Experimental Physiology最新文献

Advanced age is the strongest risk factor for Alzheimer's disease and related dementias (ADRDs). Traumatic brain injury (TBI) has also been recognized as a risk factor for ADRD, potentially contributing to an earlier onset of the disease. Thus, elucidating the mechanisms underlying brain ageing and TBI is critical for developing strategies to preserve brain health. Accumulating evidence indicates that arterial ageing, manifested as increased central arterial stiffness, is closely associated with cerebral blood flow (CBF) dysregulation and brain ageing, whereas improvement of CBF regulation through aerobic exercise training contributes to brain health. Emerging studies suggest that central arterial stiffness is elevated after TBI but can be ameliorated by aerobic exercise training, which benefits TBI recovery. In this brief review, we summarize evidence demonstrating that (1) age- or TBI-related increases in central arterial stiffness are associated with CBF dysregulation, and (2) aerobic exercise training improves CBF regulation by reducing central arterial stiffness in both healthy older adults and individuals with chronic TBI. Collectively, these findings support the hypothesis that central arterial stiffness impacts CBF regulation and highlight aerobic exercise as a promising intervention for preserving brain health in ageing and after TBI.

The conventional approach to aerobic exercise prescription involves large muscle mass exercise and the manipulation of variables such as training intensity, duration and frequency to promote desired adaptations. However, during whole-body exercise, central limitations (i.e., neural, pulmonary and/or cardiac) constrain exercise tolerance and limit the increase in muscle blood flow and the degree of intramuscular metabolic perturbation incurred. Consequently, even during high-intensity large muscle mass exercise, a substantial peripheral reserve remains, potentially diminishing the adaptive stimuli that drive improvements in peripheral function and, in turn, exercise tolerance. In contrast, these central constraints are markedly attenuated during small muscle mass aerobic exercise, such as single-leg cycling or knee extension. As a result, muscle activation, blood flow, work rate and the magnitude of metabolic perturbation per unit of muscle are considerably greater during small compared with large muscle mass exercise. Because many of these responses are thought to represent key triggers initiating peripheral adaptations, such as angiogenesis and mitochondrial biogenesis, small muscle mass exercise might confer unique advantages for enhancing peripheral vascular and metabolic function. This review outlines the key physiological differences between small and large muscle mass exercise, their relevance to peripheral adaptations, and current evidence on the efficacy of small muscle mass exercise in improving peripheral function and exercise tolerance in performance, health and disease.

Chronic obstructive pulmonary disease (COPD) is an inflammatory lung disease caused by inhalation of noxious particles, most commonly cigarette smoking. The consequent changes in airways, lung parenchyma and pulmonary vasculature lead to increased resistive, elastic and threshold loads and impaired capacity of the respiratory muscle pump. COPD is characterized by progressive expiratory flow limitation. During exercise, increases in respiratory rate lead to shortening of expiratory time with consequent gas trapping. The resultant increase in end-expiratory lung volume is referred to as dynamic hyperinflation. Dynamic hyperinflation leads to further load-capacity imbalance with consequent increased neural respiratory drive to maintain ventilatory homeostasis, which is closely related to exertional breathlessness intensity. Neuromechanical dissociation, resulting in uncoupling of increased neural respiratory drive from ventilatory output, develops due to mechanical limitations on tidal volume expansion and reduced force-generating capacity of the diaphragm as dynamic hyperinflation progresses during exercise. This review provides an overview of methods of measuring dynamic hyperinflation in COPD and clinical interventions that aim to alleviate lung hyperinflation and improve exercise tolerance.

