Experimental Physiology最新文献

Physical activity is widely recognized for its ability to promote brain health, with acute exercise transiently enhancing cognition and long-term training attenuating cognitive decline. However, the mechanisms underlying these benefits remain incompletely understood. Cerebral blood flow (CBF) has traditionally been considered central to exercise-induced cognitive improvements, given the brain's dependence on a continuous supply of oxygen and glucose. Yet, accumulating evidence indicates that changes in global CBF alone cannot fully explain enhanced cognitive performance. Instead, regional CBF responses through neurovascular coupling, as well as cerebral metabolism - including oxygen extraction, glucose utilization and lactate uptake - are likely more critical determinants of brain function in response to exercise. Importantly, substantial individual differences exist in these responses. While some individuals experience robust cognitive gains from identical exercise regimens, others show little or no benefit. Emerging evidence suggests that variability in glucose tolerance, lactate dynamics and exercise capacity may underlie this heterogeneity, reflecting differences in metabolic responses and cerebrovascular regulation. For example, impaired glucose utilization might be linked to diminished exercise-induced cognitive improvement, whereas lactate uptake appears to support high-intensity exercise-related gains. These findings highlight that the cognitive effects of exercise are not uniform, but rather influenced by individual physiological characteristics. This review therefore emphasizes the integrative regulation of CBF and metabolism as key factors mediating exercise-induced cognitive improvements, while emphasizing the importance of inter-individual variability. Understanding why some individuals benefit more than others is essential for adapting exercise prescriptions to maximize brain health across diverse populations.

Ageing is a risk factor for cardiovascular and neurodegenerative diseases. The myogenic response in resistance arteries is responsible for basal (myogenic) tone and blood flow autoregulation. G-protein-coupled receptors and G₁₂/RhoA/Rho kinase are implicated in myogenic tone (MT), and we aimed to clarify their role in pressure sensing and ageing. We studied MT in third-order mesenteric arteries (MA) ex vivo and first-fourth order cerebral arteries (CA) in vivo in young versus middle-aged male mice. Inhibition of α₁-, AT₁-, ET_A- and TP-receptors and thromboxane synthase did not affect MT in MA from young mice. The P2Y-receptor blocker suramin inhibited MT, whereas PPADS and apyrase did not. MT in intact or endothelium-denuded MAs was not affected by the knockout of P2Y₆-receptor (P2Y₆-R). qPCR showed upregulation of P2Y₂-R in P2Y₆-deficient arteries. MT was not affected in P2Y₂-R knock-out mice. The sphingosine-kinase (SK) blocker SKI-II inhibited MT in young mice, and the sphingosine 1-phosphate receptor 2 (S1P₂-R) blocker JTE-013 inhibited MT in young and middle-aged mice. MT was impaired in middle-aged mice. Furthermore, MT was reduced in young mice carrying familial Alzheimer's disease mutations (5xFAD), and JTE-013 abolished MT in 5xFAD mice and their wild-type littermates. JTE-013 did not affect calcium signalling in cultured human coronary artery smooth muscle cells. High-resolution microangiography confirmed that infusion of JTE-013 or KD025 (a Rho-kinase 2 inhibitor) preferentially dilated small (distal) CAs, and infusion of nifedipine (an L-type channel inhibitor) dilated all CAs in all mice, independent of age. SK and S1P₂-R are crucially involved in pressure sensing in MT. RhoA/Rho-kinase signalling might be involved in age-related MT deficiency.

