Many animal species do not breathe in a continuous, rhythmic fashion, but rather display a variety of breathing patterns characterized by prolonged periods between breaths (inter-breath intervals), during which the heart continues to beat. Examples of intermittent breathing abound across the animal kingdom, from crustaceans to cetaceans. With respect to human physiology, intermittent breathing-also termed 'periodic' or 'episodic' breathing-is associated with a variety of pathologies. Cardiovascular phenomena associated with intermittent breathing in diving species have been termed 'diving bradycardia', 'submersion bradycardia', 'immersion bradycardia', 'ventilation tachycardia', 'respiratory sinus arrhythmia' and so forth. An examination across the literature of terminology applied to these physiological phenomena indicates, unfortunately, no attempt at standardization. This might be viewed as an esoteric semantic problem except for the fact that many of the terms variously used by different authors carry with them implicit or explicit suggestions of underlying physiological mechanisms and even human-associated pathologies. In this article, we review several phenomena associated with diving and intermittent breathing, indicate the semantic issues arising from the use of each term, and make recommendations for best practice when applying specific terms to particular cardiorespiratory patterns. Ultimately, we emphasize that the biology-not the semantics-is what is important, but also stress that confusion surrounding underlying mechanisms can be avoided by more careful attention to terms describing physiological changes during intermittent breathing and diving. What is the topic of this review? This review examines the rather confusing semantics that has been used to describe patterns in the field of cardiorespiratory physiology as it applies to intermittent breathing, particularly in diving species. What advances does it highlight? This review highlights the various cardiorespiratory phenomena associated with intermittent breathing and diving. It highlights the semantic issues associated with describing each and offers a rationale for standardizing terms based on underlying mechanisms to reduce confusion and advance the study of cardiorespiratory phenomena in both medical and comparative physiological investigations.

New Findings What is the topic of this review? It has been suggested that human brown adipose tissue (BAT) is more similar to the brite/beige adipose tissue of mice than to classical BAT of mice. The basis of this is discussed in relationship to the physiological conditions of standard experimental mice.

New Findings: What is the central question of this study? Splenic contractions occur in response to apnoea-induced hypoxia with and without face immersion in water. However, the splenic responses to a series of static or dynamic apnoeas with whole-body water immersion in non-divers and elite breath-hold divers are unknown. What is the main finding and its importance? Static and dynamic apnoeas were equally effective in stimulating splenic contractions across non-divers and elite breath-hold divers. These findings demonstrate that the magnitude of the splenic response is largely dictated by the degree of the hypoxemic stress encountered during voluntary apnoeic epochs. Abstract: Splenic contractions occur in response to apnoea-induced hypoxia with and without facial water immersion. However, the splenic responses to a series of static (STA) or dynamic (DYN) apnoeas with whole-body water immersion in non-divers (NDs) and elite breath-hold divers (EBHDs) are unknown. EBHD (n = 8), ND (n = 10) and control participants (n = 8) were recruited. EBHD and ND performed a series of five maximal DYN or STA on separate occasions. Control performed a static eupnoeic (STE) protocol to control against any effects of water immersion and diurnal variation on splenic volume and haematology. Heart rate (HR) and peripheral oxygen saturation (SpO2) were monitored for 30 s after each apnoea. Pre- and post-apnoeic splenic volumes were quantified ultrasonically, and blood samples were drawn for haematology. For EBHD and ND end-apnoeic HR was higher (P < 0.001) and SpO2 was lower in DYN (P = 0.024) versus STA. EBHD attained lower end-apnoeic SpO2 during DYN and STA than NDs (P < 0.001). Splenic contractions occurred following DYN (EBHD, −47 ± 6%; ND, −37 ± 4%; P < 0.001) and STA (EBHD, −26 ± 4%; ND, −26 ± 8%; P < 0.01). DYN-associated splenic contractions were greater than STA in EBHD only (P = 0.042). Haemoglobin concentrations were higher following DYN only (EBHD, +5 ± 8g/L, +4 ± 2%; ND, +8 ± 3 g/L, +4.9 ± 3%; P = 0.019). Haematocrit remained unchanged after each protocol. There were no between group differences in post-apnoeic splenic volume or haematology. In both groups, splenic contractions occurred in response to STA and DYN when combined with whole-body immersion. DYN apnoeas, were effective at increasing haemoglobin concentrations but not STA apnoeas. Thus, the magnitude of the splenic response relates to the hypoxemic stress encountered during apnoeic epochs.

NEW FINDINGS: What is the central question of this study? Is performing a 30-min whole-body vibration (WBV) prior to a continuous 90-min exposure at 24,000 ft sufficient to prevent venous gas emboli (VGE) formation? What is the main finding and its importance? WBV preconditioning significantly reduces the formation and delays the manifestation of high-altitude-induced VGE. This study suggests that WBV is an effective strategy in lowering decompression stress.

ABSTRACT: Rapid decompression may give rise to formation of venous gas emboli (VGE) and resultantly, increase the risk of sustaining decompression sickness. Preconditioning aims at lowering the prevalence of VGE during decompression. The purpose of this study was to investigate the efficacy of whole-body vibration (WBV) preconditioning on high-altitude-induced VGE. Eight male subjects performed, on separate days in a randomised order, three preconditioning strategies: 40-min seated-rest (control), 30-min seated-rest followed by 150 knee-squats performed over a 10-min period (exercise) and 30-min WBV proceeded by a 10-min seated-rest. Thereafter, subjects were exposed to an altitude of 24,000 ft (7315 m) for 90 min whilst laying in a supine position and breathing 100% oxygen. VGE were assessed ultrasonically both during supine rest (5-min intervals) and after three fast, unloaded knee-bends (15-min intervals) and were scored using a 5-grade scale and evaluated using the Kisman Integrated Severity Score (KISS). There was a significant difference in VGE grade (P < 0.001), time to VGE manifestation (P = 0.014) and KISS score following knee-bends (P = 0.002) across protocols, with a trend in KISS score during supine rest (P = 0.070). WBV resulted in lower VGE grades (median (range), 1 (0-3)) and KISS score (2.69 ± 4.56 a.u.) compared with control (2 (1-3), P = 0.002; 12.86 ± 8.40 a.u., P = 0.011) and exercise (3 (2-4) , P < 0.001; 22.04 ± 13.45 a.u., P = 0.002). VGE were detected earlier during control (15 ± 14 min, P = 0.024) and exercise (17 ± 24 min, P = 0.032) than WBV (54 ± 38 min). Performing a 30-min WBV prior to a 90-min continuous exposure at 24,000 ft both delays the manifestation and reduces the formation of VGE compared with control and exercise preconditioning.

