Experimental Physiology最新文献

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.

Menopause increases the risk of hypertension in women, yet the factors contributing to this important change remain unclear. Because early life stress has persistent and sex-specific consequences on health, we hypothesized that ageing reveals the latent effects of neonatal maternal separation (NMS) on cardiovascular homeostasis in female rats. Following birth, rats were either subjected to NMS (3 h/day from postnatal days 3 to 12) or raised under standard conditions (CTRL). Cardiovascular and neuroendocrine functions were evaluated at three distinct ages: young adult (12 weeks), middle-age (35 weeks) and old (64 weeks). Measurements included hormonal profile (multiplex assay), mean arterial blood pressure (MAP; tail cuff method), activity of the plasma angiotensin-converting enzymes (ACE and ACE2), and activation of the paraventricular nucleus of the hypothalamus (PVN; FosB immunolabelling). Age-related decline in 17β-oestradiol (E₂) was greater in NMS rats than CTRL. Age-related rise in MAP was observed only in NMS; MAP was inversely correlated with E₂ levels in NMS rats but not CTRL. In old females, ACE2 activity was 35% less in NMS than CTRL. ACE2 activity was inversely correlated with MAP in old but not young females, regardless of treatment. In the PVN, the number of FosB expressing cells decreased with age; this effect was greater in NMS females. Experiencing stress during early life is an important determinant of the ageing trajectory of females and reproductive senescence marks a turning point in regulation of cardiovascular function. Disruption of estrogen signaling and/or the renin-angiotensin system are plausible mechanisms by which NMS stress compromises cardiovascular health.

While exercise induces physiological cardiac growth, the underlying cellular mechanisms remain incompletely understood. This study investigated the role of cardiac telocytes (TCs) and the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway in mediating exercise intensity-dependent cardiac adaptation. Twenty-four male Wistar rats were assigned to control (CTRL), high-intensity interval training (HIIT) or low-intensity interval training (LIIT) groups for 8 weeks. Physiological hypertrophy was assessed via heart weight/body weight ratio, left ventricular wall thickness, cardiomyocyte size and number. Cardiac TCs were quantified by immunofluorescence (CD34-platelet-derived growth factor receptor (PDGFR)-α/β). Gene expression of IL-6, cardiotrophin-1 (CTF1), GP130, JAK2, STAT3 and GATA4 was analysed by qPCR, and interleukin (IL)-6 protein levels were measured by ELISA. Both HIIT and LIIT robustly induced physiological cardiac hypertrophy and cardiomyogenesis, with HIIT producing a significantly greater response. This was accompanied by a significant, intensity-dependent expansion of the cardiac TC population in both HIIT and LIIT groups compared to CTRL, with HIIT inducing a greater increase than LIIT (P < 0.001). Furthermore, GATA4 expression, a marker of cardiac stem cell activation, was significantly upregulated in both trained groups. While cardiac IL-6 gene expression and protein levels were elevated, particularly after HIIT (P = 0.003), the core components of the JAK/STAT pathway (GP130, JAK2, STAT3) remained transcriptionally unaltered. Our findings establish cardiac TCs as novel, intensity-sensing cellular mediators of exercise-induced physiological growth. The adaptive process, linked to stem cell activation, occurs without concomitant transcriptional upregulation of the core JAK/STAT signalling pathway components, suggesting the involvement of alternative, potentially non-canonical, mechanistic pathways. This highlights the TC-cardiac stem cell axis as a potential target for optimizing exercise regimens for cardiac repair.

A lack of consensus remains on whether normobaric hypoxia (NH) and hypobaric hypoxia (HH) may differentially impact physiological factors affecting cerebrovascular regulation, particularly with an additional strenuous exercise component. We sought to compare the acute effects of NH and HH on global cerebral blood flow (gCBF) at an altitude corresponding to 4000 m. In this randomised, single-blind crossover study, eight lowlanders (3 females) completed three identical trials inside a hypobaric chamber: the first in normobaric normoxia, for familiarisation, followed in random order by one in NH and one in HH. In each trial, gCBF was measured at two time points via duplex ultrasound, first after 25 min of rest, and second, directly after a graded exercise test (GXT) to volitional exhaustion. Cardiorespiratory responses and cerebral oxygenation ( $r{S}_{c{O}_2}$ ) were assessed during all gCBF measurements. At rest, gCBF was higher in HH than in NH (944 ± 230 vs. 883 ± 226 mL min^-1; P = 0.027, respectively), whereas $r{S}_{c{O}_2}$ remained unchanged. Cardiorespiratory parameters did not differ, except for a reduction in the ratio of dead space to tidal volume in HH compared to NH (P = 0.028). Post-GXT, no differential response between the two hypoxic conditions was found. In comparison to NH, at rest gCBF is increased in HH for a given partial pressure of inspired oxygen, a response that is subsequently abolished post maximal cycling exercise. Although subtle, this response indicates that cerebrovascular regulation is affected differently in NH and HH, despite negligible changes in ventilation, and thus, alternative explanations are explored for future investigation.