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Increased cardiac output, not pulmonary artery systolic pressure, increases intrapulmonary shunt in healthy humans breathing room air and 40% O2

Journal of Physiology - 15 October 2014

Blood flow through intrapulmonary arteriovenous anastomoses (IPAVAs) has been demonstrated to increase in healthy humans during a variety of conditions; however, whether or not this blood flow represents a source of venous admixture (Q VA /QT) that impairs pulmonary gas exchange efficiency (i.e. increases the alveolar-to-arterial PO2 difference (A–aDO2)) remains controversial and unknown. We hypothesized that blood flow through IPAVAs does provide a source of Q VA /QT. To test this, blood flow through IPAVAs was increased in healthy humans at rest breathing room air and 40% O2: (1) during intravenous adrenaline (epinephrine) infusion at 320 ng kg–1 min–1 (320 ADR), and (2) with vagal blockade (2 mg atropine), before and during intravenous adrenaline infusion at 80 ng kg–1 min–1 (ATR + 80 ADR). When breathing room air the A–aDO2 increased by 6 ± 2 mmHg during 320 ADR and by 5 ± 2 mmHg during ATR + 80 ADR, and the change in calculated Q VA /QT was +2% in both conditions. When breathing 40% O2, which minimizes contributions from diffusion limitation and alveolar ventilation-to-perfusion inequality, the A–aDO2 increased by 12 ± 7 mmHg during 320 ADR, and by 9 ± 6 mmHg during ATR + 80 ADR, and the change in calculated Q VA /QT was +2% in both conditions. During 320 ADR cardiac output (QT) and pulmonary artery systolic pressure (PASP) were significantly increased; however, during ATR + 80 ADR only QT was significantly increased, yet blood flow through IPAVAs as detected with saline contrast echocardiography was not different between conditions. Accordingly, we suggest that blood flow through IPAVAs provides a source of intrapulmonary shunt, and is mediated primarily by increases in QT rather than PASP.

Muscle disuse alters skeletal muscle contractile function at the molecular and cellular levels in older adult humans in a sex-specific manner

Journal of Physiology - 15 October 2014
Key points

  • Muscle disuse that accompanies ageing and chronic disease may hasten physical disability by impairing skeletal muscle contractility.

  • We compared skeletal muscle contractile function at the various anatomic levels between two groups of older men and women matched for sex, health status and body size, of which one group was habitually active and the other inactive.

  • Muscle disuse reduced force generation, power output and contractile velocity in single muscle fibres, with differential adaptations in some parameters in men and women. Sex-specific cellular phenotypes were explained by differential adaptations in molecular muscle function. Moreover, aspects of the molecular functional phenotype apparent in inactive women could be recapitulated in vitro by chemical modification of protein thiols.

  • Our results identify molecular and cellular contractile dysfunction in skeletal muscle that may contribute to reduced physical function with muscle disuse, with sex-specific differences that may explain a greater disposition towards disability in women.

  • Abstract

    Physical inactivity that accompanies ageing and disease may hasten disability by reducing skeletal muscle contractility. To characterize skeletal muscle functional adaptations to muscle disuse, we compared contractile performance at the molecular, cellular and whole-muscle levels in healthy active older men and women (n = 15) and inactive older men and women with advanced-stage, symptomatic knee osteoarthritis (OA) (n = 16). OA patients showed reduced (P < 0.01) knee extensor function. At the cellular level, single muscle fibre force production was reduced in OA patients in myosin heavy chain (MHC) I and IIA fibres (both P < 0.05) and differences in IIA fibres persisted after adjustments for fibre cross-sectional area (P < 0.05). Although no group differences in contractile velocity or power output were found for any fibre type, sex was found to modify the effect of OA, with a reduction in MHC IIA power output and a trend towards reduced shortening velocity in women, but increases in both variables in men (P < 0.05 and P = 0.07, respectively). At the molecular level, these adaptations in MHC IIA fibre function were explained by sex-specific differences (P ≤ 0.05) in myosin–actin cross-bridge kinetics. Additionally, cross-bridge kinetics were slowed in MHC I fibres in OA patients (P < 0.01), attributable entirely to reductions in women with knee OA (P < 0.05), a phenotype that could be reproduced in vitro by chemical modification of protein thiol residues. Our results identify molecular and cellular functional adaptations in skeletal muscle that may contribute to reduced physical function with knee OA-associated muscle disuse, with sex-specific differences that may explain a greater disposition towards disability in women.