The dive response, or the master switch of life, is probably the most studied physiological trait in marine mammals and is thought to conserve the available O-2 for the heart and brain. Although generally thought to be an autonomic reflex, several studies indicate that the cardiovascular changes during diving are anticipatory and can be conditioned. The respiratory adaptations, where the aquatic breathing pattern resembles intermittent breathing in land mammals, with expiratory flow exceeding 160 litres s(-1) has been measured in cetaceans, and where exposure to extreme pressures results in alveolar collapse (atelectasis) and recruitment upon ascent. Cardiorespiratory coupling, where breathing results in changes in heart rate, has been proposed to improve gas exchange. Cardiorespiratory coupling has also been reported in marine mammals, and in the bottlenose dolphin, where it alters both heart rate and stroke volume. When accounting for this respiratory dependence on cardiac function, several studies have reported an absence of a diving-related bradycardia except during dives that exceed the duration that is fuelled by aerobic metabolism. This review summarizes what is known about the respiratory physiology in marine mammals, with a special focus on cetaceans. The cardiorespiratory coupling is reviewed, and the selective gas exchange hypothesis is summarized, which provides a testable mechanism for how breath-hold diving vertebrates may actively prevent uptake of N-2 during routine dives, and how stress results in failure of this mechanism, which results in diving-related gas emboli.

Voluntary apnea causes splenic contraction and reductions in heart rate (HR; bradycardia), and subsequent transient increases in hemoglobin concentration ([Hb]). Ascent to high altitude (HA) induces systemic hypoxia and reductions in oxygen saturation (SpO2 ), which may cause tonic splenic contraction, which may contribute to hematological acclimatization associated with HA ascent. We measured resting cardiorespiratory variables (HR, SpO2 , [Hb]) and resting splenic volume (via ultrasound) during incremental ascent from 1400 m (day 0), to 3440 m (day 3), 4240 m (day 7), and 5160 m (day 10) in non-acclimatized native lowlanders during assent to HA in the Nepal Himalaya. In addition, apnea-induced responses in HR, SpO2 and splenic volume were measured before and after two separate voluntary maximal apneas (A1-A2) at 1400 m, 3440 m and 4240 m. Resting spleen volume decreased -14.3% (-15.2 mL)/1000 m with ascent, from 140±41 mL (1400 m), to 108±28 mL (3440 m; P > 0.99), 94±22 mL (4240 m; P = 0.009) and 84±28 mL (5160 m; P = 0.029), with concomitant increases in [Hb] from 125±18.3 g/L (1400 m) to 128±10.4 g/L (3440 m), 138.8±12.7 g/L (4240 m) and 157.5±8 g/L (5160 m; P = 0.021). Apnea-induced splenic contraction was 50±15 mL (1400 m), 44±17 mL (3440 m; P > 0.99) and 26±8 mL (4240 m; P = 0.002), but was not consistently associated with increases in [Hb]. The apnea-induced bradycardia was more pronounced at 3440 m (A1:P = 0.04; A2:P = 0.094) and at 4240 m (A1:P = 0.037 A2:P = 0.006) compared to values at 1400 m. We conclude that hypoxia-induced splenic contraction at rest (a) may contribute to restoring arterial oxygen content through its [Hb]-enhancing contractile function and (b) eliminates further apnea-induced [Hb] increases in hypoxia. We suggest that tonic splenic contraction may contribute to hematological acclimatization early in HA ascent in humans.

The human spleen contracts in response to stress-induced catecholamine secretion, resulting in a temporary rise in haemoglobin concentration ([Hb]). Recent findings highlighted enhanced splenic response to exercise at high altitude in Sherpa, possibly due to a blunted splenic response to hypoxia. To explore the potential blunted splenic contraction in Sherpas at high altitude, we examined changes in spleen volume during hyperoxic breathing, comparing acclimatized Sherpa with acclimatized individuals of lowland ancestry. Our study included 14 non-Sherpa (7 female) residing at altitude for a mean continuous duration of 3 months and 46 Sherpa (24 female) with an average of 4 years altitude exposure. Participants underwent a hyperoxic breathing test at altitude (4300 m; barrometric pressure = ∼430 torr; (Formula presented.) = ∼90 torr). Throughout the test, we measured spleen volume using ultrasonography and monitored oxygen saturation ((Formula presented.)). During rest, Sherpa exhibited larger spleens (226 ± 70 mL) compared to non-Sherpa (165 ± 34 mL; P < 0.001; effect size (ES) = 0.95, 95% CI: 0.3–1.6). In response to hyperoxia, non-Sherpa demonstrated 22 ± 12% increase in spleen size (35 ± 17 mL, 95% CI: 20.7–48.9; P < 0.001; ES = 1.8, 95% CI: 0.93–2.66), while spleen size remained unchanged in Sherpa (−2 ± 13 mL, 95% CI: −2.4 to 7.3; P = 0.640; ES = 0.18, 95% CI: −0.10 to 0.47). Our findings suggest that Sherpa and non-Sherpas of lowland ancestry exhibit distinct variations in spleen volume during hyperoxia at high altitude, potentially indicating two distinct splenic functions. In Sherpa, this phenomenon may signify a diminished splenic response to altitude-related hypoxia at rest, potentially contributing to enhanced splenic contractions during physical stress. Conversely, non-Sherpa experienced a transient increase in spleen size during hyperoxia, indicating an active tonic contraction, which may influence early altitude acclimatization in lowlanders by raising [Hb]. 

bstractRelatively short periods of inadequate sleep provoke physiological and psychological perturbations, typically leading to functional impairments and degradation in performance. It is commonly accepted that sleep deprivation also disturbs thermal homeostasis, plausibly enhancing susceptibility to cold- and heat-related illnesses. Herein, we summarize the current state of human-based evidence on the impact of short-term (i.e., ≤4 nights) sleep deprivation on autonomic and behavioural thermoeffectors during acute exposure to low and high ambient temperatures. The purpose of this brief narrative review is to highlight knowledge gaps in the area and stimulate future research to investigate whether sleep deprivation constitutes a predisposing factor for the development of thermal injuries.

