of nutrition-based interventions on athletic performance throughout the menstrual cycle have not been fully elucidated. We addressed this gap by conducting a focused critical review of clinical studies that reported athletic outcomes as well as menstrual status for healthy eumenorrheic female participants. In total, 1443 articles were identified, and 23 articles were included. These articles were published between 2011 and 2021, and were retrieved from Google Scholar, Medline, and PubMed. Our literature search revealed that hydration-, micronutrient-, and phytochemical-based interventions can improve athletic performance (measured by aerobic capacity, anaerobic power, and strength performance) or attenuate exercise-induced damage (measured by dehydration biomarkers, muscle soreness, and bone resorption biomarkers). Most performance trials, however, only assessed these interventions in one menstrual phase, limiting the application throughout the entire menstrual cycle. Improvements in athletic performance through nutrition-based interventions may be contingent upon female sex hormone variation in eumenorrheic women.

Effects of Acute Beta-Alanine Ingestion and Immersion-Plus-Exercise on Connectedness to Nature and Perceived Pain.

This double-blinded, placebo-controlled, crossover study examined the effect of induced painful sensation (via acute Beta Alanine (B-ALA) ingestion) on Love and Care of Nature (LCN), heart rate (HR), rating of perceived exertion (RPE), and McGill Pain Questionnaire (MPQ) during outdoor exercise. Twenty participants volunteered on consecutive days to complete a 0.8 km (0.5 mi) up-hill hike after consuming either B-ALA (6.4 g) or placebo. Immediately after consumption participants answered LCN, RPE, and MPQ questionnaires, immersed in a natural environment for 45 min, and then completed a hike as quickly as possible without running. No difference in HR (p = 0.846), or RPE (p = 0.606) were observed between treatments. Total MPQ scores increased with consumption of B-ALA (p = 0.001). An increased LCN score was observed following exercise regardless of condition (p = 0.035). The results demonstrate that acute B-ALA supplementation is effective in increasing perceived pain sensations. The results also demonstrate an increase in LCN in the presence of increased perceptions of pain sensations during exercise.

Validity and Reliability of Three Commercially Available Smart Sports Bras during Treadmill Walking and Running.

A variety of wearable technology devices report heart rate. Heart rate sensing smart bras are manufactured for females who participate in activity, however accuracy has not been determined. The purpose was to determine the validity of heart rate measures in three commercially available sports bras during walking and running. Twenty-four healthy females completed bouts of treadmill exercise. The Adidas Smart sports bra, Berlei sports bra, and Sensoria Fitness biometric sports bra were tested. Participant perception of each garment was obtained immediately after the participant divested the sports bra. The Adidas Smart sports bra was valid only during rest (Intraclass correlation Coefficient [ICC] = 0.79, mean absolute percentage error [MAPE] = 4.5%, Limits of Agreement [LoA]=-8 to 8). The Berlei sports bra was valid across all conditions (ICC = 0.99, MAPE = 0.66%, LoA = -19 to 19), and the Sensoria biometric bra was valid during rest and walking (ICC = 0.96, MAPE = 1.9%, LoA = -15 to 12). Perception of the smart sports bras was higher for the Adidas Smart sports bra and Sensoria Fitness sports bra, and lower for the Berlei sports bra. Sports bra manufacturers designing wearable technology garments must consider the ability of returning accurate biometric data while providing necessary function and comfort to females engaging in physical activity.

Effects of Acute Dietary Polyphenols and Post-Meal Physical Activity on Postprandial Metabolism in Adults with Features of the Metabolic Syndrome.

Approximately 22% of U.S. adults and 25% of adults globally have metabolic syndrome (MetS). Key features, such as dysglycemia and dyslipidemia, predict type 2 diabetes, cardiovascular disease, premature disability, and death. Acute supplementation of dietary polyphenols and post-meal physical activity hold promise in improving postprandial dysmetabolism. To our knowledge, no published review has described the effects of either intervention on postprandial glucose, insulin, lipids, and markers of oxidative damage and inflammation in adults with features of MetS. Thus, we conducted this review of controlled clinical trials that provided dietary polyphenols from oils, fruits, teas, and legumes during a dietary challenge, or implemented walking, cycling, and stair climbing and descending after a dietary challenge. Clinical trials were identified using ClinicalTrials.gov, PubMed, and Google Scholar and were published between 2000 and 2019. Dietary polyphenols from extra virgin olive oil, grapes, blackcurrants, strawberries, black tea, and black beans improved postprandial glucose, insulin, and markers of oxidative damage and inflammation, but results were not consistent among clinical trials. Freeze-dried strawberry powder distinctly improved postprandial insulin and markers of oxidative damage and inflammation. Post-meal physical activity attenuated postprandial glucose, but effects on postprandial lipids and markers of oxidative damage and inflammation were inconclusive. Consuming dietary polyphenols with a meal and completing physical activity after a meal may mitigate postprandial dysmetabolism in adults with features of MetS.