    PGC1-{alpha} over-expression prevents metabolic alterations and soleus muscle atrophy in hindlimb unloaded mice

    Journal of Physiology - 15 October 2014

    Prolonged skeletal muscle inactivity causes muscle fibre atrophy. Redox imbalance has been considered one of the major triggers of skeletal muscle disuse atrophy, but whether redox imbalance is actually the major cause or simply a consequence of muscle disuse remains of debate. Here we hypothesized that a metabolic stress mediated by PGC-1α down-regulation plays a major role in disuse atrophy. First we studied the adaptations of soleus to mice hindlimb unloading (HU) in the early phase of disuse (3 and 7 days of HU) with and without antioxidant treatment (trolox). HU caused a reduction in cross-sectional area, redox status alteration (NRF2, SOD1 and catalase up-regulation), and induction of the ubiquitin proteasome system (MuRF-1 and atrogin-1 mRNA up-regulation) and autophagy (Beclin1 and p62 mRNA up-regulation). Trolox completely prevented the induction of NRF2, SOD1 and catalase mRNAs, but not atrophy or induction of catabolic systems in unloaded muscles, suggesting that oxidative stress is not a major cause of disuse atrophy. HU mice showed a marked alteration of oxidative metabolism. PGC-1α and mitochondrial complexes were down-regulated and DRP1 was up-regulated. To define the link between mitochondrial dysfunction and disuse muscle atrophy we unloaded mice overexpressing PGC-1α. Transgenic PGC-1α animals did not show metabolic alteration during unloading, preserving muscle size through the reduction of autophagy and proteasome degradation. Our results indicate that mitochondrial dysfunction plays a major role in disuse atrophy and that compounds inducing PGC-1α expression could be useful to treat/prevent muscle atrophy.

    Plasticity in the brainstem vagal circuits controlling gastric motor function triggered by corticotropin releasing factor

    Journal of Physiology - 15 October 2014

    Stress impairs gastric emptying, reduces stomach compliance and induces early satiety via vagal actions. We have shown recently that the ability of the anti-stress neuropeptide oxytocin (OXT) to modulate vagal brainstem circuits undergoes short-term plasticity via alterations in cAMP levels subsequent to vagal afferent fibre-dependent activation of metabotropic glutamate receptors. The aim of the present study was to test the hypothesis that the OXT-induced gastric response undergoes plastic changes in the presence of the prototypical stress hormone, corticotropin releasing factor (CRF). Whole cell patch clamp recordings showed that CRF increased inhibitory GABAergic synaptic transmission to identified corpus-projecting dorsal motor nucleus of the vagus (DMV) neurones. In naive brainstem slices, OXT perfusion had no effect on inhibitory synaptic transmission; following exposure to CRF (and recovery from its actions), however, re-application of OXT inhibited GABAergic transmission in the majority of neurones tested. This uncovering of the OXT response was antagonized by pretreatment with protein kinase A or adenylate cyclase inhibitors, H89 and di-deoxyadenosine, respectively, indicating a cAMP-mediated mechanism. In naive animals, OXT microinjection in the dorsal vagal complex induced a NO-mediated corpus relaxation. Following CRF pretreatment, however, microinjection of OXT attenuated or, at times reversed, the gastric relaxation which was insensitive to l-NAME but was antagonized by pretreatment with a VIP antagonist. Immunohistochemical analyses of vagal motoneurones showed an increased number of oxytocin receptors present on GABAergic terminals of CRF-treated or stressed vs. naive rats. These results indicate that CRF alters vagal inhibitory circuits that uncover the ability of OXT to modulate GABAergic currents and modifies the gastric corpus motility response to OXT.