Orthostatic stress reduces venous return and stroke volume (SV), risking cerebral hypoperfusion despite autonomic compensation. Although lower-limb counterpressure manoeuvres improve cerebral perfusion in upright posture, their effects on cerebral blood velocity (CBV) during lower-body negative pressure (LBNP) and the associated mechanisms are not fully defined. We therefore tested whether isometric lower-limb contraction is associated with preservation of CBV during LBNP, accompanied by attenuated effects of preload reduction. Thirteen healthy young adults (age: 25 ± 5 years; 5 women) completed randomized trials under two conditions: off-feet (saddle support, relaxed legs) and on-feet (isometric bracing against a footplate with slight knee flexion). Each condition included 6 min exposures to -30 and -50 mmHg. Systemic vascular conductance declined with increasing LBNP, whereas mean arterial pressure (MAP) was maintained in both conditions. At -50 mmHg, CBV decreased off-feet but was preserved on-feet; SV fell less and the compensatory rise in heart rate (HR) was attenuated on-feet. Repeated-measure correlations showed that CBV tracked SV (r_rm = 0.388, P = 0.002) and end-tidal CO₂ (r_rm = 0.318, P = 0.012), was inversely related to HR (r_rm = -0.448, P = 0.001) and was unrelated to MAP (r_rm = -0.003, P = 0.980) or systemic vascular conductance (r_rm = 0.193, P = 0.129). Thus, isometric lower-limb engagement is associated with preservation of CBV during LBNP, in a manner consistent with preload-mediated effects rather than augmented peripheral vasoconstriction. These findings are consistent with proposed mechanisms underlying physical counterpressure manoeuvres and support simple lower-limb isometric actions to improve orthostatic tolerance.

The contribution of persistent inward currents (PICs) to motoneuron firing in the lower limb typically increases after a remote handgrip contraction, believed to result from diffuse serotonergic input increases in spinal cord. We investigated whether handgrip contraction intensity, duration and/or impulse would affect PIC estimates in tibialis anterior motoneurons. Multi-channel electromyograms were recorded from the tibialis anterior of 21 participants (18-40 years), during dorsiflexions at 20% of the individuals' maximal torque, before and after four handgrip conditions: (i) 80% of their maximal handgrip strength sustained for 15 s (80%15s); (ii) 40% sustained for 15 s (40%15s); (iii) 40% sustained for 30 s (40%30s); and (iv) no handgrip (Control). The PIC contribution to self-sustained motoneuron firing was estimated with delta frequency (ΔF) using paired motor unit analysis. The 'brace height', normalised as a percentage of a right triangle (% rTri), was used to estimate the PIC effects on the non-linearity of firing patterns, representing the neuromodulatory drive (metabotropic regulation of motoneuron excitability) onto the motoneurons. ΔF increased by 0.33 pulses per second (pps; 95% CI: 0.16-0.49, d = 0.47) after 40%30s and by 0.24 pps (0.09-0.38, d = 0.34) after 80%15s, but remained unchanged after 40%15s and Control. Similarly, brace height increased by 2.24% rTri (0.18-4.30, d = 0.20) after 40%30s and by 2.45% rTri (0.64-4.25, d = 0.22) after 80%15s, remaining unchanged after 40%15s and Control. The increase in the PIC contribution to motoneuron firing induced by a remote handgrip contraction is impulse dependent rather than intensity or duration dependent. The parallel increases in ΔF and brace height suggest augmented neuromodulatory input onto the spinal cord.

Duchenne muscular dystrophy (DMD) is a severe life-limiting X-linked neuromuscular disorder characterised by progressive skeletal muscle degeneration and respiratory failure. The mdx mouse, lacking dystrophin, is the most widely used preclinical model of DMD, yet the trajectory of respiratory dysfunction in this model remains incompletely defined. We evaluated neural respiratory drive (NRD), neuromechanical efficiency (NME), tension-time index (TTI), inspiratory drive rate and electromyographic (EMG) frequency spectrum parameters in the diaphragm, external intercostal and parasternal muscles across the natural history of disease (aged 1-16 months). Despite early and persistent reductions in EMG activity and frequency spectrum parameters in mdx mice, NRD and TTI in respiratory muscles were largely equivalent to controls. NME was paradoxically increased in mdx mice, likely reflecting compensatory recruitment of accessory muscles rather than improved contractile efficiency of the major inspiratory muscles of breathing. The area under the pressure-time curve during sustained tracheal occlusion was reduced in mdx mice at 1 month of age but was equivalent to wild-type values at all other ages, demonstrating robust compensation even in advanced disease. No significant differences in inspiratory duty cycle, respiratory muscle effort or TTI were observed across groups. We conclude that assessments of integrative respiratory morbidity in mdx mice should focus on animals aged ≥16 months or alternative models with accelerated disease progression. Our results underscore the need for refined translational models and highlight the importance of integrating EMG-based indices for early detection and monitoring of respiratory compromise in DMD.