Diurnal, metabolic and thermogenic alterations in a murine model of accelerated aging.

Senescence-Accelerated Mouse-Prone 8 (SAMP8) mice exhibit characteristics of premature aging, including hair loss, cognitive dysfunction, reduced physical activity, impaired metabolic homeostasis, cardiac dysfunction and reduced lifespan. Interestingly, circadian disruption can induce or augment many of these same pathologies. Moreover, previous studies have reported that SAMP8 mice exhibit abnormalities in circadian wheel-running behavior, indicating possible alterations in circadian clock function. These observations led to the hypothesis that 24 h rhythms in behavior and/or circadian clock function are altered in SAMP8 mice and that these alterations may contribute to perturbations in whole-body metabolism. Here, we report that 6-month-old SAMP8 mice exhibit a more prominent biphasic pattern in daily behaviors (food intake and physical activity) and whole-body metabolism (energy expenditure, respiratory exchange ratio), relative to SAMR1 control mice. Consistent with a delayed onset of food intake at the end of the light phase, SAMP8 mice exhibit a phase delay (1.3-1.9 h) in 24 h gene expression rhythms of major circadian clock components (bmal1, rev-erbα, per2, dbp) in peripheral tissues (liver, skeletal muscle, white adipose tissue [WAT], brown adipose tissue [BAT]). Forcing mice to consume food only during the dark period improved alignment of both whole-body metabolism and oscillations in expression of clock genes in peripheral tissues between SAMP8 and SAMR1 mice. Next, interrogation of metabolic genes revealed altered expression of thermogenesis mediators (ucp1, pgc1α, dio2) in WAT and/or BAT in SAMP8 mice. Interestingly, SAMP8 mice exhibit a decreased tolerance to an acute (5 h) cold challenge. Moreover, SAMP8 and SAMR1 mice exhibited differential responses to a chronic (1 week) decrease in ambient temperature; the greatest response in whole-body substrate selection was observed in SAMR1 mice. Collectively, these observations reveal differential behaviors (e.g. 24 h food intake patterns) in SAMP8 mice that are associated with perturbations in peripheral circadian clocks, metabolism and thermogenesis.

Adult skeletal muscle deletion of Mitofusin 1 and 2 impedes exercise performance and training capacity.

Endurance exercise has been shown to be a positive regulator of skeletal muscle metabolic function. Changes in mitochondrial dynamics (fusion and fission) have been shown to influence mitochondrial oxidative capacity. We therefore tested whether genetic disruption of mitofusins (Mfns) affected exercise performance in adult skeletal muscle. We generated adult-inducible skeletal muscle-specific Mfn1 (iMS-Mfn1KO), Mfn2 (iMS-Mfn2KO), and Mfn1/2 (iMS-MfnDKO) knockout mice. We assessed exercise capacity by performing a treadmill time to exhaustion stress test before deletion and up to 8 wk after deletion. Analysis of either the iMS-Mfn1KO or the iMS-Mfn2KO did not reveal an effect on exercise capacity. However, analysis of iMS-MfnDKO animals revealed a progressive reduction in exercise performance. We measured individual electron transport chain (ETC) complex activity and observed a reduction in ETC activity in both the subsarcolemmal and intermyofibrillar mitochondrial fractions specifically for NADH dehydrogenase (complex I) and cytochrome- c oxidase (complex IV), which was associated with a decrease in ETC subunit expression for these complexes. We also tested whether voluntary exercise training would prevent the decrease in exercise capacity observed in iMS-MfnDKO animals ( n = 10/group). However, after 8 wk of training we did not observe any improvement in exercise capacity or ETC subunit parameters in iMS-MfnDKO animals. These data suggest that the decrease in exercise capacity observed in the iMS-MfnDKO animals is in part the result of impaired ETC subunit expression and ETC complex activity. Taken together, these results provide strong evidence that mitochondrial fusion in adult skeletal muscle is important for exercise performance. NEW & NOTEWORTHY This study is the first to utilize an adult-inducible skeletal muscle-specific knockout model for Mitofusin (Mfn)1 and Mfn2 to assess exercise capacity. Our findings reveal a progressive decrease in exercise performance with Mfn1 and Mfn2 deletion. The decrease in exercise capacity was accompanied by impaired oxidative phosphorylation specifically for complex I and complex IV. Furthermore, voluntary exercise training was unable to rescue the impairment, suggesting that normal fusion is essential for exercise-induced mitochondrial adaptations.

