Journal of Physiological Sciences最新文献

Background: Deficiency in apelinergic signaling (APJ/Apelin) has been shown to accelerate cardiac aging. Given our observation that high-intensity interval training (HIIT) upregulates APJ and Apelin in aged mouse hearts, this study aimed to investigate whether apelinergic signaling mediates the cardioprotective effects of exercise.

Methods: Naturally aged (20-month-old) C57BL/6 mice were subjected to an 8-week HIIT regimen. To elucidate the role of APJ in HIIT-induced cardiac adaptions, mice were randomly assigned to one of three groups: HIIT with cardiomyocyte-specific APJ knockdown via adeno-associated virus, HIIT with an empty vector, and a sedentary control group. Senescent cardiomyocytes were employed to assess the impact of Apelin-13 and SIRT3 modulation on mitochondrial function. Additionally, a pharmacological study was conducted in aged mice using the APJ agonist AMG986, with or without the SIRT3 inhibitor 3TYP, to evaluate its therapeutic potential.

Results: In aged mice, HIIT elevated myocardial APJ expression, resulting in improved cardiac function, reduced fibrosis and senescence, and preserved mitochondrial structure. Disruption of APJ/Apelin signaling pathway blunted these benefits, particularly impairing mitochondrial biogenesis, motility, mitophagy, and energy metabolism. In vitro, SIRT3 deficiency abolished Apelin-13-induced enhancements in mitochondrial membrane potential, respiratory capacity and morphology. In vivo, pharmacological activation of APJ reproduced key anti-aging cardiac effects, which were negated by SIRT3 inhibition.

Conclusions: These findings suggested that HIIT exerted cardioprotective effects, at least in part, by enhancing apelinergic signaling and potentially modulating mitochondrial function through a SIRT3-dependent pathway. Targeting this pathway may provide potential therapeutic avenues for age-related cardiac dysfunction.

Frailty in aging is a major health challenge, requiring solution. Older people with frailty often exhibit malnutrition and dysregulated feeding. Feeding behavior displays circadian rhythm, while aging and frailty involve rhythm disorders, suggesting possible role of circadian feeding in frailty and treatment. Herbal medicine, Ninjin'yoeito (NYT), reportedly ameliorates frail symptoms. The present study explored impacts of NYT on circadian feeding and psychological/physical functions in aged mice. Here, we report that oral NYT independent of administration timing increases food intake specifically in 18:00-20:00, the pre-active phase, in aged and young mice, an effect mimicked by Chenpi and hesperidin. NYT altered appetite-regulating hormones and neuropeptides in pre-active phase. Repeated NYT administration restored anti-anxiety behavior, memory, and grip strength that declined in aged mice. These effects were blocked by food deprivation and pair-fed to control selectively in 18:00-20:00. These results reveal pre-active phase feeding promotion as a novel avenue to intervene aging-related frailty.

Blackout (BO) in breath-hold diving is attributed to cerebral hypoxia, yet direct observations are rare. We continuously recorded arterial oxygen saturation (SpO₂) and heart rate (HR) in 11 trained freedivers (5 females) performing two dynamic apneas (75 m, 100 m) using a waterproof forehead oximeter. One diver experienced BO at the end of a 100 m dive (SpO₂ 51 %), recovering within 5 s. Group SpO₂ fell from 98 ± 1 % to 77 ± 9 % (75 m) and 68 ± 9 % (100 m; range 51-83 %), while mean HR declined from 83 ± 12 to 43 ± 8 and 40 ± 4bpm, respectively. No arrhythmias were detected. Within-diver SpO₂ nadirs were consistent between distances (r = 0.93), whereas HR nadirs were not (r = 0.40). This case confirms BO can occur at SpO₂ values around 50 %, even in the absence of arrhythmia. The BO diver consistently showed the lowest SpO₂, indicating profound hypoxemia as the most likely contributing factor. Findings support individualized risk screening based on early desaturation patterns in submaximal dives.

While post-exercise cooling is known to enhance skeletal muscle adaptations, the effects of pre-exercise cooling remain unclear. This study investigated whether local muscle cooling immediately before exercise augments training-induced mitochondrial biogenesis in male C57BL/6 mice. Pre-exercise cooling involved 6 cycles of 6 min at 13°C followed by 4 min at 35°C on one hindlimb for 60 min before treadmill running. Acutely, this pre-cooling protocol increased exercise-induced PGC-1α mRNA expression by ∼13 % (p < 0.05) compared to exercise alone; this effect was abolished when cooling and exercise were separated by 3 h. Chronically, over 4 weeks, combined pre-cooling and exercise training significantly enhanced mitochondrial enzyme activities: citrate synthase (both main effects) and β-hydroxyacyl-CoA dehydrogenase (+23.9 % compared with exercise alone). However, mitochondrial structural protein levels remained unchanged. These results indicate that pre-exercise cooling promotes mitochondrial enzymatic adaptations in skeletal muscle, potentially offering a practical strategy to optimize the outcomes of endurance training.

