The neuromodulatory role of dopamine in improved reaction time by acute cardiovascular exercise.

Acute cardiovascular physical exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Here, using positron emission tomography (PET) with [11 C]raclopride, in a multi-experiment study we investigated whether acute exercise releases endogenous dopamine (DA) in the brain. We hypothesized that acute exercise augments the brain DA system, and that RT improvement is correlated with this endogenous DA release. The PET study (Experiment 1: n = 16) demonstrated that acute physical exercise released endogenous DA, and that endogenous DA release was correlated with improvements in RT of the Go/No-Go task. Thereafter, using two electrical muscle stimulation (EMS) studies (Experiments 2 and 3: n = 18 and 22 respectively), we investigated what triggers RT improvement. The EMS studies indicated that EMS with moderate arm cranking improved RT, but RT was not improved following EMS alone or EMS combined with no load arm cranking. The novel mechanistic findings from these experiments are: (1) endogenous DA appears to be an important neuromodulator for RT improvement and (2) RT is only altered when exercise is associated with central signals from higher brain centres. Our findings explain how humans rapidly alter their behaviour using neuromodulatory systems and have significant implications for promotion of cognitive health. KEY POINTS: Acute cardiovascular exercise improves cognitive performance, as evidenced by a reduction in reaction time (RT). However, the mechanistic understanding of how this occurs is elusive and has not been rigorously investigated in humans. Using the neurochemical specificity of [11 C]raclopride positron emission tomography, we demonstrated that acute supine cycling released endogenous dopamine (DA), and that this release was correlated with improved RT. Additional electrical muscle stimulation studies demonstrated that peripherally driven muscle contractions (i.e. exercise) were insufficient to improve RT. The current study suggests that endogenous DA is an important neuromodulator for RT improvement, and that RT is only altered when exercise is associated with central signals from higher brain centres.

Effects of electrical muscle stimulation on cerebral blood flow.

BACKGROUND: Electrical muscle stimulation (EMS) induces involuntary muscle contraction. Several studies have suggested that EMS has the potential to be an alternative method of voluntary exercise; however, its effects on cerebral blood flow (CBF) when applied to large lower limb muscles are poorly understood. Thus, the purpose of this study was to examine the effects of EMS on CBF, focusing on whether the effects differ between the internal carotid (ICA) and vertebral (VA) arteries. METHODS: The participants performed the experiments under EMS and control (rest) conditions in a randomized crossover design. The ICA and VA blood flow were measured before and during EMS or control. Heart rate, blood pressure, minute ventilation, oxygen uptake, and end-tidal partial pressure of carbon dioxide (PETCO2) were monitored and measured as well. RESULTS: The ICA blood flow increased during EMS [Pre: 330 ± 69 mL min-1; EMS: 371 ± 81 mL min-1, P = 0.001, effect size (Cohen's d) = 0.55]. In contrast, the VA blood flow did not change during EMS (Pre: 125 ± 47 mL min-1; EMS: 130 ± 45 mL min-1, P = 0.26, effect size = 0.12). In the EMS condition, there was a significant positive linear correlation between ΔPETCO2 and ΔICA blood flow (R = 0.74, P = 0.02). No relationships were observed between ΔPETCO2 and ΔVA blood flow (linear: R = - 0.17, P = 0.66; quadratic: R = 0.43, P = 0.55). CONCLUSIONS: The present results indicate that EMS increased ICA blood flow but not VA blood flow, suggesting that the effects of EMS on cerebral perfusion differ between anterior and posterior cerebral circulation, primarily due to the differences in cerebrovascular response to CO2.

The interactive effects of acute exercise and hypoxia on cognitive performance: A narrative review.