International Society of Sports Nutrition Position Stand: nutritional considerations for single-stage ultra-marathon training and racing.

Background In this Position Statement, the International Society of Sports Nutrition (ISSN) provides an objective and critical review of the literature pertinent to nutritional considerations for training and racing in single-stage ultra-marathon. Recommendations for Training. i) Ultra-marathon runners should aim to meet the caloric demands of training by following an individualized and periodized strategy, comprising a varied, food-first approach; ii) Athletes should plan and implement their nutrition strategy with sufficient time to permit adaptations that enhance fat oxidative capacity; iii) The evidence overwhelmingly supports the inclusion of a moderate-to-high carbohydrate diet (i.e., ~ 60% of energy intake, 5-8 g·kg- 1·d- 1) to mitigate the negative effects of chronic, training-induced glycogen depletion; iv) Limiting carbohydrate intake before selected low-intensity sessions, and/or moderating daily carbohydrate intake, may enhance mitochondrial function and fat oxidative capacity. Nevertheless, this approach may compromise performance during high-intensity efforts; v) Protein intakes of ~ 1.6 g·kg- 1·d- 1 are necessary to maintain lean mass and support recovery from training, but amounts up to 2.5 g.kg- 1·d- 1 may be warranted during demanding training when calorie requirements are greater; Recommendations for Racing. vi) To attenuate caloric deficits, runners should aim to consume 150-400 Kcal·h- 1 (carbohydrate, 30-50 g·h- 1; protein, 5-10 g·h- 1) from a variety of calorie-dense foods. Consideration must be given to food palatability, individual tolerance, and the increased preference for savory foods in longer races; vii) Fluid volumes of 450-750 mL·h- 1 (~ 150-250 mL every 20 min) are recommended during racing. To minimize the likelihood of hyponatraemia, electrolytes (mainly sodium) may be needed in concentrations greater than that provided by most commercial products (i.e., > 575 mg·L- 1 sodium). Fluid and electrolyte requirements will be elevated when running in hot and/or humid conditions; viii) Evidence supports progressive gut-training and/or low-FODMAP diets (fermentable oligosaccharide, disaccharide, monosaccharide and polyol) to alleviate symptoms of gastrointestinal distress during racing; ix) The evidence in support of ketogenic diets and/or ketone esters to improve ultra-marathon performance is lacking, with further research warranted; x) Evidence supports the strategic use of caffeine to sustain performance in the latter stages of racing, particularly when sleep deprivation may compromise athlete safety.

Differential tissue response to growth hormone in mice.

Growth hormone (GH) has been shown to act directly on multiple tissues throughout the body. Historically, it was believed that GH acted directly in the liver and only indirectly in other tissues via insulin-like growth hormone 1 (IGF-1). Despite extensive work to describe GH action in individual tissues, a comparative analysis of acute GH signaling in key metabolic tissues has not been performed. Herein, we address this knowledge gap. Acute tissue response to human recombinant GH was assessed in mice by measuring signaling via phospho-STAT5 immunoblotting. STAT5 activation is an easily and reliably detected early marker of GH receptor engagement. We found differential tissue sensitivities; liver and kidney were equally GH-sensitive and more sensitive than white adipose tissue, heart, and muscle (gastrocnemius). Gastrocnemius had the greatest maximal response compared to heart, liver, white adipose tissue, and whole kidney. Differences in maximum responsiveness were positively correlated with tissue STAT5 abundance, while differences in sensitivity were not explained by differences in GH receptor levels. Thus, GH sensitivity and responsiveness of distinct metabolic tissues differ and may impact physiology and disease.