Showing papers in "The Journal of Physiology in 2013"
TL;DR: I‐waves, input–output curves and cortical silent period are unaffected immediately after 2 mA stimulation and short intracortical inhibition and facilitation are shifted towards excitability enhancement after both anodal and cathodal stimulation.
Abstract: Transcranial direct current stimulation (tDCS) of the human motor cortex at an intensity of 1 mA with an electrode size of 35 cm(2) has been shown to induce shifts of cortical excitability during and after stimulation. These shifts are polarity-specific with cathodal tDCS resulting in a decrease and anodal stimulation in an increase of cortical excitability. In clinical and cognitive studies, stronger stimulation intensities are used frequently, but their physiological effects on cortical excitability have not yet been explored. Therefore, here we aimed to explore the effects of 2 mA tDCS on cortical excitability. We applied 2 mA anodal or cathodal tDCS for 20 min on the left primary motor cortex of 14 healthy subjects. Cathodal tDCS at 1 mA and sham tDCS for 20 min was administered as control session in nine and eight healthy subjects, respectively. Motor cortical excitability was monitored by transcranial magnetic stimulation (TMS)-elicited motor-evoked potentials (MEPs) from the right first dorsal interosseous muscle. Global corticospinal excitability was explored via single TMS pulse-elicited MEP amplitudes, and motor thresholds. Intracortical effects of stimulation were obtained by cortical silent period (CSP), short latency intracortical inhibition (SICI) and facilitation (ICF), and I wave facilitation. The above-mentioned protocols were recorded both before and immediately after tDCS in randomized order. Additionally, single-pulse MEPs, motor thresholds, SICI and ICF were recorded every 30 min up to 2 h after stimulation end, evening of the same day, next morning, next noon and next evening. Anodal as well as cathodal tDCS at 2 mA resulted in a significant increase of MEP amplitudes, whereas 1 mA cathodal tDCS decreased corticospinal excitability. A significant shift of SICI and ICF towards excitability enhancement after both 2 mA cathodal and anodal tDCS was observed. At 1 mA, cathodal tDCS reduced single-pulse TMS-elicited MEP amplitudes and shifted SICI and ICF towards inhibition. No significant changes were observed in the other protocols. Sham tDCS did not induce significant MEP alterations. These results suggest that an enhancement of tDCS intensity does not necessarily increase efficacy of stimulation, but might also shift the direction of excitability alterations. This should be taken into account for applications of the stimulation technique using different intensities and durations in order to achieve stronger or longer lasting after-effects.
814 citations
TL;DR: Recent work has identified cell‐type‐specific inhibitory and excitatory interactions, the dichotomy between neuronal firing and the non‐local measurement of local field potentials distant to that firing, and the reflection of the neuronal dark matter problem in non‐firing neurons active in seizures.
Abstract: Epilepsy has been historically seen as a functional brain disorder associated with excessive synchronization of large neuronal populations leading to a hypersynchronous state. Recent evidence showed that epileptiform phenomena, particularly seizures, result from complex interactions between neuronal networks characterized by heterogeneity of neuronal firing and dynamical evolution of synchronization. Desynchronization is often observed preceding seizures or during their early stages; in contrast, high levels of synchronization observed towards the end of seizures may facilitate termination. In this review we discuss cellular and network mechanisms responsible for such complex changes in synchronization. Recent work has identified cell-type-specific inhibitory and excitatory interactions, the dichotomy between neuronal firing and the non-local measurement of local field potentials distant to that firing, and the reflection of the neuronal dark matter problem in non-firing neurons active in seizures. These recent advances have challenged long-established views and are leading to a more rigorous and realistic understanding of the pathophysiology of epilepsy.
478 citations
TL;DR: It is suggested that somatic polarization together with axon terminal polarization may be important for synaptic pathway‐specific modulation of DCS, which underlies modulation of neuronal excitability during transcranial DCS.
