Experimental Physiology

Intense unilateral muscle contractions evoke measurable activity within the contralateral neuroaxis, which can be detected with surface electromyographic activity in the resting homologous muscle. Physiological mirror activity (PMA), the unintentional increase in contralateral muscle excitation, has been implicated in cross-limb interactions and adaptations. Despite longstanding observations of PMA, it remains unknown whether this low-level muscle excitation influences local muscle metabolism. We addressed this question using a vascular occlusion test in 10 healthy adults. Surface electromyography and near-infrared spectroscopy-derived measures of tissue oxygen saturation and muscle oxygen consumption (mVO2) were obtained from the resting left forearm during vascular occlusion at rest and during fatiguing unimanual contractions of the right hand. PMA in the contralateral resting arm was greater during unimanual fatigue than during rest (mean difference: 8.9%AA, 95% CI: 4.1 to 13.8; p = 0.002, g = 1.20). This increase was accompanied by a steeper rate of tissue oxygen desaturation (mean difference: -0.132 %{middle dot}s-1, 95% CI: -0.227 to -0.037; p = 0.012, g = -0.91) and greater mVO2 (mean difference: 0.188 mL O2{middle dot}min-1{middle dot}100 g-1, 95% CI: 0.057 to 0.320; p = 0.010, g = 0.94). Greater PMA was associated with both a faster rate of oxygen desaturation (r = -0.85, 95% CI: -0.96 to -0.46, p = 0.002) and greater mVO2 (r = 0.78, 95% CI: 0.28 to 0.94, p = 0.008). These findings suggest that PMA is accompanied by increased local metabolic demand, consistent with a coupling between unintentional muscle excitation and oxygen extraction in the resting limb.

Skeletal muscles secrete a variety of cytokines in response to inflammatory stimuli such as lipopolysaccharide (LPS); however, the contributions of resident macrophages or other non-muscle cells to the secretory responses are not well understood. To determine the potential impact of resident macrophages to inflammatory cytokine production, we tested the LPS responsiveness of isolated mouse soleus muscle when a critical toll receptor adapter protein (Myd88) was knocked down only in myeloid-derived cells within the muscle (e.g. resident macrophages). The phenotype is referred to as LyzMyd88-/- ; the litter mate controls were Myd88fl/fl. In solei from LyzMyd88-/- mice, cytokine secretory rates for interleukin-6 (IL-6) and keratinocyte-derived cytokine (KC, CXCL1) were significantly reduced to 56.3%, and 60.6% of control, respectively, over the first hour of LPS exposure. In the second hour, secretion of granulocyte colony stimulating factor (G-CSF), IL-6, KC(CXCL1) and monocyte chemoattractant protein-1 (MCP-1, CCL2) were greatly elevated by 5-10-fold in both phenotypes compared to the first hour. However, only MCP-1 secretion was decreased to 70.6% of control in the second hour. We also tested the secretory response to buffer containing 1% sterile mouse plasma because dilute plasma is known to amplify the responses of macrophages to LPS. Treatment with 1% plasma alone affected baseline measures of some cytokines but resulted in no further increases in secretion during either hour of exposure. However, small and gradual increases in secretory rates were observed for several cytokines over the study period, with or without plasma, with the largest responses seen in IL-6 and KC. Overall, the results are consistent with a significant early contribution of myeloid-derived, resident immune cells to the cytokine secretory responses of intact oxidative skeletal muscle. In addition, small quantities of plasma in the buffer have no independent stimulatory effects on cytokine secretion