The leading cause of epilepsy-related mortality is sudden unexpected death in epilepsy (SUDEP), resulting from seizure-induced cardiorespiratory arrest by mechanisms that remain unresolved. Mutations in ion channel genes expressed in both brain and heart represent SUDEP risk factors because they can disrupt neural and cardiac rhythms, providing a unified explanation for seizures and lethal arrhythmias. However, the relative contributions of brain-driven mechanisms, heart-intrinsic processes and seizures to cardiac dysfunction in epilepsy remain unclear. Here, we investigated the heart-specific role of the Kcna1 gene, which encodes Kv1.1 voltage-gated potassium channel α-subunits expressed in both neurons and cardiomyocytes, where they shape action potential firing and influence seizure and arrhythmia susceptibility. We generated cardiac-specific Kcna1 conditional knockout (cKO) mice lacking Kv1.1 selectively in cardiomyocytes and assessed their cardiac function using in vitro and in vivo electrophysiology. Cardiac Kv1.1 deficiency prolonged action potentials in atrial, but not ventricular, cardiomyocytes, demonstrating a direct role for Kv1.1 in atrial repolarization. Despite these cellular effects, cKO mice exhibited normal lifespans, electrocardiographic features, heart rate variability, pacing-induced arrhythmia susceptibility, contractility, seizure susceptibility and seizure-induced mortality. Thus, while loss of cardiac Kv1.1 was sufficient to impair atrial repolarization, it did not reproduce the broader cardiac abnormalities seen in global Kcna1 knockouts. Given the higher mortality rates of global compared with neural-specific knockouts in our previous studies, cardiac Kv1.1 deficiency, while not lethal alone, may increase vulnerability to seizure-related death when combined with neural deficiency, consistent with a brain-heart dyssynergy that lowers the threshold for fatal events.

Unpredictable gait disturbances, particularly in the mediolateral direction, pose a significant challenge to stability and are a common contributor to falls. Although the corticospinal tract is critical for gait and postural control, its response to such instabilities remains unclear. To investigate if corticospinal excitability increases during laterally destabilised gait, single-pulse transcranial magnetic stimulations were delivered over the primary motor cortex of 15 healthy individuals during steady-state and laterally destabilised treadmill gait. Full-body kinematics were recorded using an optoelectronic motion capture system. Stimulations with coil displacement >5 mm from the targeted location were excluded. Corticospinal excitability was quantified for four upper- and three lower-leg muscles by the motor evoked potential (MEP) amplitude and compared between steady-state and destabilised gait. Destabilisation resulted in a wider step width and shorter stride duration with increased variability and greater dynamic instability. Foot placement control was increased at mid-swing, along with greater average foot placement error. No differences in corticospinal excitability were observed in the lower-leg muscles. All upper-leg muscles demonstrated greater absolute MEPs in destabilised relative to steady-state gait. After normalising MEP to the pre-stimulus muscle activity, these periods became less pronounced; however, increases were observed in all but the gastrocnemius muscles. These findings suggest heightened readiness of the corticospinal tract projecting to upper-leg muscles during destabilised gait, which could reflect general stabilising strategies such as decreasing stride time and increasing step width.

The effects of muscle disuse on the propagation of action potentials along motor unit (MU) muscle fibres, a key process for effective muscle activation and force generation, remain poorly understood. The aim of this study was to investigate changes in action potential propagation and to identify biological factors influencing these changes following unilateral lower-limb suspension (ULLS) and active recovery (AR). Eleven young males underwent 10 days of ULLS followed by 21 days of AR involving resistance exercise. Maximal force of the knee extensors (MVC), high-density surface EMG recordings and muscle biopsies of the vastus lateralis muscle were collected before ULLS, after ULLS and after AR. EMG recordings collected during submaximal isometric contractions were decomposed to estimate single-MU conduction velocity (CV). Biopsies were used to measure muscle fibre diameters via histochemical analysis and ion channel transcriptomic profiles via mRNA sequencing. The MVC declined by 29% after ULLS and returned to baseline after AR. MU CV decreased after ULLS and recovered fully, even exceeding baseline values after AR. Muscle fibre diameters did not change across the interventions and showed no correlation with MU CV. Conversely, a feature importance analysis revealed that mRNA expression levels of specific ion channel genes, particularly those involved in K⁺ transport, were correlated with MU CV at baseline and across the interventions. This study highlights the crucial role of K⁺ ion channels in influencing MU CV in humans, offering new insights into MU CV modulation and the mechanisms of changes in muscle force after disuse and active recovery.