Abstract: Transcranial direct current stimulation (tDCS) is a non-invasive brain stimulation technique to modulate cortical excitability. Although increased/decreased excitability under the anode/cathode electrode is nominally associated with membrane depolarization/hyperpolarization, which cellular compartments (somas, dendrites, axons and their terminals) mediate changes in cortical excitability remains unaddressed. Here we consider the acute effects of DCS on excitatory synaptic efficacy. Using multi-scale computational models and rat cortical brain slices, we show the following. (1) Typical tDCS montages produce pre- dominantly tangential (relative to the cortical surface) direction currents (4-12 times radial direction currents), even directly under electrodes. (2) Radial current flow (parallel to the somatodendritic axis) modulates synaptic efficacy consistent with somatic polarization, with depolarization facilitating synaptic efficacy. (3) Tangential current flow (perpendicular to the somatodendritic axis) modulates synaptic efficacy acutely (during stimulation) in an afferent pathway-specific manner that is consistent with terminal polarization, with hyperpolarization facilitating synaptic efficacy. (4) Maximal polarization during uniform DCS is expected at distal (the branch length is more than three times the membrane length constant) synaptic terminals, independentofandtwo-threetimesmoresusceptiblethanpyramidalneuronsomas.Weconclude that during acute DCS the cellular targets responsible for modulation of synaptic efficacy are concurrently somata and axon terminals, with the direction of cortical current flow determining the relative influence.
452 citations
TL;DR: The results indicate that repeated ingestion of 20 g of protein was superior for stimulating muscle protein synthesis during the 12 h experimental period, and shows that the distribution of protein intake is an important variable to promote attainment and maintenance of peak muscle mass.
Abstract: Quantity and timing of protein ingestion are major factors regulating myofibrillar protein synthesis (MPS). However, the effect of specific ingestion patterns on MPS throughout a 12 h period is unknown. We determined how different distributions of protein feeding during 12 h recovery after resistance exercise affects anabolic responses in skeletal muscle. Twenty-four healthy trained males were assigned to three groups (n = 8/group) and undertook a bout of resistance exercise followed by ingestion of 80 g of whey protein throughout 12 h recovery in one of the following protocols: 8 × 10 g every 1.5 h (PULSE); 4 × 20 g every 3 h (intermediate: INT); or 2 × 40 g every 6 h (BOLUS). Muscle biopsies were obtained at rest and after 1, 4, 6, 7 and 12 h post exercise. Resting and post-exercise MPS (l-[ring-(13)C6] phenylalanine), and muscle mRNA abundance and cell signalling were assessed. All ingestion protocols increased MPS above rest throughout 1-12 h recovery (88-148%, P INT>PULSE hierarchy in magnitude of phosphorylation. MuRF-1 and SLC38A2 mRNA were differentially expressed with BOLUS. In conclusion, 20 g of whey protein consumed every 3 h was superior to either PULSE or BOLUS feeding patterns for stimulating MPS throughout the day. This study provides novel information on the effect of modulating the distribution of protein intake on anabolic responses in skeletal muscle and has the potential to maximize outcomes of resistance training for attaining peak muscle mass.
376 citations
TL;DR: It is reported here that HMB stimulates muscle protein synthesis to a similar extent to leucine, and HMB was also found to decrease muscle protein breakdown.
Abstract: Maintenance of skeletal muscle mass is contingent upon the dynamic equilibrium (fasted losses–fed gains) in protein turnover. Of all nutrients, the single amino acid leucine (Leu) possesses the most marked anabolic characteristics in acting as a trigger element for the initiation of protein synthesis. While the mechanisms by which Leu is ‘sensed’ have been the subject of great scrutiny, as a branched-chain amino acid, Leu can be catabolized within muscle, thus posing the possibility that metabolites of Leu could be involved in mediating the anabolic effect(s) of Leu. Our objective was to measure muscle protein anabolism in response to Leu and its metabolite HMB. Using [1,2-13C2]Leu and [2H5]phenylalanine tracers, and GC-MS/GC-C-IRMS we studied the effect of HMB or Leu alone on MPS (by tracer incorporation into myofibrils), and for HMB we also measured muscle proteolysis (by arteriovenous (A–V) dilution). Orally consumed 3.42 g free-acid (FA-HMB) HMB (providing 2.42 g of pure HMB) exhibited rapid bioavailability in plasma and muscle and, similarly to 3.42 g Leu, stimulated muscle protein synthesis (MPS; HMB +70%vs. Leu +110%). While HMB and Leu both increased anabolic signalling (mechanistic target of rapamycin; mTOR), this was more pronounced with Leu (i.e. p70S6K1 signalling ≤90 min vs. ≤30 min for HMB). HMB consumption also attenuated muscle protein breakdown (MPB; −57%) in an insulin-independent manner. We conclude that exogenous HMB induces acute muscle anabolism (increased MPS and reduced MPB) albeit perhaps via distinct, and/or additional mechanism(s) to Leu.