Resistance training lasting a few weeks increases maximal force mainly through neural adaptations that enhance the drive from the nervous system to muscle. While these adaptations have been well documented at the motor unit (MU) level during submaximal force contractions, the mechanisms underlying force increases during maximal voluntary contractions are poorly understood. This is due to a classic technical limitation in tracking MUs longitudinally during maximal force tasks. Here, we solved this technical challenge, enabling the investigation of MU adaptations during MVCs in both the trained and untrained limbs following unilateral resistance training. High-density surface electromyography was recorded from the biceps brachii of both limbs before and after a 4-week unilateral resistance-training intervention, and the same MUs were longitudinally tracked across sessions during MVCs by concatenation of three MVC trials of ~5-s each.Unilateral training increased maximal force in the trained limb (+16%) and induced strength transfer to the untrained limb (+8%). In both limbs, maximal contractions after training were characterized by greater EMG amplitude, faster muscle-fiber conduction velocity, and higher MU discharge rates, indicating enhanced neural drive to the motoneuron pool. These adaptations were strongly associated with improvements in maximal force (R2 > 0.7 for all). Importantly, longitudinal MU tracking revealed a non-uniform adaptation across the MU pool: MUs with higher baseline conduction velocity, indicative of higher recruitment threshold, exhibited the largest pre-post increases in discharge rate, whereas lower-threshold units showed smaller changes. Collectively, these findings demonstrate that gains in maximal force and their transfer to the untrained limb are primarily mediated by enhanced rate coding of higher-threshold MUs during MVCs.

After myocardial infarction (MI), pathological autonomic remodeling, including vagal dysfunction and sympathoexcitation, occurs and predisposes to ventricular arrhythmias (VT/VF). The underlying factors that drive this remodeling, including the observed neuroinflammation and glial activation, remain unknown. We hypothesized that sympathetic nociceptive afferents underlie this remodeling post-MI. Epidural resiniferatoxin (RTX, to ablate sympathetic cardiac afferent neurons) vs. saline was administered in pigs prior to MI and autonomic and electrophysiological effects assessed four to six weeks post-infarction. Acute effects of afferent ablation after chronic MI were also assessed in a separate group of animals. Baroreflex sensitivity and vagal tone, as measured by parasympathetic neuronal activity and cardiac nociceptive responses, were improved in infarcted animals which received epidural RTX prior to MI. These animals also demonstrated reduced spinal cord inflammation and glial activation, downregulation of circulating stress and inflammatory pathways, and stabilization of electrophysiological parameters, with reduced VT/VF-inducibility. Epidural RTX after chronic MI also acutely restored vagal function and decreased VT/VF. These data suggest that cardiac spinal nociceptive afferents directly contribute to VT/VF susceptibility and MI-induced autonomic remodeling, including oxidative stress, inflammation, glial activation, and reduced vagal function, providing novel insights into the causal role of these afferents in driving sympathovagal imbalance after MI.

Advanced footwear technology (AFT) improves running economy and is widely credited with recent performance improvements in road running, with observational analyses consistently demonstrating that women have improved more than men. In contrast, laboratory studies generally report similar running economy responses to AFT in both sexes, leaving the observational-experimental divergence unresolved. A fundamental limitation of observational work is the absence of a control condition, making it impossible to separate AFT-related gains from concurrent performance trends. We addressed this by comparing performances between pre-AFT (2009-2015) and AFT (2017-2024) eras across road-running events (10km, half marathon, marathon) and throwing events (shot put, discus, javelin, hammer), the latter serving as an active control condition subject to the same broad athletic trends but unaffected by footwear technology. The top 50 performances per event, era, and sex were converted to World Athletics points and analysed using linear mixed-effects models. Performances improved significantly between eras ({beta} = 0.294, p < .001), with gains substantially larger in road running than in throwing ({beta} = 0.731, p < .001). The sex-specific pattern of improvement also differed between event categories (era x event type x sex interaction, {beta} = 0.786, p < .001): road-running improvements were greater in women than men (4.51% vs 2.62%), whereas throwing improvements did not differ by sex (0.93% vs 1.14%). These findings suggest that AFT benefits women more than men in competition, whether through a greater physiological response or more effective translation of economy gains to race performance, and suggest current laboratory protocols may be insufficiently sensitive to detect potential sex-specific effects.