We examined whether hypoxia would modulate thermoeffector responses during repeated cold stress encountered in a single day. Eleven men completed two ∼10 h sessions, while breathing, in normobaria, either normoxia or hypoxia (PO2 : 12 kPa). During each session, subjects underwent sequentially three 120 min immersions to the chest in 20◦C water (CWI), interspersed by 120 min rewarming. In normoxia, the final drop in rectal temperature (Trec) was greater in the third (∼1.2◦C) than in the first and second (∼0.9◦C) CWIs (P < 0.05). The first hypoxic CWI augmented the Trec fall (∼1.2◦C; P = 0.002), but the drop in Trec did not vary between the three hypoxic CWIs (P = 0.99). In normoxia, the metabolic heat production (Ṁ ) was greater during the first half of the third CWI than during the corresponding part of the first CWI (P = 0.02); yet the difference was blunted during the second half of the CWIs (P = 0.89). In hypoxia, by contrast, the increase in Ṁ was augmented by ∼25% throughout the third CWI (P < 0.01). Regardless of the breathing condition, the cold-induced elevation in mean arterial pressure was blunted in the second and third CWI (P < 0.05). Hypoxia aggravated the sensation of coldness (P = 0.05) and thermal discomfort (P = 0.04) during the second half of the third CWI. The present findings therefore demonstrate that prolonged hypoxia mediates, in a gradual manner, metabolic and thermoperceptual sensitization to repeated cold stress.

NEW FINDINGS: What is the central question of this study? What are the distinct and interactive effects of a 10 day exposure to hypoxia and horizontal bedrest on the whole-body peak oxygen uptake and on the regional cerebral and skeletal muscle tissue oxygenation during upright cycle ergometry in male lowlanders? What is the main finding and its importance? A 10 day sustained exposure to hypoxia aggravates the bedrest-induced reduction in peak oxygen uptake during dynamic exercise engaging large muscle groups, but mitigates the skeletal muscle oxidative capacity impairment elicited by bedrest. The study examined the interactive effects of a 10 day exposure to hypoxia and bedrest on the whole-body peak oxygen uptake (V̇O2 peak ) during maximal exercise and on skeletal muscle and cerebral oxygenation during submaximal exercise. Nine males underwent three 10 day confinements, in a Latin-square order, as follows: (i) a normoxic bedrest [NBR; partial pressure of inspired O2 (PI,O2) = 134.2 ± 0.7 mmHg]; (ii) a hypoxic bedrest (HBR; PI,O2 = 102.9 ± 0.1 mmHg at day 1, 91.5 ± 1.2 mmHg at days 3-10); and (iii) a hypoxic ambulation (HAMB; PI,O2 as in HBR). Before, 1 (R+1) and 3 days (R+3) after each confinement, subjects performed exhaustive, incremental-load and moderate-intensity constant-load (CLTs) cycle-ergometry trials, while breathing either room air or a hypoxic gas mixture. During the CLTs, changes in the regional oxygenation of the cerebral frontal cortex and the vastus lateralis and intercostal muscles were monitored with near-infrared spectroscopy. At R+1, the confinement-related impairment in V̇O2 peak was greater after HBR than after NBR or HAMB, regardless of whether the trial was performed in room air or hypoxia (HBR, -16.2%; NBR, -8.3%; HAMB, -4.1%; P = 0.001). During the CLTs, bedrest aggravated the exercise-induced reduction in locomotor and respiratory muscle oxygenation (P ≤ 0.05); an effect that was less after HBR than after NBR (P ≤ 0.05). The hypoxic exercise-induced cerebral vasodilatory response was blunted by HBR, probably because of the marked hyperventilation-dependent hypocapnia, attendant to the sustained hypoxic stimulus. Hence, short-term exposure to hypoxia potentiates the reduction in V̇O2 peak , but it mitigates the impairment in skeletal muscle oxidative capacity induced by bedrest.

NEW FINDINGS: What is the central question of this study? Does a 35-day horizontal bedrest impair thermoeffector responses during whole-body submaximal exercise performed in temperate conditions? What is the main finding and its importance? Cardiovascular and muscular deconditioning ensued from prolonged recumbency, seems to augment, at least to a degree, the exercise-induced increase in body core temperature, most likely due to an impairment in non-evaporative heat loss. The response is a function of the absolute exercise intensity imposed.

ABSTRACT: We examined the effects of a 35-day horizontal bedrest on thermoregulation during whole-body exercise. Fifteen healthy men were randomly assigned to either a bedrest (BR; n = 10), or a control (CON; n = 5) group. Prior to bedrest, both groups performed a 40-min constant-load upright cycling at 30% of their peak workload (W_peak ; PRE). One and two days after bedrest, the BR group performed, in a randomised counterbalanced order, two 40-min trials at 30% of: (i) the pre-bedrest W_peak (i.e., at a fixed absolute intensity; POST-A), and (ii) the post-bedrest W_peak (i.e., at a fixed relative intensity; POST-R). The CON group conducted only the POST-A trial, at the same time intervals. During the trials, rectal (T_rec ) and skin temperatures, and the forehead sweating rate (SwR) were monitored. In the CON group, no differences were observed between the trials. Bedrest potentiated moderately the T_rec elevation during the latter part of POST-A (∼0.10°C; P≤0.05), but not of POST-R (∼0.04°C; P = 0.11). In both post-bedrest trials, was attenuated by ∼1.5-2.0^° C throughout (P<0.01), whereas the forehead SwR was not modulated. T_rec and were similar in POST-A and POST-R; yet the forehead SwR was more dependent on the relative workload imposed (P = 0.04). Present findings therefore suggest that the cardiovascular and muscular deconditioning ensued from a 35-day bedrest may aggravate the exercise-induced increase in body core temperature when working at a given absolute intensity, most likely due to an impairment in non-evaporative heat loss. This article is protected by copyright. All rights reserved.

When the contractile properties of single muscle fibres are studied, force is typically normalized by fibre cross-sectional area and expressed as specific force. We studied a set of 2725 chemically skinned human single muscle fibres from 119 healthy adults to determine whether specific force is the optimal way to express the relationship between single-fibre force and size. A linear mixed effects model was used to estimate the slope and slope variability among individuals of log-log plots of force and diameter. For type I fibres, the slope estimate was 0.99 (95% confidence interval 0.36-1.62), and for type IIa fibres it was 0.94 (95% confidence interval 0.77-1.11), indicating that force is proportional to fibre diameter, rather than to cross-sectional area. If force were proportional to cross-sectional area, the slope estimate would be 2.0. In future studies using the chemically skinned single fibre preparation, force may be normalized to fibre diameter rather than cross-sectional area. We propose that a new term, 'normalized force', be used for this variable, with units of newtons per metre. We demonstrate using our data set that when populations of single fibres are compared with one another, the determination of whether the size and force relationship is the same or different is dependent upon the method used to account for fibre size (i.e. specific force versus 'normalized force').