375 citations
TL;DR: It is demonstrated that ventilation prior to cord clamping markedly improves cardiovascular function by increasing pulmonary blood flow before the cord is clamped, thus further stabilising the cerebral haemodynamic transition.
Abstract: Delayed cord clamping improves circulatory stability in preterm infants at birth, but the underlying physiology is unclear. We investigated the effects of umbilical cord clamping, before and after ventilation onset, on cardiovascular function at birth. Prenatal surgery was performed on lambs (123 days) to implant catheters into the pulmonary and carotid arteries and probes to measure pulmonary (PBF), carotid (CaBF) and ductus arteriosus blood flows. Lambs were delivered at 126 ± 1 days and: (1) the umbilical cord was clamped at delivery and ventilation was delayed for about 2 min (Clamp 1st; n = 6), and (2) umbilical cord clamping was delayed for 3-4 min, until after ventilation was established (Vent 1st; n = 6). All lambs were subsequently ventilated for 30 min. In Clamp 1st lambs, cord clamping rapidly (within four heartbeats), but transiently, increased pulmonary and carotid arterial pressures (by ∼30%) and CaBF (from 30.2 ± 5.6 to 40.1 ± 4.6 ml min(-1) kg(-1)), which then decreased again within 30-60 s. Following ventilation onset, these parameters rapidly increased again. In Clamp 1st lambs, cord clamping reduced heart rate (by ∼40%) and right ventricular output (RVO; from 114.6 ± 14.4 to 38.8 ± 9.7 ml min(-1) kg(-1)), which were restored by ventilation. In Vent 1st lambs, cord clamping reduced RVO from 153.5 ± 3.8 to 119.2 ± 10.6 ml min(-1) kg(-1), did not affect heart rates and resulted in stable blood flows and pressures during transition. Delaying cord clamping for 3-4 min until after ventilation is established improves cardiovascular function by increasing pulmonary blood flow before the cord is clamped. As a result, cardiac output remains stable, leading to a smoother cardiovascular transition throughout the early newborn period.
349 citations
TL;DR: It is demonstrated that inorganic NO3− supplementation improves vascular control and elevates skeletal muscle O2 delivery during exercise predominantly in fast‐twitch type II muscles, and provide a potential mechanism by which NO3+ supplementation improves metabolic control.