Recent clinical studies suggest that individual psychosocial traits play a significant role in the onset and progression of diabetes. To examine whether glucose homeostasis depends on the social rank of individual mice, we analyzed the effects of dietary fat content on the hierarchy formed among co-housed mice and evaluated how perturbing rank by inhibiting amygdala neuronal activity influences glucose regulation. Social rank among four co-housed mice was assessed using the tube test. Switching to a high-fat diet altered blood glucose homeostasis, particularly by affecting rapid responses, and disrupted the established hierarchy, with the degree of disruption varying according to each mouse's rank. In contrast, chemogenetic inhibition of neuronal activities in the basolateral amygdala and surrounding area in the lowest-ranking mice modified both glucose homeostasis and its association with social rank. These findings provide mechanistic insight into the interaction between glucose regulation and psychosocial status.

Oral squamous cell carcinoma cell (OSCC) comprises malignant neoplasms arising within the oral cavity. Early-stage detection is associated with favorable prognosis, whereas progression to advanced stages with lymph node metastasis significantly worsens outcomes. We previously reported that the prostaglandin E₂ (PGE₂) receptor EP4 regulates OSCC migration. RNA sequencing reanalysis suggested that EP4 stimulation is strongly associated with cell migration and adhesion, with interleukin-6 (IL-6) emerging as a central mediator of these processes. In OSCC cells, ONO-AE1-437 (EP4 agonist) increased IL-6 mRNA expression and protein secretion. EP4-overexpressing cells showed increased IL-6 expression without stimulation, further enhanced by ONO-AE1-437 or PGE₂. xCELLigence demonstrated that PGE₂ promoted cell adhesion, which was suppressed by ONO-AE3-208 (EP4 antagonist) and Tocilizumab (IL-6 inhibitor). Scratch and transwell assays revealed enhanced migration under PGE₂ and ONO-AE1-437, blocked by IL-6 inhibition. These results suggest that EP4 promotes cell adhesion and migration through IL-6 in OSCC cells. (147 words).

We investigated whether monosodium aspartate (MSA), an umami compound structurally analogous to monosodium glutamate (MSG), influences aggressive behavior in a rat model of attention-deficit/hyperactivity disorder. Spontaneously hypertensive rats (SHR/Izm) were subjected to post-weaning social isolation and assessed using the resident-intruder paradigm. MSA ingestion significantly reduced aggression, particularly the frequency and duration of attacks, while the open field test showed no differences in anxiety-like behavior. c-Fos immunohistochemistry revealed increased neuronal activation in the intermediate nucleus of the solitary tract (iNTS) and decreased activation in the central amygdala (CeA) following MSA ingestion. This effect, along with the reduction in aggression, was abolished by vagotomy, suggesting gut-brain involvement. These findings indicate that MSA, like MSG, can reduce aggression via the gut-brain axis, implicating the vagus nerve, iNTS and CeA as key mediators. This highlights that the modulation of aggression by ingested amino acids is a broader effect acting through shared mechanisms.

Atherosclerosis leads to severe clinical complications, and biomarkers for asymptomatic atherosclerosis are desired. Plasma levels of myosin-11 have been reported to increase in patients with symptomatic atherosclerosis. To investigate the association between circulating myosin-11 levels and atherosclerotic cardiovascular disease (ASCVD) risk in patients without symptomatic atherosclerosis, this study recruited 161 participants: 80 patients with ASCVD risk, 50 patients with ischemic heart disease (IHD), and 31 control participants (Controls). We developed an ELISA that consists of rat monoclonal antibodies specific for the coiled-coil domain of myosin-11. Myosin-11 levels were highest in the IHD group, followed by the ASCVD risk group. The area under the receiver-operating characteristic curve of myosin-11 was 0.980 for IHD versus Controls and 0.874 for ASCVD risk versus Controls. The association between myosin-11 levels and hypertension remained significant after multivariate logistic regression analysis. Myosin-11 levels may be a biomarker for stratification of asymptomatic individuals with ASCVD risk.

Adaptations in cardiac autonomic regulation induced by physical training are central to the health benefits of exercise. We investigated the interaction between central motor command, breathing rate, and expiration timing during an isolated joint movement. Fifteen volunteers (30.9 ± 7.2 years; 8 women) performed twelve 3-min leg extension tasks in a seated position under three randomized conditions: movement type (active vs. passive), breathing pattern (spontaneous, 12 or 6 cycles/min), and expiration timing (during extension vs. return). RR intervals and their variability were analyzed. Voluntary motor control reduced indices of autonomic and parasympathetic regulation (p < 0.05), whereas slow-paced breathing enhanced them. However, motor control exerted a dominant influence over cardiac autonomic regulation (p < 0.001), regardless of breathing rate. Expiration during the return phase was associated with greater parasympathetic activity (p < 0.05). These results highlight the central role of motor command in autonomic modulation and suggest that emphasizing expiration during recovery may help preserve parasympathetic regulation.

Changes in reaction times (RTs) during attentional processing may be associated with the state of breathing. Although breathing and cardiac activity interact, the functional importance of the cardiorespiratory system for modulating attentional processing remains unclear. To determine the involvement of respiration and RR interval (RRI) variability in successful task performance, thirty-six healthy participants performed a short-term memory task. For RTs limited to correct responses, increases were observed under two conditions: i) when inspiratory onset (or exhalation-to-inhalation transition) occurred and ii) when RRI velocity increased during retrieval. Importantly, multilevel model analysis revealed that the timing of inspiratory onset and the increase in RRI velocity were temporally mismatched, suggesting that at least two independent mechanisms may prolong RT. These findings contribute to a better understanding of how respiration and RRI variability may be functionally differentiated and how each could be linked to attentional processes that influence performance.