Accumulated data indicate that cell‐mediated contraction of reconstituted collagenous gels in vitro can serve as a model for cell‐mediated control of interstitial fluid pressure (P_IF) in vivo. A central role for collagen‐binding β₁‐integrins in both processes has been established. Furthermore, integrin α_Vβ₃ takes over the role of collagen‐binding β₁‐integrins in mediating contraction after perturbations of collagen‐binding β₁‐integrins in vitro. Integrin α_Vβ₃ is also instrumental for normalization of dermal P_IF that has been lowered due to mast cell degranulation with compound 48/80 (C48/80) in vivo. Here we demonstrate a role of integrin α_Vβ₃ in maintaining a long term homeostatic dermal P_IF in mice lacking the collagen‐binding integrin  α₁₁β₁ (α11^−/− mice). Measurements of P_IF were performed after circulatory arrest. Furthermore, cell‐mediated integrin α_Vβ₃‐directed contraction of collagenous gels in vitro depends on free access to a collagen site known to bind several extracellular matrix (ECM) proteins that form substrates for α_Vβ₃‐directed cell attachment, such as fibronectin and fibrin. A streptococcal collagen‐binding protein, CNE, specifically binds to and blocks this site on the collagen triple helix. Here we show that whereas CNE perturbed α_Vβ₃‐directed and platelet‐derived growth factor BB‐induced normalization of dermal P_IF after C48/80, it did not affect α_Vβ₃‐dependent maintenance of a homeostatic dermal P_IF. These data imply that dynamic modification of the ECM structure is needed during acute patho‐physiological modulations of P_IF but not for long‐term maintenance of a homeostatic P_IF. Our data thus show that collagen‐binding β₁‐integrins, integrin α_Vβ₃ and ECM structure are potential targets for novel therapy aimed at modulating oedema formation and hypovolemic shock during anaphylaxis.

NEW FINDINGS: What is the central question of this study? Orthostatic stress is mostly caused by venous blood pooling in the lower limbs. Venous distension elicits sympathetic responses, and increased distension speed enhances the cardiovascular response. We examine whether lower limb blood pooling rate during lower body negative pressure is linked to orthostatic intolerance. What is the main finding and its importance? A similar amount of blood was pooled in the lower limb, but at a slower rate in women who developed signs of orthostatic intolerance. The difference in blood pooling rate increased with orthostatic stress and was most prominent at a presyncope-inducing level of lower body negative pressure. The findings have implications for the pathophysiology as well as treatment of orthostatic intolerance. Vasovagal syncope is common in young women, but its aetiology remains elusive. Orthostatic stress-induced lower limb blood pooling is linked with central hypovolaemia and baroreceptor unloading. Venous distension in the arm elicits a sympathetic response, which is enhanced with more rapid distension. Our aim was to study both the amount and the speed of lower limb pooling during orthostatic stress and its effects on compensatory mechanisms to maintain cardiovascular homeostasis in women with orthostatic intolerance. Twenty-seven healthy women, aged 20-27 years, were subjected to a lower body negative pressure (LBNP) of 11-44 mmHg. Five women developed symptoms of vasovagal syncope (orthostatic intolerant) and were compared with the remaining women, who tolerated LBNP well (orthostatic tolerant). Lower limb blood pooling, blood flow and compensatory mobilization of venous capacitance blood were measured. Lower body negative pressure induced equal lower limb blood pooling in both groups, but at a slower rate in orthostatic intolerant women (e.g. time to 50% of total blood pooling, orthostatic intolerant 44 ± 7 s and orthostatic tolerant 26 ± 2 s; P < 0.001). At presyncope-inducing LBNP, the mobilization of venous capacitance blood was both reduced (P < 0.05) and much slower in orthostatic intolerant women (P = 0.0007). Orthostatic intolerant women elicited blunted arterial vasoconstriction at low-grade LBNP, activating only cardiopulmonary baroreceptors, while orthostatic tolerant women responded with apparent vasoconstriction (P < 0.0001). In conclusion, slower lower limb blood pooling could contribute to orthostatic intolerance in women. Mobilization of venous capacitance blood from the peripheral to the central circulation was both slower and decreased; furthermore, reduced cardiopulmonary baroreceptor sensitivity was found in women who developed orthostatic intolerance. Further studies including women who experience syncope in daily life are needed.

Wound healing is a general response of the body to injury. All organs share in commonthree response elements to wound healing: inflammation to prevent infection andstimulate the removal of dead cells, active anti-inflammatory signalling to turn off theinflammatory response, and a repair phase characterized by extracellular matrix scarformation. The extent of scar formed depends on the ability of endogenous cells thatpopulate each organ to regenerate. The skin has keratinocytes that have regenerativecapacity, and in general, wounds are fully re-epithelialized. Heart, in contrast, hascardiac myocytes that have little to no regenerative capacity, and necrotic myocytesare entirely replaced by scars. Despite differences in tissue regeneration, the skin andheart share many wound-healing properties that can be exploited to predict the cardiacresponse to pathology. We summarize in this review article our current understandingof how the response of the skin to a wounding event can inform us about the ability ofthe myocardium to respond to a myocardial infarction.

This comparative study of myonuclear domain (MND) size in mammalian species representing a 100 000-fold difference in body mass, ranging from 25 g to 2500 kg, was undertaken to improve our understanding of myonuclear organization in skeletal muscle fibres. Myonuclear domain size was calculated from three-dimensional reconstructions in a total of 235 single muscle fibre segments at a fixed sarcomere length. Irrespective of species, the largest MND size was observed in muscle fibres expressing fast myosin heavy chain (MyHC) isoforms, but in the two smallest mammalian species studied (mouse and rat), MND size was not larger in the fast-twitch fibres expressing the IIA MyHC isofom than in the slow-twitch type I fibres. In the larger mammals, the type I fibres always had the smallest average MND size, but contrary to mouse and rat muscles, type IIA fibres had lower mitochondrial enzyme activities than type I fibres. Myonuclear domain size was highly dependent on body mass in the two muscle fibre types expressed in all species, i.e. types I and IIA. Myonuclear domain size increased in muscle fibres expressing both the β/slow (type I; r= 0.84, P < 0.001) and the fast IIA MyHC isoform (r= 0.90; P < 0.001). Thus, MND size scales with body size and is highly dependent on muscle fibre type, independent of species. However, myosin isoform expression is not the sole protein determining MND size, and other protein systems, such as mitochondrial proteins, may be equally or more important determinants of MND size.

This comparative study of myonuclear domain (MND) size in mammalian species representing a 100,000-fold difference in body mass, ranging from 25 g to 2500 kg, was undertaken to improve our understanding of myonuclear organization in skeletal muscle fibres. Myonuclear domain size was calculated from three-dimensional reconstructions in a total of 235 single muscle fibre segments at a fixed sarcomere length. Irrespective of species, the largest MND size was observed in muscle fibres expressing fast myosin heavy chain (MyHC) isoforms, but in the two smallest mammalian species studied (mouse and rat), MND size was not larger in the fast-twitch fibres expressing the IIA MyHC isofom than in the slow-twitch type I fibres. In the larger mammals, the type I fibres always had the smallest average MND size, but contrary to mouse and rat muscles, type IIA fibres had lower mitochondrial enzyme activities than type I fibres. Myonuclear domain size was highly dependent on body mass in the two muscle fibre types expressed in all species, i.e. types I and IIA. Myonuclear domain size increased in muscle fibres expressing both the beta/slow (type I; r = 0.84, P < 0.001) and the fast IIA MyHC isoform (r = 0.90; P < 0.001). Thus, MND size scales with body size and is highly dependent on muscle fibre type, independent of species. However, myosin isoform expression is not the sole protein determining MND size, and other protein systems, such as mitochondrial proteins, may be equally or more important determinants of MND size.