Abstract: Dietary nitrate (NO(3)(-)) supplementation, via its reduction to nitrite (NO(2)(-)) and subsequent conversion to nitric oxide (NO) and other reactive nitrogen intermediates, reduces blood pressure and the O(2) cost of submaximal exercise in humans. Despite these observations, the effects of dietary NO(3)(-) supplementation on skeletal muscle vascular control during locomotory exercise remain unknown. We tested the hypotheses that dietary NO(3)(-) supplementation via beetroot juice (BR) would reduce mean arterial pressure (MAP) and increase hindlimb muscle blood flow in the exercising rat. Male Sprague-Dawley rats (3-6 months) were administered either NO(3)(-) (via beetroot juice; 1 mmol kg(-1) day(-1), BR n = 8) or untreated (control, n = 11) tap water for 5 days. MAP and hindlimb skeletal muscle blood flow and vascular conductance (radiolabelled microsphere infusions) were measured during submaximal treadmill running (20 m min(-1), 5% grade). BR resulted in significantly lower exercising MAP (control: 137 ± 3, BR: 127 ± 4 mmHg, P < 0.05) and blood [lactate] (control: 2.6 ± 0.3, BR: 1.9 ± 0.2 mm, P < 0.05) compared to control. Total exercising hindlimb skeletal muscle blood flow (control: 108 ± 8, BR: 150 ± 11 ml min(-1) (100 g)(-1), P < 0.05) and vascular conductance (control: 0.78 ± 0.05, BR: 1.16 ± 0.10 ml min(-1) (100 g)(-1) mmHg(-1), P < 0.05) were greater in rats that received BR compared to control. The relative differences in blood flow and vascular conductance for the 28 individual hindlimb muscles and muscle parts correlated positively with their percentage type IIb + d/x muscle fibres (blood flow: r = 0.74, vascular conductance: r = 0.71, P < 0.01 for both). These data support the hypothesis that NO(3)(-) supplementation improves vascular control and elevates skeletal muscle O(2) delivery during exercise predominantly in fast-twitch type II muscles, and provide a potential mechanism by which NO(3)(-) supplementation improves metabolic control.
281 citations
TL;DR: Experimental evidence is provided in favour of a direct role of decreased glycogen, localized within the myofibrils, for the reduction in SR Ca2+ release during fatigue, consistent with compartmentalized energy turnover and distinctly localized glycogen pools being of key importance for SR Ca1+ release and thereby affecting muscle contractility and fatigability.
Abstract: Studies performed at the beginning of the last century revealed the importance of carbohydrate as a fuel during exercise, and the importance of muscle glycogen on performance has subsequently been confirmed in numerous studies. However, the link between glycogen depletion and impaired muscle function during fatigue is not well understood and a direct cause-and-effect relationship between glycogen and muscle function remains to be established. The use of electron microscopy has revealed that glycogen is not homogeneously distributed in skeletal muscle fibres, but rather localized in distinct pools. Furthermore, each glycogen granule has its own metabolic machinery with glycolytic enzymes and regulating proteins. One pool of such glycogenolytic complexes is localized within the myofibrils in close contact with key proteins involved in the excitation-contraction coupling and Ca2+ release from the sarcoplasmic reticulum (SR). We and others have provided experimental evidence in favour of a direct role of decreased glycogen, localized within the myofibrils, for the reduction in SR Ca2+ release during fatigue. This is consistent with compartmentalized energy turnover and distinctly localized glycogen pools being of key importance for SR Ca2+ release and thereby affecting muscle contractility and fatigability.
259 citations
TL;DR: The data suggest that the effects of exercise on FNDC5 and irisin are not consistent, and that their role in health is questionable, and the regulatory mechanisms should be studied further.
Abstract: Recently, contradictory findings have been reported concerning the function of irisin and its precursor gene, skeletal muscle FNDC5, in energy homeostasis, and the associated regulatory role of exercise and PGC-1α. We therefore evaluated whether muscle FNDC5 mRNA and serum irisin are exercise responsive and whether PGC-1α expression is associated with FNDC5 expression. The male subjects in the study performed single exercises: (1) 1 h low-intensity aerobic exercise (AE) (middle-aged, n = 17), (2) a heavy-intensity resistance exercise (RE) bout (young n = 10, older n = 11) (27 vs. 62 years), (3) long-term 21 weeks endurance exercise (EE) training alone (twice a week, middle-aged, n = 9), or (4) combined EE and RE training (both twice a week, middle-aged, n = 9). Skeletal muscle mRNA expression was analysed by quantitative PCR and serum irisin by ELISA. No significant changes were observed in skeletal muscle PGC-1α, FNDC5 and serum irisin after AE, EE training or combined EE + RE training. However, a single RE bout increased PGC-1α by 4-fold in young and by 2-fold in older men, while FNDC5 mRNA only increased in young men post-RE, by 1.4-fold. Changes in PGC-1α or serum irisin were not consistently accompanied by changes in FNDC5. In conclusion, for the most part, neither longer-term nor single exercise markedly increases skeletal muscle FNDC5 expression or serum irisin. Therefore their changes in response to exercise are probably random and not consistent excluding the confirmation of any definitive link between exercise and FNDC5 expression and irisin release in humans. Moreover, irisin and FNDC5 were not associated with glucose tolerance and being overweight, or with metabolic disturbances, respectively. Finally, factor(s) other than PGC-1α and transcription may regulate FNDC5 expression.