Advanced footwear technology (AFT) has transformed competitive running, yet individual and sex-specific responses to different AFT models remain unclear, particularly near race pace. This study examined running economy (RE) and gait biomechanics in response to three top-tier AFT models (Shoe A: adidas Pro Evo 2; Shoe B: Nike Alphafly 3; Shoe C: On CloudBoom Strike 2) in 14 male and 12 female well-trained runners at sex-specific submaximal speeds (16 and 14 km{middle dot}h-{superscript 1}). RE, spatiotemporal, and joint kinematic/kinetic data were collected via indirect calorimetry, accelerometry, and three-dimensional motion capture with force platforms. RE was significantly lower in Shoe C than Shoe A (males: 2.1%; females: 1.4%) and Shoe B (males: 1.9%; females: 0.9%), with 73% of runners responding favourably to Shoe C, a more consistent response than previously reported. Despite being lightest, Shoe A produced the poorest RE, challenging conventional mass-economy assumptions. Biomechanically, Shoe C elicited greater impact magnitude, lower ankle quasi-stiffness, and greater ankle angular velocity during early stance. Female runners showed smaller RE improvements, potentially related to lower running velocity and body mass limiting midsole engagement. The most efficient AFT enabled these well-trained runners to be more spring-like through tolerating higher forces and faster angular velocities without greater demand on metabolic cost.

Older adults sustain disproportionately severe injuries from trip-induced falls during obstacle crossing. Such falls depend partly on forward momentum when the foot crosses the obstacle. MOSAP, an index of passive dynamic gait stability, reflects this momentum. We quantified MOSAP and a synergy index from uncontrolled manifold analysis of step length and extrapolated center of mass in 25 young (21.6 {+/-} 3.5 yr) and 23 older adults (68 {+/-} 4.3 yr) during unobstructed and obstructed walking, to test whether MOSAP increases during obstacle crossing and whether it is actively stabilized at each step. Both groups increased MOSAP progressively over two approach steps by reducing forward momentum and shifting the center of mass posteriorly. Older adults showed greater increases at the crossing steps. The synergy index was positive for all steps, showing that deviations in step length and extrapolated center of mass covaried to stabilize MOSAP at step-specific values. The synergy index was not influenced by age. We conclude that adults actively recruit passive body mechanics while approaching and crossing obstacles to reduce the risk of a trip becoming a fall. Older adults amplify this strategy to compensate for diminished neuromuscular corrective capabilities.

Fascicle operating length during dynamic tasks is often compared to the isometric torque-length relationship, but there is a lack of evidence regarding the influence of joint velocity on optimal fascicle length. Moreover, there is no consensus in the literature regarding the influence of contraction initiation (pre-activation or passive start), although it could alter the interaction between fascicles and the tendon. This study aimed to investigate the effect of joint velocity and pre-activation on the torque-angle and torque-length relationships of the vastus lateralis during mono-articular isokinetic knee extensions. Twenty-one participants performed isometric, isokinetic (50{degrees}.s-1 to 450{degrees}.s-1), and isokinetic knee extensions with maximal isometric or eccentric pre-activation at 100{degrees}.s-1 and 300{degrees}.s-1. Torque, joint angle, fascicle length, and electromyographic activity of the quadriceps femoris muscles were recorded during contractions and then used to model the torque-angle and torque-length relationships. We were able to successfully fit the torque-angle and torque-length relationships (R{superscript 2}=0.93 and R{superscript 2}=0.92, respectively). A main effect of velocity was detected regarding the optimal angle (p<0.05), but no significant change was observed for the optimal fascicle length. Isometric pre-activation induced a reduction in maximal torque production compared with eccentric pre-activation and passive conditions at both isokinetic velocities (p<0.001), with no change in muscle activity. Our results suggest that muscle-tendon interactions may permit a dissimilar behavior between the torque-angle and the torque-fascicle length relationships. The reduction in torque following isometric pre-activation may be related to a contraction history-dependent phenomenon. NEW & NOTEWORTHYWe demonstrated that, at a given joint angle, increasing velocity altered fascicle operating length without shifting optimal fascicle length, likely because of muscle-tendon interactions. We also showed that maximal isometric pre-activation before a concentric contraction reduced mean and maximal torque during the isokinetic phase compared with eccentric pre-activation or no pre-activation. This effect may be linked to contraction history, since muscle activity did not differ between conditions.