    Determination of cable parameters in skeletal muscle fibres during repetitive firing of action potentials

    Journal of Physiology - 15 October 2014

    Recent studies in rat muscle fibres show that repetitive firing of action potentials causes changes in fibre resting membrane conductance (Gm) that reflect regulation of ClC-1 Cl– and KATP K+ ion channels. Methodologically, these findings were obtained by inserting two microelectrodes at close proximity in the same fibres enabling measurements of fibre input resistance (Rin) in between action potential trains. Since the fibre length constant () could not be determined, however, the calculation of Gm relied on the assumptions that the specific cytosolic resistivity (Ri) and muscle fibre volume remained constant during the repeated action potential firing. Here we present a three-microelectrode technique that enables determinations of multiple cable parameters in action potential-firing fibres including Rin and as well as waveform and conduction velocities of fully propagating action potentials. It is shown that in both rat and mouse extensor digitorum longus (EDL) fibres, action potential firing leads to substantial changes in both muscle fibre volume and Ri. The analysis also showed, however, that regardless of these changes, rat and mouse EDL fibres both exhibited initial decreases in Gm that were eventually followed by a ~3-fold, fully reversible increase in Gm after the firing of 1450–1800 action potentials. Using this three-electrode method we further show that the latter rise in Gm was closely associated with excitation failures and loss of action potential signal above –20 mV.

    Fluorescence recovery after photobleaching reveals regulation and distribution of connexin36 gap junction coupling within mouse islets of Langerhans

    Journal of Physiology - 15 October 2014
    Key points

  • Gap junctions provide electrical coupling that is critical to the function of pancreatic islets. Disruptions to connexin36 (Cx36) have been suggested to occur in diabetes.

  • No accurate and non-invasive technique has yet been established to quantify changes in Cx36 gap junction coupling in the intact islet.

  • This study developed fluorescence recovery after photobleaching (FRAP) as a non-invasive technique for quantifying Cx36 gap junction coupling in living islets.

  • The study identified treatments that modulate gap junction coupling, confirmed that the cellular distribution of coupling throughout the islet is highly heterogeneous and confirmed that α cells and β cells do not form functional Cx36 gap junctions.

  • This technique will enable future studies to examine the regulation of Cx36 gap junction coupling and its disruption in diabetes, and to uncover potential novel therapeutic targets associated with gap junction coupling.

  • Abstract

    The pancreatic islets are central to the maintenance of glucose homeostasis through insulin secretion. Glucose-stimulated insulin secretion is tightly linked to electrical activity in β cells within the islet. Gap junctions, composed of connexin36 (Cx36), form intercellular channels between β cells, synchronizing electrical activity and insulin secretion. Loss of gap junction coupling leads to altered insulin secretion dynamics and disrupted glucose homeostasis. Gap junction coupling is known to be disrupted in mouse models of pre-diabetes. Although approaches to measure gap junction coupling have been devised, they either lack cell specificity, suitable quantification of coupling or spatial resolution, or are invasive. The purpose of this study was to develop fluorescence recovery after photobleaching (FRAP) as a technique to accurately and robustly measure gap junction coupling in the islet. The cationic dye Rhodamine 123 was used with FRAP to quantify dye diffusion between islet β cells as a measure of Cx36 gap junction coupling. Measurements in islets with reduced Cx36 verified the accuracy of this technique in distinguishing between distinct levels of gap junction coupling. Analysis of individual cells revealed that the distribution of coupling across the islet is highly heterogeneous. Analysis of several modulators of gap junction coupling revealed glucose- and cAMP-dependent modulation of gap junction coupling in islets. Finally, FRAP was used to determine cell population specific coupling, where no functional gap junction coupling was observed between α cells and β cells in the islet. The results of this study show FRAP to be a robust technique which provides the cellular resolution to quantify the distribution and regulation of Cx36 gap junction coupling in specific cell populations within the islet. Future studies utilizing this technique may elucidate the role of gap junction coupling in the progression of diabetes and identify mechanisms of gap junction regulation for potential therapies.

    Fine spatiotemporal activity in contracting myometrium revealed by motion-corrected calcium imaging

    Journal of Physiology - 15 October 2014

    Successful childbirth depends on the occurrence of precisely coordinated uterine contractions during labour. Calcium indicator fluorescence imaging is one of the main techniques for investigating the mechanisms governing this physiological process and its pathologies. The effective spatiotemporal resolution of calcium signals is, however, limited by the motion of contracting tissue: structures of interest in the order of microns can move over a hundred times their width during a contraction. The simultaneous changes in local intensity and tissue configuration make motion tracking a non-trivial problem in image analysis and confound many of the standard techniques. This paper presents a method that tracks local motion throughout the tissue and allows for the almost complete removal of motion artefacts. This provides a stabilized calcium signal down to a pixel resolution, which, for the data examined, is in the order of a few microns. As a byproduct of image stabilization, a complete kinematic description of the contraction–relaxation cycle is also obtained. This contains novel information about the mechanical response of the tissue, such as the identification of a characteristic length scale, in the order of 40–50 μm, below which tissue motion is homogeneous. Applied to our data, we illustrate that the method allows for analyses of calcium dynamics in contracting myometrium in unprecedented spatiotemporal detail. Additionally, we use the kinematics of tissue motion to compare calcium signals at the subcellular level and local contractile motion. The computer code used is provided in a freely modifiable form and has potential applicability to in vivo calcium imaging of neural tissue, as well as other smooth muscle tissue.