New Findings<list id="eph1595-list-0001" list-type="bulleted"> What is the central question of this study? The effect of ageing on hyperthermia-induced changes in cardiac function is unknown. What is the main finding and its importance? Using echocardiography, we show that during hyperthermia the systolic and diastolic function can be appropriately augmented to meet cardiac demand in healthy older adults, although overall age-related impairments remain. One exception was late diastolic ventricular filling [i.e. E/A ratio and A/(A+E) ratio], which in the older adults was not further augmented during hyperthermia, unlike their young counterparts. To meet cardiac demand, therefore, healthy older adults appear to depend on an increased left ventricular systolic strain and proportion of their cardiac reserve. The effect of ageing on hyperthermia-induced changes in cardiac function is unknown. This study tested the hypothesis that hyperthermia-induced changes in left ventricular systolic and diastolic function are attenuated in older adults when compared with young adults. Eight older (71 +/- 5years old) and eight young adults (29 +/- 5years old), matched for sex, physical activity and body mass index, underwent whole-body passive hyperthermia. Mean arterial pressure (Finometer Pro), heart rate, forearm vascular conductance (venous occlusion plethysmography) and echocardiographic indices of diastolic and systolic function were measured during a normothermic supine period and again after an increase in internal temperature of approximate to 1.0 degrees C. Hyperthermia decreased mean arterial pressure and left ventricular end-diastolic volumes and increased heart rate to a similar extent in both groups (P>0.05). Ageing did not alter the magnitude of hyperthermia-induced changes in indices of systolic (lateral mitral annular S velocity) or diastolic function (lateral mitral annular E velocity, peak early diastolic filling and isovolumic relaxation time; P>0.05). However, with hyperthermia the global longitudinal systolic strain increased in the older group, but was unchanged in the young group (P=0.03). Also, older adults were unable to augment late diastolic ventricular filling [i.e. E/A ratio and A/(A+E) ratio] during hyperthermia, unlike the young (P<0.05). These findings indicate that older adults depend on a greater systolic contribution (global longitudinal systolic strain) to meet hyperthermic demand and that the atrial contribution to diastolic filling was not further augmented in older adults when compared with young adults.

Low-frequency electroacupuncture restores sex steroid synthesis and sympathetic activity in women with polycystic ovary syndrome, which may improve its metabolic disturbances likely by modulating sympathetic nerve activity or sex steroid synthesis. We investigated whether low-frequency electroacupuncture regulates the metabolic function to the same extent as treatment with estradiol or -adrenergic blocking in a rat model of polycystic ovary syndrome induced by a P450 aromatase inhibitor (letrozole). Letrozole (β00 μg per day) or placebo pellets were implanted in pre-pubertal Wistar rats. Six weeks thereafter, rats were treated for 5–6 weeks with: low-frequency electroacupuncture (5 days per week), a -adrenergic blocker (propranolol hydrochloride, 0.1 mg kg-1) (5 days per week), or 17-estradiol (β.0 μg) every fourth day. Body weight development, body composition, locomotor activity, insulin sensitivity, tissue specific glucose uptake, lipid profile, adipocyte size, adiponectin and insulin serum concentrations, and gene expression in inguinal fat were measured. All treatments increased circulating levels of LDL-cholesterol. Estradiol treatment restored locomotor activity and increased insulin sensitivity but did not modify the glucose uptake in muscle and fat. An upregulation of genes related to insulin sensitivity and downregulation of genes related to adipogenesis were observed in subcutaneous adipose tissue from rats exposed to letrozole. Only estradiol treatment normalized the expression of these genes. In conclusions, low-frequency electroacupuncture increased LDL-cholesterol without affecting the insulin sensitivity or adipose tissue function, which could suggest effects on hepatic lipid regulation probably mediated by estradiol action or -adrenergic pathway.

Recent studies revealed that in vivo the inner blood vessel surface is lined with an endothelial surface layer at least 0.5 mu m thick, which serves as an aegis, protecting the vessel wall from arteriosclerosis. Hyaluronan seems to be a constitutive component in regard to the atheroprotective properties of this surface structure. It has been shown that arterial pulsatile laminar blood flow increases the thickness of this surface layer in vivo, while it is significantly reduced at atheroprone regions with disturbed flow. This study was undertaken to reveal whether endothelial hyaluronan synthesis via hyaluronan synthase 2 (HAS2) can be changed by different shear stress conditions in vitro, especially in regard to an undisturbed, arterial-like pulsatile flow profile. Human umbilical vein endothelial cells, exposed to constant or pulsatile shear stress in a cone-and-plate system, were analysed for HAS2 expression by real-time RT-PCR and immunoblotting, and for hyaluronan by ELISA. Hyaluronan synthase 2 mRNA and protein were found to be transiently increased in a shear stress-dependent manner via the phosphatidylinositol 3-kinase-Akt pathway. Especially pulsatile, arterial-like shear stress conditions induced enzyme and hyaluronan effectively, while lower shear stress that continuously changed its direction did not induce any differences in comparison with control cultures not exposed to shear stress. These experiments provide a link between the production of a constitutive component of the endothelial surface layer by endothelial cells and blood flow.

NEW FINDINGS: What is the central question of this study? It is well established that muscle and bone atrophy in conditions of inactivity or unloading, but there is little information regarding the effect of a hypoxic environment on the time course of these deconditioning physiological systems. What is the main finding and its importance? The main finding is that a horizontal 10 day bed rest in normoxia results in typical muscle atrophy, which is not aggravated by hypoxia. Changes in bone mineral content or in metabolism were not detected after either normoxic or hypoxic bed rest.