Background Perioperative incidents such as hypoxic cardiac injury often have subtle or nonspecific clinical manifestations. Reduction in myocardial oxygenation precedes biochemical changes, as well as electrical and functional changes. Photoacoustic imaging (PAI) is a modality that uses laser irradiation of tissue to generate ultrasonic waves, enabling spatially resolved quantitative mapping of oxygenated and deoxygenated haemoglobin. We investigated the utility of PAI for real-time monitoring of myocardial and great vessel oxygenation. Methods Male CD-1 mice were anaesthetised, and photoacoustic and simultaneous B-mode images were acquired of the myocardium and right ventricular outflow tract (RVOT), the pulmonary artery, and aorta. PAI was performed at fractional inspired oxygen levels (FiO2) of 100%, 21%, and then 10%. Separate cohorts of mice were exposed to increasing intravenous doses of either combined phenylephrine and isoprenaline, or individual administration of vasoactive or adrenergic agents. Results PAI reliably distinguished changes in oxygenation in the RVOT cavity, pulmonary artery, aorta, and myocardium. PAI detected hypoxia-induced changes in oxygenation, revealing greater desaturation in the myocardium than in the RVOT (-9.85%, 95% CI -14.94 to -4.77, P<0.0001). Escalating doses of phenylephrine and isoprenaline caused a progressive desaturation of the myocardium and RVOT (mean [95% CI]; myocardium 16 mg/kg: -14.64% [-27.62 to -1.65], P=0.0038 and RVOT 32 mg/kg: -18.71% [-32.15 to -5.27], P=0.0003). Myocardial deoxygenation was detected before changes in systolic function or electrical abnormalities. Conclusions This work demonstrates that PAI can reliably monitor cardiac oxygen desaturation, potentially offering an earlier warning of cardiac dysfunction and injury compared to existing monitoring tools. Keywords: Echocardiography, hypoxaemia, hypoxia, myocardial injury, oxygenation, perioperative monitoring, photoacoustic imaging

Synthetic opioids like fentanyl are a leading cause of overdose mortality. Although the hallmark of fentanyl overdose is ventilatory depression, fentanyl also induces tonic activation of skeletal musculature, including the diaphragm, which may advance progression of overdose towards death. While tonicity may further restrict diaphragmatic contractility, phase-specific dysregulation may also reflect a larger state of discoordination in respiratory control. Using urethane-anesthetized mice exposed to fentanyl, we test the hypothesis that fentanyl-induced diaphragm tonicity results from a loss of coordinated motor activity. Fentanyl produced two distinct phases: an initial phase of maximal ventilatory depression with preserved phasic activity, and a later phase characterized by unstable ventilation that partially rebounds, tonic diaphragmatic activation with loss of inspiratory phase dominance in EMG activity, and diminished bilateral diaphragmatic coordination. Carotid body denervation eliminated tonic activity and expiratory-phase EMG elevation, but it did not prevent hemi-diaphragm discoordination or ventilatory instability. Rhythmic brainstem slice recordings showed that bilateral preBotzinger complex burst-amplitude coupling was disrupted by u-opioid receptor (MOR) agonism. Furthermore, disordered diaphragm activity was reversed by administration of the MOR antagonist, Naloxone. Our findings reframe fentanyl overdose as a temporally evolving syndrome that involves distinct mechanisms to disrupt respiratory motor coordination.

Predictions of skeletal muscle energy consumption under a diverse range of muscle contractile conditions are critical for improving our understanding of locomotion. Existing mathematical models, while capturing the mechanical dependence of energy consuming processes, neglect the time-dependent behaviour and recovery costs associated with regenerating ATP. This time-dependence is important for predicting the energetic response of muscles during repetitive or cyclical tasks like locomotion, where muscle undergoes many contraction cycles. This study presents a novel model to predict energetic rates based on physiological processes: Ca2+ transport costs, cross-bridge cycling costs, and ATP regeneration. Previous mathematical models include the dependence on Ca2+ transport and cross-bridge cycling, but neglect the time-dependent response and the subsequent recovery of ATP following the contraction. Model parameters were obtained from existing data on isolated muscle preparations, and predicted energetic rates were validated on separate datasets across a range of contractile conditions including dynamic, sub-maximal, and twitch contractions. The time-dependent model was able to capture the influence of contraction frequency on peak energetic rates and the time-course of energetic recovery observed experimentally. The model captures key physiological processes while maintaining a minimal number of free parameters and low computational cost. This enables generalisability across muscles and species, and implementation into larger scale musculoskeletal models.