Acute moderate intensity exercise has been shown to improve cognitive performance. In contrast, hypoxia is believed to impair cognitive performance. The detrimental effects of hypoxia on cognitive performance are primarily dependent on the severity and duration of exposure. In this review, we describe how acute exercise under hypoxia alters cognitive performance, and propose that the combined effects of acute exercise and hypoxia on cognitive performance are mainly determined by interaction among exercise intensity and duration, the severity of hypoxia, and duration of exposure to hypoxia. We discuss the physiological mechanism(s) of the interaction and suggest that alterations in neurotransmitter function, cerebral blood flow, and possibly cerebral metabolism are the primary candidates that determine cognitive performance when acute exercise is combined with hypoxia. Furthermore, acclimatization appears to counteract impaired cognitive performance during prolonged exposure to hypoxia although the precise physiological mechanism(s) responsible for this amelioration remain to be elucidated. This review has implications for sporting, occupational, and recreational activities at terrestrial high altitude where cognitive performance is essential. Further studies are required to understand physiological mechanisms that determine cognitive performance when acute exercise is performed in hypoxia.

One week, but not 12 hours, of cast immobilization alters promotor DNA methylation patterns in the nNOS gene in mouse skeletal muscle.

KEY POINTS: DNA methylation may play an important role in regulating gene expression in skeletal muscle to adapt to physical activity and inactivity. Neuronal nitric oxide synthase (nNOS) in skeletal muscle is a key regulator of skeletal muscle mass; however, it is unclear whether nNOS expression is regulated by DNA methylation. We found that 1 week of cast immobilization increased nNOS DNA methylation levels and downregulated nNOS gene expression in atrophic slow-twitch soleus muscle from the mouse leg. These changes were not detected in non-atrophic fast-twitch extensor digitorum longus muscle. Twelve hours of cast immobilization decreased nNOS gene expression, whereas nNOS DNA methylation levels were unchanged, suggesting that downregulation of nNOS gene expression by short-term muscle inactivity is independent of the DNA methylation pattern. These findings contribute to a better understanding of the maintenance of skeletal muscle mass and prevention of muscle atrophy by epigenetic mechanisms via the nNOS/NO pathway. ABSTRACT: DNA methylation is a mechanism that controls gene expression in skeletal muscle under various environmental stimuli, such as physical activity and inactivity. Neuronal nitric oxide synthase (nNOS) regulates muscle atrophy in skeletal muscle. However, the mechanisms regulating nNOS expression in atrophic muscle remain unclear. We hypothesized that nNOS expression in atrophic muscle is regulated by DNA methylation of the nNOS promotor in soleus (Sol; slow-twitch fibre dominant) and extensor digitorum longus (EDL; fast-twitch fibre dominant) muscles. One week of cast immobilization induced significant muscle atrophy in Sol but not in EDL. We showed that 1 week of cast immobilization increased nNOS DNA methylation levels in Sol, although only a minor change was detected in EDL. Consistent with the increased DNA methylation levels in atrophic Sol, the gene expression levels of total nNOS and nNOSµ (i.e. the major splicing variant of nNOS in skeletal muscle) decreased. The abundance of the nNOS protein and cell membrane (especially type IIa fibre) immunoreactivity also decreased in atrophic Sol. These changes were not observed in EDL after 1 week of cast immobilization. Furthermore, despite the lack of significant atrophy, 12 h of cast immobilization decreased gene expression levels of total nNOS and nNOSµ in Sol. However, no association was detected between nNOS DNA methylation and gene expression. The expression of the nNOSß gene, another splicing variant of nNOS, in EDL was unchanged by cast immobilization, whereas its expression was not detected in Sol. We concluded that chronic adaptation of nNOS gene expression in cast immobilized muscle may involve nNOS DNA methylation.

Repeated blood flow restriction induces muscle fiber hypertrophy.

INTRODUCTION: We recently developed an animal model to investigate the effects of eccentric contraction (ECC) and blood flow restriction (BFR) on muscle tissue at the cellular level. This study clarified the effects of repeated BFR, ECC, and BFR combined with ECC (BFR+ECC) on muscle fiber hypertrophy. METHODS: Male Wistar rats were assigned to 3 groups: BFR, ECC, and BFR+ECC. The contralateral leg in the BFR group served as a control (CONT). Muscle fiber cross-sectional area (CSA) of the tibialis anterior was determined after the respective treatments for 6 weeks. RESULTS: CSA was greater in the BFR+ECC group than in the CONT (P < 0.01) and ECC (P < 0.05) groups. CSA was greater in the BFR group than that in the CONT group (P < 0.05). CNCLUSIONS: These results suggest that repeated BFR alone as well as BFR+ECC induces muscle fiber hypertrophy at the cellular level. Muscle Nerve 55: 274-276, 2017.