ABSTRACT: Musculoskeletal atrophy constitutes a typical adaptation to inactivity and unloading of weightbearing bones. The reduced-gravity environment in future Moon and Mars habitats is likely to be hypobaric hypoxic, and there is an urgent need to understand the effect of hypoxia on the process of inactivity-induced musculoskeletal atrophy. This was the principal aim of the present study. Eleven males participated in three 10 day interventions: (i) hypoxic ambulatory confinement; (ii) hypoxic bed rest; and (iii) normoxic bed rest. Before and after the interventions, the muscle strength (isometric maximal voluntary contraction), mass (lean mass, by dual-energy X-ray absorptiometry), cross-sectional area and total bone mineral content (determined with peripheral quantitative computed tomography) of the participants were measured. Blood and urine samples were collected before and on the 1st, 4th and 10th day of the intervention and analysed for biomarkers of bone resorption and formation. There was a significant reduction in thigh and lower leg muscle mass and volume after both normoxic and hypoxic bed rests. Muscle strength loss was proportionately greater than the loss in muscle mass for both thigh and lower leg. There was no indication of bone loss. Furthermore, the biomarkers of resorption and formation were not affected by any of the interventions. There was no significant effect of hypoxia on the musculoskeletal variables. Short-term normoxic (10 day) bed rest resulted in muscular deconditioning, but not in the loss of bone mineral content or changes in bone metabolism. Hypoxia did not modify these results.

New Findings: What is the central question of this study? Do females and males exhibit a similar sarcopenic response as a consequence of normoxic and hypoxic bed rest? What is the main finding and its importance? During 10-day bed rest, exposure to a simulated (normobaric hypoxia) altitude of ∼4000 m does not exert additional significant structural or functional effect on the weight-bearing muscles in females compared to those noted under normoxic conditions. Whereas males and females exhibit decrements in muscle cross-sectional area and mass during normoxic and hypoxic bed rest, a concomitant strength decrement was only observed in males. Abstract: This study investigated the effects of hypoxia on the known processes of adaptation of body composition and muscle function to normoxic inactivity. Females (n = 12) and males (n = 11) took part in the following interventions: hypoxic ambulation (HAMB; ∼4000 m); hypoxic bed rest (HBR; ∼4000 m) and normoxic bed rest (NBR). Prior to and immediately following each intervention, body composition, thigh and lower leg cross-sectional area (CSA) and isometric muscular strength were recorded. Participants lost body mass (HAMB: male −1.5 ± 0.9 kg, female −1.9 ± 0.7 kg; HBR: male −2.0 ± 1.8 kg, female −2.4 ± 0.8 kg; NBR: male −1.4 ± 1.3 kg, female −1.4 ± 0.9 kg) and lean mass (HAMB: male −3.9 ± 3.0%, female −3.4 ± 2.0%; HBR: male −4.0 ± 4.4%, female −4.1 ± 2.0%; NBR: male −4.0 ± 3.4%, female −2.2 ± 2.7%) with no between-condition or sex differences. Knee extension decreased for males in NBR compared to HAMB (HAMB: male −0.2 ± 9.1%, female 1.3 ± 4.9%; HBR: male −7.8 ± 10.3%, female −3.3 ± 10.9%; NBR: male −14.5 ± 11%, female −3.4 ± 6.9%). Loss of force during maximal voluntary contraction (MVC) in the knee extensors was significantly different between males and females following NBR. There were no other significant changes noted following the experimental interventions. There were no differences recorded between sexes in maximal MVC for elbow or ankle joints. Female lower leg CSA decreased following bed rest (HAMB: -4.5 ± 2.0%; HBR: -9.9 ± 2.6%; NBR: -8.0 ± 1.6%). These findings indicate that a 10-day hypoxic bed rest does not exert any significant additional effect on muscle atrophy when compared to NBR, except for female thigh CSA. In contrast to males, who exhibited a significant loss of muscle strength, no such decrement in strength was observed in the female participants.

Preferential loss of the motor protein myosin, as observed in patients with acute quadriplegic myopathy (AQM) or cancer cachexia, causes generalized muscle wasting, muscle weakness and a decrease in muscle fibre force normalized to cross-sectional area. It remains unclear, however, whether this myosin loss influences other important features of muscle fibre function, such as Ca2+ activation of the contractile proteins. To address this question, we have studied Ca2+ sensitivity of force generation using skinned muscle fibres from four patients with AQM or cancer cachexia and a preferential loss of myosin; and from seven healthy control individuals. Force and apparent rate constant of force redevelopment (k(tr)) were assessed in solutions with varying Ca2+ concentrations (pCa), allowing construction of relative force-pCa and k(tr)-pCa relationships. Results showed a rightward shift of the relative force-pCa relationship and a leftward shift of the relative k(tr)-pCa curve in muscle fibres with a preferential myosin loss. To improve the understanding of the mechanisms underlying these alterations, the relative stiffness-pCa relationship was evaluated. A rightward shift of this curve was observed, suggesting that the changes in the Ca2+ activation of force and k(tr) were predominantly due to a decrease in the relative number of attached cross-bridges at different pCa values. Thus, a change in Ca2+ activation of the contractile apparatus in patients with preferential myosin loss is proposed as an additional factor contributing to the muscle function impairment in these patients.

Hyponatraemia is common clinically, and if it develops rapidly, brain oedema evolves, and severe morbidity and even death may occur. Experimentally, acute hyponatraemia is most frequently studied in small animal models, in which the hyponatraemia is produced by intraperitoneal instillation of hypotonic fluids (I.P. model). This hyponatraemia model is described as 'dilutional' or 'syndrome of inappropriate ADH (SIADH)', but seminal studies contradict this interpretation. To confront this issue, we developed an I.P. model in a large animal (the pig) and studied water and electrolyte responses in brain, muscle, plasma and urine. We hypothesized that hyponatraemia was induced by simple water dilution, with no change in organ sodium content. Moderate hypotonic hyponatraemia was induced by a single I.V. dose of desmopressin and intraperitoneal instillation of 2.5% glucose. All animals were anaesthetized and intensively monitored. In vivo brain and muscle water was determined by magnetic resonance imaging and related to the plasma sodium concentration. Muscle water content increased less than expected as a result of pure dilution, and muscle sodium content decreased significantly (by 28%). Sodium was redistributed to the peritoneal fluid, resulting in a significantly reduced plasma volume. This shows that the I.P. model induces hypovolaemic hyponatraemia and not dilutional/SIADH hyponatraemia. Brain oedema evolved, but brain sodium content decreased significantly (by 21%). To conclude, the I.P. model induces hypovolaemic hyponatraemia attributable to sodium redistribution and not water dilution. The large reduction in brain sodium is probably attributable to the specific mechanism that causes the hyponatraemia. This is not accounted for in the current understanding of the brain response to acute hyponatraemia.