Heart rate (HR) and its variability (HRV), mediated by the autonomic nervous system are key indicators of diving physiology and behavioral state, in vertebrates. However, these indicators remain understudied in cetaceans due to the technical challenges of recording electrocardiograms (ECGs) underwater. To overcome these challenges, we developed a waterproof device based on an all-in-one suction-cup that integrate an ECG-accelerometer logger with bipolar electrodes. Using this device, we obtained high-resolution ECG signals in bottlenose dolphins (Tursiops truncatus, n=8), belugas (Delphinapterus leucas, n=2), and orcas (Orcinus orca, n=1) during breathing and apnea. This approach allowed us to highlight species-specific features of the ECG waveform, consistent with a biphasic T wave in the three species of cetaceans and a bifid P wave unique to belugas, which were independent from the respiration state. Resting surface HRs were 70 {+/-} 4 bpm in dolphins, 51 {+/-} 1 bpm in belugas, and 50 {+/-} 2 bpm in the orca and exhibited pronounced oscillation related to the mechanism of respiratory sinus arrhythmia. As expected, short apneas ([~] 1 min) induced bradycardia in all three species (53 {+/-} 5, 33 {+/-} 3, and 37 {+/-} 2 bpm, respectively). In dolphins this bradycardia was coupled with a significant decrease of the coefficient of variability of RR intervals, one of the indices of HRV. Moreover, we were surprised to observe HR oscillations throughout apnea, suggesting a persistent fluctuation of autonomic modulation. Thus, to better understand autonomic modulation in cetaceans we employed food (fishes, squids, gelatin, etc.) as a strong rewarding stimulus. For that we compared HR and HRV during 2-min of food deprivation versus continuous feeding periods. In dolphins, food deprivation produced no significant change in HR or HRV from resting surface values, whereas continuous feeding decreased HR of about 20 % and increased HRV metrics (StDRR, CVRR, RMSSD). Belugas showed similar responses, with a HR decline of about 40 % and an increase HRV indices. These findings established baseline HR and HRV parameters during breathing or apnea for three cetacean species and demonstrate that autonomic responses to appetitive stimuli can be non-invasively quantified, validating a novel tool to investigate cetacean cardiovascular physiology and environmental perception.

Despite extensive research on vestibular function in microgravity, particularly during orbital and parabolic flight exposure, several gaps remain regarding the spontaneous behavior of vestibular organs under non-terrestrial gravitoinertial conditions. In particular, semicircular canal function, typically assessed through vestibulo-ocular reflex (VOR) recordings, has yielded inconsistent findings, with reports describing either no effect or reduced performance in microgravity. Moreover, many of these studies are limited by methodological constraints that reduce the interpretability of their conclusions. To clarify these discrepancies, we evaluated horizontal and vertical VOR responses during parabolic flights to assess semicircular canal function under transient weightlessness. Participants were passively rotated at a constant frequency and amplitude during normogravity and microgravity phases, centered along the head vertical or inter-aural axis. Eye movements were recorded binocularly using infrared eye-tracking in darkness to eliminate visual influences, while participants were tightly restrained to minimize proprioceptive variability. Results show a reduction in VOR gain during microgravity in both axes, despite consistent rotational stimulation across gravity conditions. In addition, VOR gain remained reduced after parabolas in the horizontal plane, whereas vertical VOR performance was preserved. These are the first results to demonstrate an immediate alteration of semicircular canal function in weightlessness. Possible sources of the reduction in VOR performance in 0g are discussed. We also propose that the observed post-flight effects reflect a down-weighting of semicircular canal inputs during multisensory integration.