    Cooperative subunit interactions mediate fast C-type inactivation of hERG1 K+ channels

    Journal of Physiology - 15 October 2014

    At depolarized membrane potentials, the conductance of some voltage-gated K+ channels is reduced by C-type inactivation. This gating process is voltage independent in Kv1 and involves a conformational change in the selectivity filter that is mediated by cooperative subunit interactions. C-type inactivation in hERG1 K+ channels is voltage-dependent, much faster in onset and greatly attenuates currents at positive potentials. Here we investigate the potential role of subunit interactions in C-type inactivation of hERG1 channels. Point mutations in hERG1 known to eliminate (G628C/S631C), inhibit (S620T or S631A) or enhance (T618A or M645C) C-type inactivation were introduced into subunits that were combined with wild-type subunits to form concatenated tetrameric channels with defined subunit composition and stoichiometry. Channels were heterologously expressed in Xenopus oocytes and the two-microelectrode voltage clamp was used to measure the kinetics and steady-state properties of inactivation of whole cell currents. The effect of S631A or T618A mutations on inactivation was a graded function of the number of mutant subunits within a concatenated tetramer as predicted by a sequential model of cooperative subunit interactions, whereas M645C subunits increased the rate of inactivation of concatemers, as predicted for subunits that act independently of one another. For mutations located within the inactivation gate proper (S620T or G628C/S631C), the presence of a single subunit in a concatenated hERG1 tetramer disrupted gating to the same extent as that observed for mutant homotetramers. Together, our findings indicate that the final step of C-type inactivation of hERG1 channels involves a concerted, all-or-none cooperative interaction between all four subunits, and that probing the mechanisms of channel gating with concatenated heterotypic channels should be interpreted with care, as conclusions regarding the nature of subunit interactions may depend on the specific mutation used to probe the gating process.

    Action of the isolated canine diaphragm on the lower ribs at high lung volumes

    Journal of Physiology - 15 October 2014

    The normal diaphragm has an inspiratory action on the lower ribs, but subjects with chronic obstructive pulmonary disease commonly have an inward displacement of the lateral portions of the lower rib cage during inspiration. This paradoxical displacement, conventionally called ‘Hoover's sign’, has traditionally been attributed to the direct action of radially oriented diaphragmatic muscle fibres. In the present study, the inspiratory intercostal muscles in all interspaces in anaesthetized dogs were severed so that the diaphragm was the only muscle active during inspiration. The displacements of the lower ribs along the craniocaudal and laterolateral axes and the changes in pleural pressure (Ppl) and transdiaphragmatic pressure were measured during occluded breaths and mechanical ventilation at different lung volumes between functional residual capacity (FRC) and total lung capacity. From these data, the separate effects on rib displacement of Ppl and of the force exerted by the diaphragm on the ribs were determined. Isolated spontaneous diaphragm contraction at FRC displaced the lower ribs cranially and outward, but this motion was progressively reversed into a caudal and inward motion as lung volume increased. However, although the force exerted by the diaphragm on the ribs decreased with increasing volume, it continued to displace the ribs cranially and outward. These observations suggest that Hoover's sign is usually caused by the decrease in the zone of apposition and, thus, by the dominant effect of Ppl on the lower ribs, rather than an inward pull from the diaphragm.