Colorectal cancer (CRC) and cardiovascular disease (CVD) are leading causes of morbidity and mortality worldwide, traditionally studied as distinct pathologies. However, emerging evidence suggests a significant physiological and molecular overlap between these conditions, indicating that they might share common pathophysiological pathways. The aim of this paper is to explore the interconnected mechanisms linking CRC and CVD to identify shared risk factors, underlying molecular processes and potential avenues for integrated prevention and treatment strategies. The review highlights chronic inflammation, oxidative stress, metabolic dysregulation and gut microbiota dysbiosis as central factors contributing to CRC and CVD. Key inflammatory mediators, such as interleukin-6, C-reactive protein and tumour necrosis factor-α, are discussed in the context of their dual role in tumour progression and atherogenesis. Additionally, metabolic disorders, including obesity, insulin resistance and hyperlipidaemia, are shown to elevate the risk of both diseases synergistically, with shared pathways involving insulin-like growth factors and endothelial dysfunction. The manuscript also addresses the role of lifestyle and environmental factors, such as diet, physical activity and carcinogen exposure, in modulating the risk for CRC and CVD. Furthermore, it considers the implications of commonly used therapies, such as aspirin and statins, which exhibit cross-benefits in both conditions. In conclusion, understanding the molecular and physiological crosstalk between CRC and CVD provides valuable insight into their co-occurrence and offers opportunities for integrated screening, prevention and management approaches. This unified perspective supports the development of multidisciplinary strategies that could improve patient outcomes and reduce the global burden of these major chronic diseases.

Resistance exercise provides numerous health benefits, including improved glucose control and enhanced muscular strength. However, it remains unclear whether the time of day resistance exercise is performed affects these benefits. The objective of this work was to determine the effect of time of day on muscle and metabolic responses to resistance exercise training in young healthy adults. The study included 36 participants (30 ± 7 years old; and 28 ± 4 kg/m²) who were randomised into control, morning (06.00-10.00 h) or evening (16.00-20.00 h) groups. Exercise groups performed eight resistance exercises, 3 times per week, for 6 weeks, at their allocated time. At baseline and post-intervention, insulin sensitivity, flash glucose monitor data, muscle strength and vastus lateralis muscle thickness were measured. Over the 6-week intervention, there were significant main effects of time on insulin sensitivity (P < 0.001), muscle thickness (P = 0.008) and knee extensor maximal torque (P < 0.001), indicating improvements with resistance exercise training. However, there were no significant time × group interactions for any outcome measures (insulin sensitivity P = 0.206, muscle thickness P = 0.279, knee extensor torque P = 0.151), demonstrating that exercise timing did not differentially affect training adaptations. Both exercise groups showed similar improvements compared to controls, regardless of whether training occurred in the morning or evening. No significant effects were observed for flash glucose monitor data. This study highlights the benefits of resistance exercise and demonstrates that timing has little influence on these effects. Promotion of resistance exercise at convenient times is recommended. This study was registered at ClinicalTrials: ClinicalTrials.gov ID: NCT05321914.

The principal processes that govern interstitial K⁺ ([K⁺]_o) buffering in mouse optic nerve (MON), a central white matter tract, either directly consume energy (Na⁺-K⁺-ATPase) or use transmembrane ion gradients created by energy-dependent pumps to enable the K⁺ fluxes that maintain a stable [K⁺]_o, and thus ready availability of utilisable energy substrate is vital in supporting MON function. We switched the artificial cerebrospinal fluid (aCSF) bathing isolated ex vivo MON from a glucose and physiological [K⁺] (3 mM) formulation to one in which glucose was replaced by lactate and [K⁺] was increased to supra-physiological concentrations ('stress aCSF'), to test the ability of an oxidative fuel to support astrocyte function when faced with the buffering-related increased energy demand that accompanies elevating [K⁺]_o. We recorded simultaneously the compound action potential (CAP) and [K⁺]_o with suction electrodes and ion-sensitive microelectrodes, respectively. Increases in aCSF [K⁺] were not matched by equivalent increases in [K⁺]_o, evidence of powerful buffering. The stress aCSF caused unexpected reciprocal CAP and [K⁺]_o oscillations and exhaustion of astrocyte energy reserves coupled with elevation of [K⁺]_o sufficient to activate axonal Na⁺ channels, the key factors required for their initiation. The oscillation profile was of a rise in [K⁺]_o towards aCSF [K⁺], followed by a restoration of [K⁺]_o towards baseline, driven by intermittent activation of the axonal Na⁺-K⁺-ATPase, a cyclical process that continued for several hours. These oscillations exposed the contrasting utility of lactate, supporting axonal CAPs and axonal dominance of buffering during the oscillations, but incapable of fuelling astrocyte function.