Executive function after exhaustive exercise.

PURPOSE: Findings concerning the effects of exhaustive exercise on cognitive function are somewhat equivocal. The purpose of this study was to identify physiological factors that determine executive function after exhaustive exercise. METHODS: Thirty-two participants completed the cognitive tasks before and after an incremental exercise until exhaustion (exercise group: N = 18) or resting period (control group N = 14). The cognitive task was a combination of a Spatial Delayed-Response (Spatial DR) task and a Go/No-Go task, which requires executive function. Cerebral oxygenation and skin blood flow were monitored during the cognitive task over the prefrontal cortex. Venous blood samples were collected before and after the exercise or resting period, and blood catecholamines, serum brain-derived neurotrophic factor, insulin-like growth hormone factor 1, and blood lactate concentrations were analyzed. RESULTS: In the exercise group, exhaustive exercise did not alter reaction time (RT) in the Go/No-Go task (pre: 861 ± 299 ms vs. post: 775 ± 168 ms) and the number of error trials in the Go/No-Go task (pre: 0.9 ± 0.7 vs. post: 1.8 ± 1.8) and the Spatial DR task (pre: 0.3 ± 0.5 vs. post: 0.8 ± 1.2). However, ΔRT was negatively correlated with Δcerebral oxygenation (r = -0.64, P = 0.004). Other physiological parameters were not correlated with cognitive performance. Venous blood samples were not directly associated with cognitive function after exhaustive exercise. CONCLUSION: The present results suggest that recovery of regional cerebral oxygenation affects executive function after exhaustive exercise.

Effects of environmental enrichment in aged mice on anxiety-like behaviors and neuronal nitric oxide synthase expression in the brain.

Previous studies have shown that an enriched environment (EE) has an important effect on brain function via the neuronal nitric oxide synthase/nitric oxide (nNOS/NO) pathway in young and aged animals. However, whether EE induces its effect by altering nNOS expression levels and whether it lowers anxiety-like behaviors in aged mice remains unclear. Here, we show that nNOS expression levels increased with age in the hippocampus and cerebellum in aged mice, but not in the cortex. Moreover, EE reduced anxiety-like behaviors in aged mice and reduced nNOS expression levels in the cerebellum, but not in the cortex. The present study suggests that EE improves anxiety-like behaviors in aged mice by altering nNOS expression levels in the hippocampus or cerebellum.

Functional analysis of iPSC-derived myocytes from a patient with carnitine palmitoyltransferase II deficiency.

INTRODUCTION: Carnitine palmitoyltransferase II (CPT II) deficiency is an inherited disorder involving ß-oxidation of long-chain fatty acids (FAO), which leads to rhabdomyolysis and subsequent acute renal failure. The detailed mechanisms of disease pathogenesis remain unknown; however, the availability of relevant human cell types for investigation, such as skeletal muscle cells, is limited, and the development of novel disease models is required. METHODS: We generated human induced pluripotent stem cells (hiPSCs) from skin fibroblasts of a Japanese patient with CPT II deficiency. Mature myocytes were differentiated from the patient-derived hiPSCs by introducing myogenic differentiation 1 (MYOD1), the master transcriptional regulator of myocyte differentiation. Using an in vitro acylcarnitine profiling assay, we investigated the effects of a hypolipidemic drug, bezafibrate, and heat stress on mitochondrial FAO in CPT II-deficient myocytes and controls. RESULTS: CPT II-deficient myocytes accumulated more palmitoylcarnitine (C16) than did control myocytes. Heat stress, induced by incubation at 38°C, leads to a robust increase of C16 in CPT II-deficient myocytes, but not in controls. Bezafibrate reduced the amount of C16 in control and CPT II-deficient myocytes. DISCUSSION: In this study, we induced differentiation of CPT II-deficient hiPSCs into mature myocytes in a highly efficient and reproducible manner and recapitulated some aspects of the disease phenotypes of CPT II deficiency in the myocyte disease models. This approach addresses the challenges of modeling the abnormality of FAO in CPT II deficiency using iPSC technology and has the potential to revolutionize translational research in this field.