    Glycogen metabolism protects against metabolic insult to preserve carotid body function during glucose deprivation

    Journal of Physiology - 15 October 2014

    The view that the carotid body (CB) type I cells are direct physiological sensors of hypoglycaemia is challenged by the finding that the basal sensory neuronal outflow from the whole organ is unchanged in response to low glucose. The reason for this difference in viewpoint and how the whole CB maintains its metabolic integrity when exposed to low glucose is unknown. Here we show that, in the intact superfused rat CB, basal sensory neuronal activity was sustained during glucose deprivation for 29.1 ± 1.2 min, before irreversible failure following a brief period of excitation. Graded increases in the basal discharge induced by reducing the superfusate PO2 led to proportional decreases in the time to the pre-failure excitation during glucose deprivation which was dependent on a complete run-down in glycolysis and a fall in cellular energy status. A similar ability to withstand prolonged glucose deprivation was observed in isolated type I cells. Electron micrographs and immunofluorescence staining of rat CB sections revealed the presence of glycogen granules and the glycogen conversion enzymes glycogen synthase I and glycogen phosphorylase BB, dispersed throughout the type I cell cytoplasm. Furthermore, pharmacological attenuation of glycogenolysis and functional depletion of glycogen both significantly reduced the time to glycolytic run-down by ~33 and 65%, respectively. These findings suggest that type I cell glycogen metabolism allows for the continuation of glycolysis and the maintenance of CB sensory neuronal output in periods of restricted glucose delivery and this may act as a key protective mechanism for the organ during hypoglycaemia. The ability, or otherwise, to preserve energetic status may thus account for variation in the reported capacity of the CB to sense physiological glucose concentrations and may even underlie its function during pathological states associated with augmented CB discharge.

    Hypercapnia attenuates ventilator-induced lung injury via a disintegrin and metalloprotease-17

    Journal of Physiology - 15 October 2014
    Key points

  • Hypercapnia is common in mechanically ventilated patients with lung injury; while CO2 can ameliorate experimental lung injury, it can also cause harm.

  • Because hypercapnia can protect against ventilator-induced lung injury (VILI), understanding its impact on key signalling pathways may provide insight into the mechanisms of VILI.

  • We show that hypercapnia blocks stretch-mediated activation of p44/42 mitogen-activated protein kinase (MAPK) signalling in alveolar epithelial cells; this occurs through inhibition of sheddase (i.e. the metalloprotease, ADAM17), which releases ligands that bind to the epidermal growth factor receptor.

  • In vivo pharmacological blockade of ADAM17 reduces downstream MAPK activation and attenuates VILI in a two-hit mouse model.

  • Thus, hypercapnia uncovered a novel ADAM17-dependent mechanism of VILI, and this represents a potential therapeutic target.

  • Abstract

    Hypercapnic acidosis, common in mechanically ventilated patients, has been reported to exert both beneficial and harmful effects in models of lung injury. Understanding its effects at the molecular level may provide insight into mechanisms of injury and protection. The aim of this study was to establish the effects of hypercapnic acidosis on mitogen-activated protein kinase (MAPK) activation, and determine the relevant signalling pathways. p44/42 MAPK activation in a murine model of ventilator-induced lung injury (VILI) correlated with injury and was reduced in hypercapnia. When cultured rat alveolar epithelial cells were subjected to cyclic stretch, activation of p44/42 MAPK was dependent on epidermal growth factor receptor (EGFR) activity and on shedding of EGFR ligands; exposure to 12% CO2 without additional buffering blocked ligand shedding, as well as EGFR and p44/42 MAPK activation. The EGFR ligands are known substrates of the matrix metalloprotease ADAM17, suggesting stretch activates and hypercapnic acidosis blocks stretch-mediated activation of ADAM17. This was corroborated in the isolated perfused mouse lung, where elevated CO2 also inhibited stretch-activated shedding of the ADAM17 substrate TNFR1 from airway epithelial cells. Finally, in vivo confirmation was obtained in a two-hit murine model of VILI where pharmacological inhibition of ADAM17 reduced both injury and p44/42 MAPK activation. Thus, ADAM17 is an important proximal mediator of VILI; its inhibition is one mechanism of hypercapnic protection and may be a target for clinical therapy.