New insights suggest the existence of telomere regulatory mechanisms in several adult tissues. In this study, we aimed to assess in vivo telomere length and the presence of specific proteins involved in telomere regulation in a model of human skeletal muscle with (patients with dermatomyosis or polymyositis) and without ongoing regenerative events (healthy subjects). Mean (meanTRF) and minimal telomere (miniTRF) lengths and the expression of telomerase, tankyrase 1, TRF2 (telomeric repeat binding factor 2) and POT1 (protection of telomeres 1) were investigated in skeletal muscle samples from 12 patients (MYO) and 13 healthy subjects (CON). There was no significant shortening of telomeres in skeletal muscle from patients compared with control subjects (MYO, meanTRF length 11.0 ± 1.8 kbp and miniTRF length 4.7 ± 0.8 kbp; CON, meanTRF length 10.4 ± 1.1 kbp and miniTRF length 4.6 ± 0.5 kbp). Theoretically, telomere length can be controlled by endogenous mechanisms. Here, we show for the first time that expression levels of telomerase, tankyrase 1, TRF2 and POT1 were, respectively, six-, seven-, three- and fivefold higher in the nuclear fraction of skeletal muscle of MYO compared with CON (P < 0.05). This suggests the existence of endogenous mechanisms allowing for telomere regulation in skeletal muscle with ongoing cycles of degeneration and regeneration and a model where regulatory factors are possibly involved in the protection of skeletal muscle telomeres.

In anaesthetized female rats, the β-adrenoceptor agonist isoprenaline was intravenously infused (20 μg kg^-1 min^-1) for 30 min or the ascending cervical sympathetic nerve trunk was intermittently stimulated (50 Hz, 1 s every tenth second) on one side for 30 min. The incorporation of [³H]leucine into trichloroacetic acid (TCA)-insoluble material was used as an index of protein synthesis. In response to isoprenaline, the [³H]leucine incorporation increased by 79% in the parotid glands and by 82% in the submandibular glands. The neuronal type NO-synthase inhibitor N-PLA, reduced (P < 0.001) this response to 26% and 20%, respectively. Sympathetic stimulation under α-adrenoceptor blockade increased the [³H]leucine incorporation by 192% in the parotid glands and by 35% in the submandibular glands. N-PLA reduced the corresponding percentage figures to 86% (P < 0.01) and 8% (P < 0.05). When tested in the parotid glands, the non-selective NO-synthase inhibitor L-NAME reduced (P < 0.01) the nerve-evoked response to 91%. The increase in [³H]leucine incorporation in response to sympathetic stimulation under β-adrenoceptor blockade was not affected by N-PLA in the parotid (139% versus 144%) and submandibular glands (39% versus 34%). In non-stimulated glands, the [³H]leucine incorporation was not influenced by the NO-synthase inhibitors. In conclusion, β-adrenoceptor mediated salivary gland protein synthesis is largely dependent on NO generation by neuronal type NO-synthase, most likely of parenchymal origin. 

The basal in vitro release of amylase was similar from rat parotid lobules of innervated and chronically denervated glands and was unaffected by the inhibitors used in this study. The secretion of amylase induced by isoprenaline or vasoactive intestinal peptide (VIP) was reduced by one-third to one-half from the lobules of the innervated glands and even more so from the lobules of the denervated glands by ODQ, an inhibitor of soluble guanyl cyclase which is activated by nitric oxide (NO) and catalyses the cGMP production. The use of Nω-propyl-L-arginine (N-PLA) revealed that the evoked secretion of amylase in the denervated glands depended on the activity of neuronal type NO synthase to synthesize NO. Since the denervated gland is virtually devoid of NO synthase-containing nerve fibres, the neuronal type NO synthase was most probably of a non-neuronal source. NO-dependent amylase secretion was agonist related, since amylase secretion evoked by bethanechol and neuropeptide Y was not reduced by ODQ or N-PLA. Hence, under physiological conditions, activation of β-adrenoceptors (sympathetic activity) and VIP receptors (parasympathetic activity) is likely to cause secretion of parotid amylase partly through a NO/cGMP-dependent intracellular pathway involving the activity of neuronal type NO synthase, possibly of acinar origin.

This study tested the hypothesis that hyperthermia attenuates the increase in cerebral perfusion during cognitive activation. Mean middle cerebral artery blood velocity (MCAV(mean)) served as an index of cerebral perfusion, while the nBack test (a test of working memory) was the cognitive task. Hyperthermia was characterized by elevations (P < 0.001) in skin (by 5.0 +/- 0.8 degrees C) and intestinal temperatures (by 1.3 +/- 0.1 degrees C) and reductions (P < 0.020) in mean arterial pressure (by 11 +/- 10 mmHg), end-tidal CO2 tension (by 3 +/- 6 mmHg) and MCAVmean (by 10 +/- 9 cm s(-1)). Hyperthermia had no influence on nBack test performance (mean difference from normothermia to hyperthermia, -1 +/- 11%; P = 0.276) or, counter to the hypothesis, the increase in MCAV(mean) during nBack testing (mean difference from normothermia to hyperthermia: 0 +/- 16 cm s(-1); P = 0.608). These findings indicate that the capacity to increase cerebral perfusion during cognitive activation is unaffected by hyperthermia.

New Findings: What is the topic of this review? This review addresses whether a mismatch between cerebral O2 demand and delivery accelerates the development of central fatigue during endurance-type exercise. What advances does it highlight? The difficulty with studying the importance of cerebral O2 availability for exercise performance is to manipulate cerebral O2 availability independently of muscular O2 availability. The different approaches to overcome this limitation indicate that cerebral oxygenation is not a major limiting factor in normoxia, but may limit performance in submaximal exercise tasks in hypoxia. Central fatigue originates within the central nervous system and is characterized by a decrease in voluntary muscle activation. Reduced systemic O2 availability can facilitate central fatigue by enhancing the afferent input of the chemosensitive nerves that play a pivotal role in development of central fatigue. There is accumulating evidence that, in some situations, inadequate O2 availability to the brain itself promotes central fatigue. This short review presents some of the recent findings supporting a direct effect of inadequate cerebral O2 availability on central fatigue and addresses the persisting limitations.

Skeletal muscle satellite cell (SC) content has been reported to increase following a single bout of exercise. Data on muscle fibre type-specific SC content and/or SC activation status are presently lacking. The objective of the study was to determine the impact of a single bout of exercise on muscle fibre type-specific SC content and activation status following subsequent overnight recovery. Eight healthy men (age, 20 ± 1 years) performed a single bout of combined endurance- and resistance-type exercise. Muscle biopsies were collected before and immediately after exercise, and following 9 h of postexercise, overnight recovery. Muscle fibre type-specific SC and myonuclear content and SC activation status were determined by immunohistochemical analyses. Satellite cell activation status was assessed by immunohistochemical staining for both Delta-like homologue 1 (DLK1) and Ki-67. Muscle fibre size and fibre area per nucleus were greater in type II compared with type I muscle fibres (P < 0.05). At baseline, no differences were observed in the percentage of SCs staining positive for DLK1 and/or Ki67 between fibre types. No significant changes were observed in SC content following 9 h of postexercise, overnight recovery; however, the percentage of DLK1-positive SCs increased significantly during overnight recovery, from 22 ± 5 to 41 ± 5% and from 24 ± 6 to 51 ± 9% in the type I and II muscle fibres, respectively. No changes were observed in the percentage of Ki-67-positive SCs. A single bout of exercise activates both type I and II skeletal muscle fibre SCs within a single night of postexercise recovery, preceding the subsequent increase in SC content.