Combined effects of electrical muscle stimulation and cycling exercise on cognitive performance.

The purpose of this study was to investigate whether a combination of electrical muscle stimulation (EMS) and cycling exercise is beneficial for improving cognitive performance. Eighteen participants (7 females and 11 males) performed a Go/No-Go task before and 2 min after i) cycling exercise (EX), ii) a combination of EMS and cycling (EMS + EX) and iii) a control (rest) intervention in a randomized controlled crossover design. In the EX intervention, the participants cycled an ergometer for 20 min with their heart rate maintained at ∼120 beats·min-1. In the EMS + EX intervention, the participants cycled an ergometer simultaneously with EMS for 20 min, with heart rate maintained at ∼120 beats·min-1. In the Control intervention, the participants remained at rest while seated on the ergometer. Cognitive performance was assessed by reaction time (RT) and accuracy. There was a significant interaction between intervention and time (p = 0.007). RT was reduced in the EX intervention (p = 0.054, matched rank biserial correlation coefficient = 0.520). In the EMS + EX intervention, RT was not altered (p = 0.243, Cohen's d = 0.285) despite no differences in heart rate between the EX and EMS + EX interventions (p = 0.551). RT was increased in the Control intervention (p = 0.038, Cohen's d = -0.529). These results indicate that combining EMS and cycling does not alter cognitive performance despite elevated heart rate, equivalent to a moderate intensity. The present findings suggest that brain activity during EMS with cycling exercise may be insufficient to improve cognitive performance when compared to exercise alone.

The effects of environmental enrichment on voluntary physical activity and muscle mass gain in growing rats.

Introduction: Environmental enrichment (EE) for rodents involves housing conditions that facilitate enhanced sensory, cognitive, and motor stimulation relative to standard housing conditions. A recent study suggested that EE induces muscle hypertrophy. However, it remains unclear whether muscle hypertrophy in EE is associated with voluntary physical activity, and the characteristics of muscle adaptation to EE remain unclarified. Therefore, this study investigated whether muscle adaptation to EE is associated with voluntary physical activity, and assessed the changes in the muscle fiber-type distribution and fiber-type-specific cross-sectional area in response to EE. Methods: Wistar rats (6 weeks of age) were randomly assigned to either the standard environment group (n = 10) or the EE group (n = 10). The voluntary physical activity of rats housed in EE conditions was measured using a recently developed three-axis accelerometer. After exposure to the standard or enriched environment for 30 days, the tibialis anterior, extensor digitorum longus, soleus, plantaris, and gastrocnemius muscles were removed and weighed. Immunohistochemistry analysis was performed on the surface (anterior) and deep (posterior) areas of the tibialis anterior and soleus muscles. Results and discussion: The EE group showed increased voluntary physical activity during the dark period compared with the standard environment group (p = 0.005). EE induced muscle mass gain in the soleus muscle (p = 0.002) and increased the slow-twitch muscle fiber cross-sectional area of the soleus muscle (p = 0.025). EE also increased the distribution of high-oxidative type IIa fibers of the surface area (p = 0.001) and type I fibers of the deep area (p = 0.037) of the tibialis anterior muscle. These findings suggest that EE is an effective approach to induce slow-twitch muscle fiber hypertrophy through increased daily voluntary physical activity.

Cmah deficiency blunts cellular senescence in adipose tissues and improves whole-body glucose metabolism in aged mice.