Obesity is associated with an elevated risk of pathological cardiac hypertrophy, whereas exercise confers cardioprotective effects; however, the cellular mechanisms underlying these opposing influences remain incompletely defined, particularly in females. We investigated how obesity and exercise affect cardiomyocyte ultrastructure, Ca{superscript 2} release, and contractility in female Zucker Diabetic Fatty rats and their lean littermates. Animals were assigned at 12 weeks to sedentary or aerobic exercise-trained groups and maintained on a standard diet. By 18 weeks, obese rats exhibited increased body mass and myocardial hypertrophy in the absence of diabetes. Sedentary obese animals showed a reduced fraction of compact dyads and diminished stimulated and caffeine-induced Ca{superscript 2} release, while contractility remained preserved. In lean rats, exercise increased dyad density but reduced Ca{superscript 2} release, whereas in obese rats, exercise enhanced both dyad compactness and Ca{superscript 2} release. Across all groups, global cardiomyocyte ultrastructure and contractile function were similar. Type III ANOVA revealed a significant obesity x exercise interaction for dyadic structure and Ca{superscript 2} release. These findings demonstrate that obesity itself, independent of diabetes, triggers early dyadic remodeling and altered Ca{superscript 2} handling in female myocardium before detectable impairment of global cardiomyocyte structure or contractile function. Furthermore, exercise exerts beneficial effects on dyadic ultrastructure and Ca{superscript 2} signaling in obese animals. New & NoteworthyUsing a female rat model of obesity without diabetes, we demonstrate that obesity induces early remodeling of the dyadic system and impairs Ca{superscript 2} release in cardiac myocytes. We further show that the effects of aerobic exercise on dyadic structure and function are obesity-dependent, improving both dyad organization and Ca{superscript 2} signaling. These findings identify the dyadic microdomain as a vulnerable cellular site in obesity and a potential target for exercise-induced recovery.

Tricuspid valve regurgitation is a frequent valve lesion and, if severe, an independent predictor of mortality. In most patients, the valve itself has historically been considered intact. Yet, we have previously shown that the valve may not be an innocent bystander. In multiple sheep models, we have shown that the tricuspid valve thickens and stiffens. This remodeling may contribute to valve disease. Our goal is to extend our investigation of tricuspid valve remodeling to a rodent model, potentially opening scientific opportunity and enabling scaling our studies. To this end, we used pulmonary artery banding (PAB) in male rats to induce pressure overload and right ventricular remodeling. After excising the tricuspid valve, we quantified anterior leaflet morphology, mapped anterior leaflet thickness using optical coherence tomography, and evaluated anterior leaflet belly mechanics using a custom bulge testing system. Compared with SHAM controls, PAB increased anterior leaflet area. Moreover, anterior leaflets in PAB animals exhibited region-specific thickening, with the largest increases near the annulus. Finally, anterior leaflets in PAB animals were significantly less compliant. However, leaflet stiffening stemmed from aforementioned thickening, i.e., structural stiffening, not constitutive stiffening. Our findings demonstrate that we can reliably quantify leaflet area, thickness, and stiffness in the minuscule tricuspid valves of rats. We also show that tricuspid valve remodeling is not ovine-specific, but also affects the tricuspid valves of rats. Together, our findings support our hypothesis that tricuspid valves are not innocent bystanders in regurgitation, and that rats may serve as a scalable model system for future investigations. NEW & NOTEWORTHYUsing a rat pulmonary artery banding model of pulmonary hypertension, we show that chronic right ventricular pressure overload induces leaflet enlargement and region-specific thickness remodeling of the tricuspid valve. Although structural mechanical metrics change under pressure loading, normalization by thickness reveals that geometric remodeling rather than intrinsic material stiffening predominates. These findings highlight leaflet structural (mal)adaptation as a potential contributor to functional tricuspid regurgitation and underscore the importance of considering leaflet geometry in therapeutic strategies.

Background Ischemic heart failure (IHF) has been shown to impair contractility and disrupt sarcomere function in the left ventricle. Left ventricular failure can cause left atrial dysfunction, which is associated with a greater risk of patient mortality. Despite this, the biochemical and biomechanical characteristics of the left atrium in IHF remain obscure. Methods Myocardial mechanical properties were measured using permeabilized muscle isolated from the left ventricle (LV) and left atrium (LA) of donors and patients with IHF. Tissue homogenates from these samples were used to measure titin and myosin isoforms as well as the phosphorylation of sarcomeric regulatory proteins. Histology was used to quantify fibrosis in the patients' left ventricle and left atrium. Results Length-dependent changes in Ca2+-sensitivity were blunted in LV myocardium from patients with IHF. LA myocardium did not show robust length-dependence of Ca2+-dependent force. The calcium sensitivity of both LA and LV myocardium was increased in IHF. The maximum force generated by LV but not LA myocardium was decreased in IHF. LA myocardial samples exhibited faster contractile kinetics than LV samples, irrespective of disease. Troponin I phosphorylation decreased in both chambers with IHF. Conclusions Left atrial IHF myocardium maintained contractile force and displayed increases in calcium sensitivity, which may allow for increased LA contraction under pathological conditions. The increases in calcium sensitivity observed in ischemic myocardium of both chambers are likely driven by decreased phosphorylation of troponin I, which alters thin filament regulation. Conversely, thick filament properties of the left ventricle, such as thick filament protein isoforms and phosphorylation of myosin binding protein-C, displayed chamber-specific differences independent of disease state. These biochemical changes may explain the chamber-specific differences in kinetics and length-dependent properties. Collectively, these biophysical and biochemical data suggest LA remodeling in IHF may assist in increasing LV end-diastolic volume to maintain adequate cardiac output.