    Effects of hyperoxia and hypoxia on the physiological traits responsible for obstructive sleep apnoea

    Journal of Physiology - 15 October 2014

    Oxygen therapy is known to reduce loop gain (LG) in patients with obstructive sleep apnoea (OSA), yet its effects on the other traits responsible for OSA remain unknown. Therefore, we assessed how hyperoxia and hypoxia alter four physiological traits in OSA patients. Eleven OSA subjects underwent a night of polysomnography during which the physiological traits were measured using multiple 3-min ‘drops’ from therapeutic continuous positive airway pressure (CPAP) levels. LG was defined as the ratio of the ventilatory overshoot to the preceding reduction in ventilation. Pharyngeal collapsibility was quantified as the ventilation at CPAP of 0 cmH2O. Upper airway responsiveness was defined as the ratio of the increase in ventilation to the increase in ventilatory drive across the drop. Arousal threshold was estimated as the level of ventilatory drive associated with arousal. On separate nights, subjects were submitted to hyperoxia (n = 9; FiO2 ~0.5) or hypoxia (n = 10; FiO2 ~0.15) and the four traits were reassessed. Hyperoxia lowered LG from a median of 3.4 [interquartile range (IQR): 2.6–4.1] to 2.1 (IQR: 1.3–2.5) (P < 0.01), but did not alter the remaining traits. By contrast, hypoxia increased LG [median: 3.3 (IQR: 2.3–4.0) vs. 6.4 (IQR: 4.5–9.7); P < 0.005]. Hypoxia additionally increased the arousal threshold (mean ± s.d. 10.9 ± 2.1 l min–1 vs. 13.3 ± 4.3 l min–1; P < 0.05) and improved pharyngeal collapsibility (mean ± s.d. 3.4 ± 1.4 l min–1 vs. 4.9 ± 1.3 l min–1; P < 0.05), but did not alter upper airway responsiveness (P = 0.7). This study demonstrates that the beneficial effect of hyperoxia on the severity of OSA is primarily based on its ability to reduce LG. The effects of hypoxia described above may explain the disappearance of OSA and the emergence of central sleep apnoea in conditions such as high altitude.

    Alterations in atrial perfusion during atrial fibrillation

    Experimental Physiology - 01 October 2014

    Left atrial (LA) perfusion during disease states has been a topic of much interest, because the clinical implications and detrimental effects of lack of blood flow to the atria are numerous. In the chronic setting, changes in perfusion may lead to LA ischaemia and structural remodelling, a factor implicated in the self-perpetuation of chronic atrial fibrillation (AF). The association between AF and altered LA perfusion has been studied, but a direct causal association between perfusion changes and AF has not been established. A comprehensive literature search of Medline, Embase and Google Scholar databases was conducted from 1960 to February 2014. We systematically analysed reference lists of physiological articles and reviews for other possibly relevant studies. The aim of this review is to provide a comprehensive discussion of the AF-mediated changes in LA perfusion and the potential mechanisms underlying the alterations in coronary flow to the LA in this setting. In addition, we discuss the clinical contexts in which changes in LA perfusion may be relevant. Finally, this article highlights the need for longitudinal studies of AF that would elucidate the changes in LA perfusion resulting from chronic AF and lead to advancements in effective treatments to prevent progression of this disease.

    Calcium in the heart: from physiology to disease

    Experimental Physiology - 01 October 2014

    Contraction of the heart results from an increase of cytoplasmic Ca2+ concentration ([Ca2+]i), the so-called systolic Ca2+ transient. Most of this results from the release of Ca2+ from the sarcoplasmic reticulum (SR) through the ryanodine receptor (RyR). In turn, the amplitude of this Ca2+ transient determines the contractility of the heart. In this lecture, I consider the factors which govern the size and stability of this Ca2+ release. The amplitude of the Ca2+ transient is a steep function of SR Ca, resulting in a requirement for very precise beat-to-beat regulation of SR Ca content. This is achieved by a simple negative feedback mechanism, in which an increase of SR Ca content increases the size of the Ca2+ transient, resulting in a decrease of Ca2+ influx on the L-type Ca2+ current and an increase of efflux through Na+–Ca2+ exchange. Changing the activity of any of the Ca2+-cycling proteins will change the steady-state SR Ca content. This feedback mechanism has many consequences, including the fact that a change of RyR open probability has a only a temporary effect on the amplitude of the Ca2+ transient due to a compensating change of SR Ca content. The remainder of the article considers the link between intracellular Ca2+ waves and arrhythmias. This is done in the context of catecholaminergic polymorphic ventricular tachycardia, which is an inherited arrhythmia syndrome, in many cases due to a RyR mutation, where arrhythmias occur during exercise as a result of β-adrenergic stimulation. Calcium waves occur only when the SR Ca content exceeds a threshold level. Our data show that the threshold is reduced by the RyR mutation and that the adrenergic stimulation increases SR Ca content.

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