AIM: Cytidine monophosphate-N-acetylneuraminic acid (Neu5Ac) hydroxylase (Cmah) is an enzyme, which converts Neu5Ac to the sialic acid Neu5Gc. Neu5Gc is thought to increase inflammatory cytokines, which are, in part, produced in senescent cells of adipose tissues. Cellular senescence in adipose tissues induces whole-body aging and impaired glucose metabolism. Therefore, we hypothesized that Cmah deficiency would prevent cellular senescence in adipose tissues and impaired glucose metabolism. METHODS: Wild-type (WT) and Cmah knockout (KO) mice aged 24-25 months were used. Whole-body metabolism was assessed using a metabolic gas analysis system. We measured blood glucose and insulin concentrations after oral glucose administration. The size of the lipid droplets in the liver was quantified. Markers of cellular senescence and senescence-associated secretory phenotypes were measured in adipose tissues. RESULTS: Cmah KO had significantly increased VO2 and energy expenditure (P < 0.01). Unlike glucose, the insulin concentration after oral glucose administration was significantly lower in the Cmah KO group than in the WT group (P < 0.001). Lipid droplets in the liver were significantly lower in the Cmah KO group than in the WT group (P < 0.05). The markers of cellular senescence and senescence-associated secretory phenotypes in the adipose tissues were significantly lower in the Cmah KO group than in the WT group (P < 0.05). CONCLUSIONS: Cmah deficiency blunted cellular senescence in adipose tissues and improved whole-body glucose metabolism. These characteristics in aged Cmah KO mice might be associated with higher energy expenditure. Geriatr Gerontol Int 2023; 23: 958-964.

The effects of acute high-intensity aerobic exercise on cognitive performance: A structured narrative review.

It is well established that acute moderate-intensity exercise improves cognitive performance. However, the effects of acute high-intensity aerobic exercise on cognitive performance have not been well characterized. In this review, we summarize the literature investigating the exercise-cognition interaction, especially focusing on high-intensity aerobic exercise. We discuss methodological and physiological factors that potentially mediate cognitive performance in response to high-intensity exercise. We propose that the effects of high-intensity exercise on cognitive performance are primarily affected by the timing of cognitive task (during vs. after exercise, and the time delay after exercise). In particular, cognitive performance is more likely to be impaired during high-intensity exercise when both cognitive and physiological demands are high and completed simultaneously (i.e., the dual-task paradigm). The effects may also be affected by the type of cognitive task, physical fitness, exercise mode/duration, and age. Second, we suggest that interactions between changes in regional cerebral blood flow (CBF), cerebral oxygenation, cerebral metabolism, neuromodulation by neurotransmitters/neurotrophic factors, and a variety of psychological factors are promising candidates that determine cognitive performance in response to acute high-intensity exercise. The present review has implications for recreational, sporting, and occupational activities where high cognitive and physiological demands are required to be completed concurrently.

Cognitive Improvement After Aerobic and Resistance Exercise Is Not Associated With Peripheral Biomarkers.

The role of peripheral biomarkers following acute physical exercise on cognitive improvement has not been systematically evaluated. This study aimed to explore the role of peripheral circulating biomarkers in executive performance following acute aerobic and resistance exercise. Nineteen healthy males completed a central executive (Go/No-Go) task before and after 30-min of perceived intensity matched aerobic and resistance exercise. In the aerobic condition, the participants cycled an ergometer at 40% peak oxygen uptake. In the resistance condition, they performed resistance exercise using elastic bands. Before and after an acute bout of physical exercise, venous samples were collected for the assessment of following biomarkers: adrenaline, noradrenaline, glucose, lactate, cortisol, insulin-like growth hormone factor 1, and brain-derived neurotrophic factor. Reaction time decreased following both aerobic exercise and resistance exercise (p = 0.04). Repeated measures correlation analysis indicated that changes in reaction time were not associated with the peripheral biomarkers (all p > 0.05). Accuracy tended to decrease in the resistance exercise condition (p = 0.054). Accuracy was associated with changes in adrenaline [r rm (18) = -0.51, p = 0.023], noradrenaline [r rm (18) = -0.66, p = 0.002], lactate [r rm (18) = -0.47, p = 0.035], and brain-derived neurotrophic factor [r rm (17) = -0.47, p = 0.044] in the resistance condition. These findings suggest that these peripheral biomarkers do not directly contribute to reduction in reaction time following aerobic or resistance exercise. However, greater sympathoexcitation, reflected by greater increase in noradrenaline, may be associated with a tendency for a reduction in accuracy after acute resistance exercise.