Facial cooling can increase ventilation and augment the hypoxic ventilatory response. Whole body cooling increases both carotid body tonic activity and sensitivity; however, whether isolated facial cooling induces similar carotid body hyperexcitability was unknown. We investigated whether facial cooling alters carotid body function by assessing tonic activity and hypoxic sensitivity. Fourteen healthy adults (11 M/3 F; age 26 ± 4 years) completed a counterbalanced, crossover study involving transient hyperoxia and poikilocapnic hypoxia (9.5% O₂) under thermoneutral (facial temperature: 34.2 ± 1.2°C) and facial cooling (19.4 ± 3.3°C) conditions. Carotid body tonic activity was inferred from the ventilatory suppression during transient hyperoxia. Sensitivity was assessed via the change in end-tidal CO₂ ( $P_{\mathrm{ETC}{O}_2}$ ) relative to oxygen saturation ( $S_{p{O}_2}$ ) during hypoxia. Facial cooling induced hyperventilation, evidenced by reduced $P_{\mathrm{ETC}{O}_2}$ (35 ± 8 vs. 41 ± 3 mmHg; P = 0.008), and elevated ventilatory equivalent for CO₂ production (28 ± 6 vs. 23 ± 2; P = 0.02). Carotid body tonic activity did not differ between facial cooling and thermoneutral conditions, but carotid body sensitivity was reduced during facial cooling (0.20 ± 0.14 vs. 0.28 ± 0.13 mmHg/%; P = 0.044). The reduction in $P_{\mathrm{ETC}{O}_2}$ experienced during facial cooling correlated with enhanced carotid body tonic activity (R² = 0.39, P = 0.022) and reduced sensitivity (R² = 0.33, P = 0.03). Collectively, facial cooling induces hyperventilation and the attendant hypocapnia reduces carotid body sensitivity. Although this hyperventilation is related to carotid body tonic activity, facial cooling likely produces a cold shock response that stimulates ventilation separately from the carotid body. These findings offer new insights on the interaction between stimuli relevant to outdoor activities in cold environments (e.g., snow shovelling, mountaineering, cold water swimming) and carotid body function.

Following acute COVID-19 infection, unvaccinated patients have been reported to exhibit elevated alveolar deadspace (̇V_D,alv/̇V_T) and intrapulmonary shunt (̇Q_s/̇Q_T) fractions. However, as there is uncertainty surrounding the upper limits of normal for ̇V_D,alv/̇V_T and ̇Q_s/̇Q_T, we sought to replicate the findings from a separate, previously reported cohort of COVID-19 patients that also included a healthy control group never infected with COVID-19. Data from 81 participants, classified into four different groups based on the severity of prior COVID-19 infection, were used. All participants had arterial blood-gas samples drawn while highly precise measurements of their respiratory gas exchange were made. The gas exchange data were used to estimate alveolar $P_{C{O}_2}$ and $P_{O_2}$ , and the differences between these values and the corresponding arterial blood-gas values provided the alveolar-arterial gradients from which ̇V_D,alv/̇V_T and ̇Q_s/̇Q_T were calculated. Mean ̇V_D,alv/̇V_T was 0.115 ± 0.062 and mean ̇Q_s/̇Q_T was 0.014 ± 0.011. No significant differences between the groups, including the uninfected control group, were detected for either ̇V_D,alv/̇V_T or ̇Q_s/̇Q_T, although if severity was instead treated as an interval measure, then a small increase in ̇Q_s/̇Q_T with severity (P = 0.00934) could be detected. Many participants, including controls, exceeded the originally proposed upper limit of normal for ̇V_D,alv/̇V_T, whereas no participant exceeded the originally proposed upper limit for ̇Q_s/̇Q_T. We conclude that prior infection with COVID-19 had no effect on ̇V_D,alv/̇V_T and little effect on ̇Q_s/̇Q_T, and that the supposedly high values of ̇V_D,alv/̇V_T are within the normal range.