What is the central question of this study? Controlled-hyperthermia heat acclimation protocols induce an array of thermoregulatory and cardiovascular adaptations that facilitate exercise in hot conditions. We investigated whether this ergogenic potential can be transferred to thermoneutral normoxic or hypoxic exercising conditions. What is the main finding and its importance? We show that heat acclimation did not affect maximal cardiac output or maximal aerobic power in thermoneutral normoxic/hypoxic conditions. Heat acclimation augmented the sweating response in thermoneutral normoxic conditions. The cross-adaptation theory according to which heat acclimation could facilitate hypoxic exercise capacity is not supported by our data. ABSTRACT: Heat acclimation (HA) mitigates heat-induced decrements in maximal aerobic power (V̇O_2peak ) and augments exercise thermoregulatory responses in the heat. Whether this beneficial effect of HA is observed in hypoxic or thermoneutral conditions remains unresolved. We explored the effects of HA on exercise cardiorespiratory and thermoregulatory responses in normoxic, hypoxic, and hot conditions. Twelve males (V̇O_2peak 54.7(5.7) mL·kg^-1 ·min^-1 ) participated in a HA protocol comprising 10 daily 90-min controlled-hyperthermia (target rectal temperature, T_re  = 38.5 °C) exercise sessions. Before and after HA, we determined V̇O_2peak in thermoneutral normoxic (NOR), thermoneutral hypoxic (13.5% F_i O₂ ; HYP) and hot (35 °C, 50% RH; HE) conditions in a randomized and counterbalanced order. Preceding each maximal cycling test, a 30-min steady-state exercise at 40% of the NOR peak power output (W_peak ) was employed to evaluate thermoregulatory responses. HA induced the expected adaptations in HE: reduced T_re and submaximal heart rate (HR), enhanced sweating response and expanded plasma volume. However, HA did not affect V̇O_2peak or maximal cardiac output (CO_max ) (P = 0.61). W_peak was increased post-HA in NOR (P < 0.001) and HE (P < 0.001) by 41 ± 21 and 26 ± 22 W, respectively but not in HYP (P = 0.14). Gross mechanical efficiency was higher (P = 0.004) whereas resting T_re and sweating thresholds were lower (P < 0.01) post-HA across environments. Nevertheless, the gain of the sweating response decreased (P = 0.05) in HYP. In conclusion, our data do not support a beneficial cross-over effect of HA on V̇O_2peak in normoxic or hypoxic conditions. This article is protected by copyright.

New Findings:

• What is the central question of this study?

Is electrical pulse stimulation (EPS) an in vitro exercise model able to elicit the hypertrophy of human muscle cells?

• What is the main finding and its importance?

The addition of a restitution period of 8h after EPS induces the enlargement of human muscle cells, a major physiological end-point to resistance exercise. This is supported by downregulationof myostatin, a negative regulator of muscle mass, and increased phosphorylated mTOR and 4E-BP1, key factors in the growth cascade. This proof-of-concept study provides a model of physiologically mediated muscle growth, which will be the basis for future studies aiming to depict molecular events governing the hypertrophy of human muscle cells.

Electrical pulse stimulation (EPS) of muscle cells has previouslybeenused as an in vitro exercise model. The present study aimedto establish an EPS protocol promoting the hypertrophy ofhuman muscle cells, which represents a major physiological end-point to resistance exercise in humans. We hypothesized that adding a resting period after EPS would be crucial for the occurrence of the morphological change. Myoblasts obtained from human muscle biopsies (n=5) were differentiated into multinucleated myotubes and exposed to 8h of EPS consisting of 2ms pulses at 12V, with a frequency of 1Hz. Myotube size was assessed using immunohistochemistry immediately, 4 and 8h after completed EPS. Gene expression and phosphorylation status of selected markers of hypertrophy were assessed using RT-PCR and Western blotting, respectively. Release of the myokine interleukin-6 in culture medium was measured using enzyme-linked immunosorbent assay. We demonstrated a significant increase (31 +/- 14%; P=0.03) in the size of myotubes when EPS was followed by an 8h resting period, but not immediately or 4h after completion of EPS. The response was supported by downregulation (P=0.04) of the gene expression of myostatin, a negative regulator of muscle mass, and an increase in phosphorylated mTOR (P=0.03) and 4E-BP1 (P=0.01), which are important factors in the cellular growth signalling cascade. The present work demonstrates that EPS is an in vitro exercise model promoting the hypertrophy of human muscle cells, recapitulating a major physiological end-point to resistance exercise in human skeletal muscle.

Short-chain fatty acids (SCFAs) are produced by bacterial fermentation in the large intestine, particularly from diets containing fibres and carbohydrates. The small intestinal epithelium is exposed to SCFAs derived mainly from oral bacteria or food supplementation. Although luminal nutrients are important in regulation of intestinal functions, the role of SCFAs in regulation of small intestinal mucosal barrier function and motility has not been fully described. The aim of the present study was to elucidate the effects of acetate and propionate on duodenal mucosal barrier function and motility. Rats were anaesthetized with thiobarbiturate, and a 30 mm segment of proximal duodenum with an intact blood supply was perfused. The effects on duodenal bicarbonate secretion, blood-to-lumen clearance of Cr-51-EDTA, motility and transepithelial net fluid flux were investigated. Perfusion of the duodenum with acetate or propionate significantly decreased mucosal paracellular permeability and transepithelial net fluid flux and significantly increased bicarbonate secretion. Acetate or propionate administered as an I.V. infusion decreased the mucosal paracellular permeability, but significantly decreased bicarbonate secretion. Luminal SCFAs changed the duodenal motility pattern from migrating motor complexes to fed patterns. Systemic administration of glucagon-like peptide-2 induced increases in both bicarbonate secretion and net fluid absorption, but did not change motility. Glucagon-like peptide-2 infusion during luminal perfusion of SCFAs significantly reduced the motility. In conclusion, SCFAs decreased duodenal paracellular permeability and net fluid flux. Short-chain fatty acids induced opposite effects on bicarbonate secretion after luminal and i.v. administration. Presence of SCFAs in the lumen induces fed motility patterns. Altered luminal chemosensing and aberrant signalling in response to SCFAs might contribute to symptoms observed in patients with suppressed barrier function.