Control of microvascular PO2 kinetics following onset of muscle contractions: role for AMPK.

The microvascular partial pressure of oxygen (Pmv(o(2))) kinetics following the onset of exercise reflects the relationship between muscle O(2) delivery and uptake (Vo(2)). Although AMP-activated protein kinase (AMPK) is known as a regulator of mitochondria and nitric oxide metabolism, it is unclear whether the dynamic balance of O(2) delivery and Vo(2) at exercise onset is dependent on AMPK activation level. We used transgenic mice with muscle-specific AMPK dominant-negative (AMPK-DN) to investigate a role for skeletal muscle AMPK on Pmv(o(2)) kinetics following onset of muscle contractions. Phosphorescence quenching techniques were used to measure Pmv(o(2)) at rest and across the transition to twitch (1 Hz) and tetanic (100 Hz, 3-5 V, 4-ms pulse duration, stimulus duration of 100 ms every 1 s for 1 min) contractions in gastrocnemius muscles (each group n = 6) of AMPK-DN mice and wild-type littermates (WT) under isoflurane anesthesia with 100% inspired O(2) to avoid hypoxemia. Baseline Pmv(o(2)) before contractions was not different between groups (P > 0.05). Both muscle contraction conditions exhibited a delay followed by an exponential decrease in Pmv(o(2)). However, compared with WT, AMPK-DN demonstrated 1) prolongation of the time delay before Pmv(o(2)) began to decline (1 Hz: WT, 3.2 ± 0.5 s; AMPK-DN, 6.5 ± 0.4 s; 100 Hz: WT, 4.4 ± 1.0 s; AMPK-DN, 6.5 ± 1.4 s; P < 0.05), 2) a faster response time (i.e., time constant; 1 Hz: WT, 19.4 ± 3.9 s; AMPK-DN, 12.4 ± 2.6 s; 100 Hz: WT, 15.1 ± 2.2 s; AMPK-DN, 9.0 ± 1.7 s; P < 0.05). These findings are consistent with the presence of substantial mitochondrial and microvascular dysfunction in AMPK-DN mice, which likely slows O(2) consumption kinetics (i.e., oxidative phosphorylation response) and impairs the hyperemic response at the onset of contractions thereby sowing the seeds for exercise intolerance.

Effects of Visual Flow Alterations on Psychophysiological Responses to Virtual Reality Exercise.

Virtual reality (VR) technology combined with exercise, called VR exercise, is believed to have beneficial effects on mood; but VR factors contributing to improved mood remain ambiguous. The purpose of this study was to examine the effect of visual flow speed on psychophysiological responses (i.e., physiological responses, ratings of perceived exertion or RPE, and mood) to immersive VR exercise in a simulated natural environment. Eighteen male participants (Mage =23.1, SD = 1.9 years) cycled an ergometer at 80 watts for 5 minutes on three separate occasions while watching a first-person VR movie through VR goggles at three different speeds of visual flow, corresponding to 7.5 km.h-1, 15 km.h-1, and 22.5 km.h-1. The order of the three speeds was randomized in a counterbalanced design. We measured heart rate, oxygen uptake, minute ventilation, respiratory rate, and cadence during the exercise, and we recorded ratings of perceived exertion (RPE) and mood immediately after the exercise. We evaluated mood states with the Two-Dimensional Mood Scale. One-way repeated measures analysis of variance or the Friedman test revealed no significant effects on any physiological variables, RPE or cadence as a result of altered visual flow speed during VR exercise (p > .05). However, speed of visual flow significantly influenced participant ratings of Vitality (p = 0.01) and Pleasure (p = 0.02), with the faster speed resulting in a more positive mood state. As these findings showed that VR exercise with faster visual flow induced positive mood states, we recommend faster visual flow to induce better mood states in VR exercise.

Sex differences in intracellular Ca(2+) accumulation following eccentric contractions of rat skeletal muscle in vivo.