Postural control depends on the ability to adapt motor responses to changing environmental and physiological conditions. Neuromuscular fatigue (NMF) is known to alter balance and muscle activation patterns, yet its effects on motor adaptation during whole-body postural tasks and on the persistence of learned strategies remain unclear. This study investigated whether localized NMF of the ankle dorsiflexors influences adaptation to a novel postural perturbation task and whether learning under fatigue induces persistent changes during subsequent re-exposure. Twenty-five healthy young adults were assigned to either a fatigue (FAT) or no-fatigue (NoFAT) group and completed two experimental sessions separated by 48-72 h allowing recovery from acute fatigue for fatigued group. Participants adapted to repeated mechanical perturbations while standing upright, while ground reaction forces and electromyographic activity of lower-limb muscles were recorded. NMF did not impair overall adaptation performance, as both groups exhibited similar reductions in performance error across practice. However, participants exposed to fatigue exhibited altered postural recovery dynamics, characterized by a reduced return toward the initial posture following perturbation release. These differences persisted during re-exposure on the subsequent day, despite the absence of acute fatigue. In parallel, NMF modified muscle activation and coactivation patterns involving both fatigued and non-fatigued muscles, several of which were retained during re-exposure. These findings indicate that the central nervous system preserves successful adaptation to postural perturbations under fatigue by reorganizing neuromuscular coordination and stabilization strategies. Learning under fatigue therefore influences not only immediate motor execution, but also shapes the longer-term representation of postural control strategies.

Background: Stability of the atherosclerotic plaque in coronary artery disease (CAD) is determined by features such as total plaque burden and necrotic core volume. Since invasive procedures are required to evaluate plaque stability, we tested whether the peripheral blood mononuclear cell (PBMC) microRNA (miR) signature could correlate with measures of plaque stability and thus serve as a non-invasive biomarker. Method: Patients from two distinct geographical locations in India were recruited to the study (Site 1: CAD=19, non-CAD=5; Site 2: CAD=12, non-CAD=7) and underwent invasive intravascular ultrasound with virtual histology to assess plaque burden and necrotic core volume. RNA from PBMCs of these patients was subjected to unbiased sequencing. Differential miR expression evaluated by DESeq2 and assessed for co-relationship with plaque stability. miR target gene prediction was performed using multiple databases, and Enrichr was used for enrichment analysis. Results: Unbiased RNA sequencing identified miR-664a-3p to be significantly downregulated in CAD patients from both sites (Site 1: log2FC=-1.02, p=0.0033 & Site 2: log2FC=-1.04, p=0.0007). miR-664a-3p expression was inversely correlated with plaque burden and necrotic core volume. Receiver operating characteristic (ROC) analysis of miR-664a-3p showed significant discriminative performance in the CAD cohort, with AUC values of 0.842 (Site 1) and 0.881 (Site 2). miR664a-3p target prediction and pathway enrichment analysis revealed selective enrichment of inflammatory signaling pathways, such as IL-17 and TNF, suggesting an association between PBMC pro-inflammatory response and plaque vulnerability. Conclusion: miR-664a-3p is downregulated in CAD patients and inversely correlates with measures of plaque stability, with potential as a biomarker for identifying patients at risk of CAD progression and plaque instability. Keywords: Coronary artery disease, peripheral blood mononuclear cells (PBMCs), microRNA, atherosclerotic plaque, necrotic core, plaque burden, biomarkers.