258 citations
TL;DR: It is concluded that many of the stimuli in current use do not provide a standard stimulus comparable between individuals and in the same individual over time, and it is suggested that carbon dioxide is the most suitable vasoactive stimulus.
Abstract: Cerebrovascular reactivity is the change in cerebral blood flow in response to a vasodilatory or vasoconstrictive stimulus. Measuring variations of cerebrovascular reactivity between different regions of the brain has the potential to not only advance understanding of how the cerebral vasculature controls the distribution of blood flow but also to detect cerebrovascular pathophysiology. While there are standardized and repeatable methods for estimating the changes in cerebral blood flow in response to a vasoactive stimulus, the same cannot be said for the stimulus itself. Indeed, the wide variety of vasoactive challenges currently employed in these studies impedes comparisons between them. This review therefore critically examines the vasoactive stimuli in current use for their ability to provide a standard repeatable challenge and for the practicality of their implementation. Such challenges include induced reductions in systemic blood pressure, and the administration of vasoactive substances such as acetazolamide and carbon dioxide. We conclude that many of the stimuli in current use do not provide a standard stimulus comparable between individuals and in the same individual over time. We suggest that carbon dioxide is the most suitable vasoactive stimulus. We describe recently developed computer-controlled MRI compatible gas delivery systems which are capable of administering reliable and repeatable vasoactive CO2 stimuli.
249 citations
TL;DR: An overview of the current understanding of the neural architecture within the amygdala and medial prefrontal cortex is provided, which describes how sensory information is processed in these two structures and the neural circuits between them thought to mediate different aspects of fear learning.
Abstract: Fear conditioning and fear extinction are Pavlovian conditioning paradigms extensively used to study the mechanisms that underlie learning and memory formation The neural circuits that mediate this learning are evolutionarily conserved, and seen in virtually all species from flies to humans In mammals, the amygdala and medial prefrontal cortex are two structures that play a key role in the acquisition, consolidation and retrieval of fear memory, as well extinction of fear These two regions have extensive bidirectional connections, and in recent years, the neural circuits that mediate fear learning and fear extinction are beginning to be elucidated In this review, we provide an overview of our current understanding of the neural architecture within the amygdala and medial prefrontal cortex We describe how sensory information is processed in these two structures and the neural circuits between them thought to mediate different aspects of fear learning Finally, we discuss how changes in circuits within these structures may mediate fear responses following fear conditioning and extinction
TL;DR: Mechanisms by which overnight rostral fluid shift, and its prevention, can contribute to the pathogenesis and therapy of sleep apnoea are explored.
Abstract: Obstructive sleep apnoea (OSA) is common in the general population and increases the risk of motor vehicle accidents due to hypersomnolence from sleep disruption, and risk of cardiovascular diseases owing to repetitive hypoxia, sympathetic nervous system activation, and systemic inflammation. In contrast, central sleep apnoea (CSA) is rare in the general population. Although their pathogenesis is multifactorial, the prevalence of both OSA and CSA is increased in patients with fluid retaining states, especially heart failure, where they are associated with increased mortality risk. This observation suggests that fluid retention may contribute to the pathogenesis of both OSA and CSA. According to this hypothesis, during the day fluid accumulates in the intravascular and interstitial spaces of the legs due to gravity, and upon lying down at night redistributes rostrally, again owing to gravity. Some of this fluid may accumulate in the neck, increasing tissue pressure and causing the upper airway to narrow, thereby increasing its collapsibility and predisposing to OSA. In heart failure patients, with increased rostral fluid shift, fluid may additionally accumulate in the lungs, provoking hyperventilation and hypocapnia, driving below the apnoea threshold, leading to CSA. This review article will explore mechanisms by which overnight rostral fluid shift, and its prevention, can contribute to the pathogenesis and therapy of sleep apnoea.