It is commonly believed that estrogen and sex influences play significant effects in skeletal muscle damage following eccentric exercise. The mechanistic bases for this sex-specific phenomenon remain to be resolved. The muscle damage has been linked to loss of Ca(2+) homeostasis and resultant intramyocyte Ca(2+) ([Ca(2+)](i)) accumulation; therefore, we tested the hypothesis that the greater eccentric exercise-induced muscle damage in males would be associated with more pronounced [Ca(2+)](i) accumulation. The intact spinotrapezius muscle of adult Wistar rats [male, female, and ovariectomized (OVX)-to investigate the effects of estrogen] was exteriorized. Tetanic eccentric contractions (100 Hz, 700-ms duration, 20 contractions/min for a total of 10 sets of 50 contractions) were elicited by electrical stimulation during synchronized muscle stretch of 10% resting muscle length. The fluorescence ratio (F(340)/F(380) nm) was determined from images captured following each set of contractions, and fura-2 AM was used to estimate [Ca(2+)](i) and changes thereof. Following eccentric contractions, [Ca(2+)](i) increased significantly in male (42.8 ± 5.3%, P < 0.01) but not in female (9.4 ± 3.5%) rats. OVX evidenced an intermediate response (17.0 ± 1.2%) that remained significantly reduced compared with males. These results demonstrate that females maintain [Ca(2+)](i) homeostasis following novel eccentric contractions, whereas males do not, which is consistent with a role for elevated [Ca(2+)](i) in eccentric exercise-induced muscle damage. The presence of normal estrogen levels is not obligatory for the difference between the sexes.

Cognitive Impairment during High-Intensity Exercise: Influence of Cerebral Blood Flow.

PURPOSE: Cognitive performance appears to be impaired during high-intensity exercise, and this occurs concurrently with a reduction in cerebral blood flow (CBF). However, it is unclear whether cognitive impairment during high-intensity exercise is associated with reduced CBF. We tested the hypothesis that a reduction in CBF is responsible for impaired cognitive performance during high-intensity exercise. METHODS: Using a randomized crossover design 17 healthy males performed spatial delayed response and Go/No-Go tasks in three conditions (exercise [EX], exercise+CO2 [EX+CO2], and a nonexercising control [CON]). In the EX and EX+CO2, they performed cognitive tasks at rest and during 8 min of moderate and high-intensity exercise. Exercise intensity corresponded to ~50% (moderate) and ~80% (high) of peak oxygen uptake. In the EX+CO2, the participants inspired hypercapnic gas (2% CO2) during high-intensity exercise. In the CON, they performed the cognitive tasks without exercise. RESULTS: Middle cerebral artery mean velocity increased during high-intensity exercise in the EX+CO2 relative to the EX (69.4 [10.6] cm·s, vs 57.2 [7.7] cm·s, P < 0.001). Accuracy of the cognitive tasks was impaired during high-intensity exercise in the EX (84.1% [13.3%], P < 0.05) and the EX+ CO2 (85.7 [11.6%], P < 0.05) relative to rest (EX: 95.1% [5.3%], EX+CO2: 95.1 [5.3%]). However, no differences between the EX and the EX+CO2 were observed (P > 0.10). These results demonstrate that restored CBF did not prevent cognitive impairment during high-intensity exercise. CONCLUSIONS: We conclude that a reduction in CBF is not responsible for impaired cognitive performance during high-intensity exercise.

Regional differences in Ca2+ entry along the proximal-middle-distal muscle axis during eccentric contractions in rat skeletal muscle.