Sustainable development is a growing global concern, but university students in scientific fields such as Physiology struggle to see its direct relevance to their studies. This research explores how an authentic assessment can integrate the United Nations (UN) sustainable development goals (SDGs) into Physiology education. Students were tasked to design and present a group poster on the connections between an SDG and Physiology. Through a mixed-methods approach utilizing questionnaires, pre- and post-assignment data were collected and the students' perceptions of the links and learning opportunities explored. Students reported a shift in how they perceived the intersection between Physiology and societal issues, with many expressing a newfound passion for sustainability. Awareness and understanding of the SDGs increased significantly (19% and 36%, respectively). Students made connections between Physiology and goals such as No Poverty (SDG1), Quality Education (SDG4), Gender Equality (SDG5), and Climate Action (SDG13). Thirteen of the 17 SDGs were rated as significantly more relevant to Physiology after the assignment, among these, several less obviously related goals like Affordable and Clean Energy (SDG7), Sustainable Cities and Communities (SDG11), Responsible Consumption and Production (SDG12), and Partnership for the Goals (SDG17). The remaining four (SDGs 2, 3, 6 and 15) had high initial relevance ratings, which did not significantly change, serving as an internal control supporting the validity of the observed increases for other goals. Responses to open questions suggested that the students' experience of the assessment was rich in context and meaning, making Physiology more than 'just being a uni topic'.

Older adults often suffer from reduced physical capability relative to young adults, in part due to impaired muscle function. This study investigated the ergogenic effects of passive thigh heating on knee extensor torque production in healthy older versus younger adults. Twenty-two younger (YOUNGER; 23 ± 3 years) and 16 older (OLDER; 68 ± 8 years) adults completed an experimental visit whereby one thigh was heated via a garment circulating 50°C water for 90 min (HEAT) with the contralateral limb unheated (CONT). Four maximal contractions were performed at three isokinetic speeds (slow, 60°/s; moderate, 180°/s; and fast, 300°/s) and an isotonic set (25% maximal voluntary isometric contraction force); contractions were performed on both limbs at baseline and every 30 min thereafter for 120 min, with the final time point used to quantify the retention/decay in response. Vastus lateralis temperature was measured every 30 min, and surface electromyography was implemented throughout. HEAT increased muscle temperature from baseline (31.7 ± 1.7°C) at 30 min (36.5 ± 1.5°C), peaking at 90 min (37.5 ± 0.7°C), all P < 0.05. HEAT increased peak torque during moderate (+11 ± 12 N m) and fast (+7 ± 11 N m) contractions in only YOUNGER participants relative to their control leg which remained unchanged (P < 0.05). After 30 min, rate of force development (RFD) in HEAT increased during slow contractions from baseline in both age groups (+229 ± 210 N m s^-1, P < 0.05) and early force production (EFP) increased in both age groups during slow contractions from 60 min in HEAT (+15 ± 15 N m, P < 0.05). Peak EMG amplitude was unchanged throughout. Despite a similar increase in the RFD and EFP in both young and older adults, passive thigh heating improves peak knee extensor torque in moderate and fast isokinetic contractions in young adults only.