Climate-driven warming is challenging the physiological limits of aquatic ectotherms, with cardiac performance emerging as one of the key determinants of thermal tolerance. Cardiac function relies on mitochondrial ATP production, and mitochondrial dysfunction has been linked to cardiac failure at critical temperatures. However, mitochondria are plastic and may represent a target for interventions aimed at improving thermal tolerance in fish. Exercise training improves whole-animal performance in fish, including cardiac thermal performance, and improves mitochondrial function in other taxa. However, its effects on the thermal sensitivity of cardiac mitochondria remain unknown. This study investigated whether exercise-training alters cardiac mitochondrial performance at optimal and critical temperatures in rainbow trout Oncorhynchus mykiss. Farmed rainbow trout were subjected to a four-week exercise training regime, while control fish remained under standard rearing conditions. Cardiac mitochondrial respiration was assessed in permeabilised heart fibres at 16{degrees}C (optimal growth temperature) and 26{degrees}C (temperature associated with cardiac arrhythmia) and several biochemical and nuclear indicators were measured. No significant differences were detected between treatments for any measured variable. However, trained fish generally exhibited higher maximal respiratory capacities and respiratory control ratios, particularly at the elevated temperature, suggesting subtle improvements in mitochondrial function despite considerable inter-individual variation. Temperature influenced mitochondrial performance, increasing proton leak and reducing coupling efficiency. These findings demonstrate that cardiac mitochondrial function is thermally sensitive and represents a potential targeted for improving thermal resilience in aquaculture species.

Osteoarthritis (OA), a degenerative joint disease, is associated with increased systemic inflammation, chronic pain, and cardiovascular dysfunction. Epidemiological evidence establishes that OA increases the risk of cardiovascular disease (CVD) threefold, yet the causal role of OAs contributions remains underexamined. We assessed cardiac function longitudinally following destabilization of the medial meniscus (DMM) surgery to induce osteoarthritis in mice. DMM-mice exhibited significant, sexually dimorphic alterations in echocardiographic parameters. Female DMM mice developed impaired relaxation with altered E/A ratios, increased E/e ratios, and prolonged intraventricular relaxation time with no change in ejection fraction, while male DMM mice showed progressive systolic dysfunction with decreasing ejection fraction, increased E/e ratio, and prolonged intraventricular contraction time. Transcriptomic profiles and biochemical analyses demonstrated divergent cellular responses involving fibrosis and oxidative stress in female mice, whereas autophagic and apoptotic responses were observed in male mice. Using a tumor necrosis factor 2 (TNFR2) agonist shown to reduce systemic inflammation, we investigated its potential therapeutic role in the context of OA-induced cardiovascular dysfunction. TNFR2 agonism proved to be effective both prophylactically and therapeutically for female diastolic dysfunction. While prophylactic and therapeutic administration delayed male systolic dysfunction, the efficacy declined over time. Our findings demonstrate evidence of a novel sexually dimorphic model of OA-induced CVD that recapitulates the sexually dimorphic pattern of patient phenotypes and a promising new therapeutic approach to CVD. Translational RelevanceOsteoarthritis patients have higher, often unrecognized, cardiovascular risk, yet preclinical models linking joint disease to cardiac dysfunction remain unexplored. Using a murine preclinical model of OA reveals the key findings. First, OA alone drives sex-specific cardiac phenotypes - females develop diastolic dysfunction, whereas males develop progressive systolic impairment. Second, selective TNFR2 agonism prevents and reverses OA-induced diastolic dysfunction in female mice and delays systolic decline in males. These findings suggest sex-dependent cardiac monitoring in OA patients and indicate that TNFR2-targeted therapy will likely be a sex-informed intervention to provide cardioprotective benefit. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=131 SRC="FIGDIR/small/736778v1_ufig1.gif" ALT="Figure 1"> View larger version (43K): org.highwire.dtl.DTLVardef@1f41661org.highwire.dtl.DTLVardef@1e94cb7org.highwire.dtl.DTLVardef@1abbac0org.highwire.dtl.DTLVardef@171cc86_HPS_FORMAT_FIGEXP M_FIG C_FIG