Eccentric (ECC) contraction-induced muscle damage is associated with calcium ion (Ca2+) influx from the extracellular milieu through stretch-activated channels. It remains unknown whether Ca2+ influx consequent to repetitive ECC contractions is nonuniform across different muscle regions. We tested the hypothesis that there are regional differences in Ca2+ entry along the proximal-middle-distal muscle axis. Tibialis anterior (TA) muscles of adult male Wistar rats were exposed by reflecting the overlying skin and fasciae and ECC contractions evoked by peroneal nerve stimulation paired with simultaneous ankle extension (50 times/set, 2 protocols: 1 set and 10 sets). During ECC in the proximal, middle, and distal TA, we determined 1) muscle fiber extension by high-speed camera (200 frames/s) and 2) Ca2+ accumulation by in vivo bioimaging (Ca2+-sensitive probe Fura-2-acetoxymethyl ester). Muscle fiber extension from resting was significantly different among regions (i.e., proximal, 4.0%: < middle, 11.2%: < distal, 17.0%; ECC phase length at 500th contraction). Intracellular Ca2+ accumulation after 1 set of ECC was higher in the distal (1.46 ± 0.04, P < 0.05) than the proximal (1.27 ± 0.04) or middle (1.26 ± 0.05) regions. However, this regional Ca2+ accumulation difference disappeared by 32.5 min after the 1 set protocol when the muscle was quiescent and by contraction set 5 for the 10-set protocol. The initial preferential ECC-induced Ca2+ accumulation observed distally was associated spatially with the greater muscle extension compared with that of the proximal and middle regions. Disappearance of the regional Ca2+ accumulation disparity in quiescent and ECC-contracting muscle might be explained, in part, by axial Ca2+ propagation and account for the uniformity of muscle damage across regions evident 3 days post-ECC.NEW & NOTEWORTHY After 1 set of 50 eccentric (ECC) contractions in the anterior tibialis muscle, intracellular Ca2+ ([Ca2+]i) accumulation evinces substantial regional heterogeneity that is spatially coherent with muscle length changes (i.e., distal [Ca2+]i > middle, proximal). However, irrespective of whether 50 or 500 ECC contractions are performed, this heterogeneity is subsequently abolished, at least in part, by axial intracellular Ca2+ propagation. This Ca2+ homogenization across regions is consistent with the absence of any interregional difference in muscle damage 3 days post-ECC.

Cognitive function during exercise under severe hypoxia.

Acute exercise has been demonstrated to improve cognitive function. In contrast, severe hypoxia can impair cognitive function. Hence, cognitive function during exercise under severe hypoxia may be determined by the balance between the beneficial effects of exercise and the detrimental effects of severe hypoxia. However, the physiological factors that determine cognitive function during exercise under hypoxia remain unclear. Here, we examined the combined effects of acute exercise and severe hypoxia on cognitive function and identified physiological factors that determine cognitive function during exercise under severe hypoxia. The participants completed cognitive tasks at rest and during moderate exercise under either normoxic or severe hypoxic conditions. Peripheral oxygen saturation, cerebral oxygenation, and middle cerebral artery velocity were continuously monitored. Cerebral oxygen delivery was calculated as the product of estimated arterial oxygen content and cerebral blood flow. On average, cognitive performance improved during exercise under both normoxia and hypoxia, without sacrificing accuracy. However, under hypoxia, cognitive improvements were attenuated for individuals exhibiting a greater decrease in peripheral oxygen saturation. Cognitive performance was not associated with other physiological parameters. Taken together, the present results suggest that arterial desaturation attenuates cognitive improvements during exercise under hypoxia.

Slowed response to peripheral visual stimuli during strenuous exercise.

Recently, we proposed that strenuous exercise impairs peripheral visual perception because visual responses to peripheral visual stimuli were slowed during strenuous exercise. However, this proposal was challenged because strenuous exercise is also likely to affect the brain network underlying motor responses. The purpose of the current study was to resolve this issue. Fourteen participants performed a visual reaction-time (RT) task at rest and while exercising at 50% (moderate) and 75% (strenuous) peak oxygen uptake. Visual stimuli were randomly presented at different distances from fixation in two task conditions: the Central condition (2° or 5° from fixation) and the Peripheral condition (30° or 50° from fixation). We defined premotor time as the time between stimulus onset and the motor response, as determined using electromyographic recordings. In the Central condition, premotor time did not change during moderate (167±19ms) and strenuous (168±24ms) exercise from that at rest (164±17ms). In the Peripheral condition, premotor time significantly increased during moderate (181±18ms, P<0.05) and strenuous exercise (189±23ms, P<0.001) from that at rest (173±17ms). These results suggest that increases in Premotor Time to the peripheral visual stimuli did not result from an impaired motor-response network, but rather from impaired peripheral visual perception. We conclude that slowed response to peripheral visual stimuli during strenuous exercise primarily results from impaired visual perception of the periphery.