TL;DR: Hypoxia‐inducible factor activates an extensive transcriptional cascade that interfaces with other cell signalling pathways, microRNA networks and RNA–protein translational control systems and the implication of dysregulating these massive physiological pathways in diseases such as cancer is discussed.
Abstract: Studies of regulation of the haematopoietic growth factor erythropoietin led to the unexpected discovery of a widespread system of direct oxygen sensing that regulates gene expression in animals. The oxygen-sensitive signal is generated by a series of non-haem Fe(II)- and 2-oxoglutarate-dependent dioxygenases that catalyse the post-translational hydroxylation of specific residues in the transcription factor hypoxia-inducible factor (HIF). These hydroxylations promote both oxygen-dependent degradation and oxygen-dependent inactivation of HIF, but are suppressed in hypoxia, leading to the accumulation of HIF and assembly of an active transcriptional complex in hypoxic cells. Hypoxia-inducible factor activates an extensive transcriptional cascade that interfaces with other cell signalling pathways, microRNA networks and RNA-protein translational control systems. The relationship of these cellular signalling pathways to the integrated physiology of oxygen homeostasis and the implication of dysregulating these massive physiological pathways in diseases such as cancer are discussed.
TL;DR: The present study is the first to demonstrate negative effects of resveratrol on training‐induced improvements in cardiovascular health parameters in humans and adds to the growing body of evidence questioning the positive effects of Resver atrol supplementation in humans.
Abstract: Ageing is thought to be associated with decreased vascular function partly due to oxidative stress. Resveratrol is a polyphenol, which in animal studies has been shown to decrease atherosclerosis, and improve cardiovascular health and physical capacity, in part through its effects on Sirtuin 1 signalling and through an improved antioxidant capacity. We tested the hypothesis that resveratrol supplementation enhances training-induced improvements in cardiovascular health parameters in aged men. Twenty-seven healthy physically inactive aged men (age: 65 ± 1 years; body mass index: 25.4 ± 0.7 kg m(-2); mean arterial pressure (MAP): 95.8 ± 2.2 mmHg; maximal oxygen uptake: 2488 ± 72 ml O2 min(-1)) were randomized into 8 weeks of either daily intake of either 250 mg trans-resveratrol (n = 14) or of placebo (n = 13) concomitant with high-intensity exercise training. Exercise training led to a 45% greater (P < 0.05) increase in maximal oxygen uptake in the placebo group than in the resveratrol group and to a decrease in MAP in the placebo group only (-4.8 ± 1.7 mmHg; P < 0.05). The interstitial level of vasodilator prostacyclin was lower in the resveratrol than in the placebo group after training (980 ± 90 vs. 1174 ± 121 pg ml(-1); P < 0.02) and muscle thromboxane synthase was higher in the resveratrol group after training (P < 0.05). Resveratrol administration also abolished the positive effects of exercise on low-density lipoprotein, total cholesterol/high-density lipoprotein ratio and triglyceride concentrations in blood (P < 0.05). Resveratrol did not alter the effect of exercise training on the atherosclerosis marker vascular cell adhesion molecule 1 (VCAM-1). Sirtuin 1 protein levels were not affected by resveratrol supplementation. These findings indicate that, whereas exercise training effectively improves several cardiovascular health parameters in aged men, concomitant resveratrol supplementation can blunt these effects.
TL;DR: Stroke induces changes in functional and effective connectivity within and across hemispheres which relate to motor impairments and recovery thereof, and connectivity analyses may hence provide new insights into the pathophysiology underlying neurological deficits and may be further used to develop novel, neurobiologically informed treatment strategies.
Abstract: Stroke causes a sudden disruption of physiological brain function which leads to impairments of functional brain networks involved in voluntary movements. In some cases, the brain has the intrinsic capacity to reorganize itself, thereby compensating for the disruption of motor networks. In humans, such reorganization can be investigated in vivo using neuroimaging. Recent developments in connectivity analyses based on functional neuroimaging data have provided new insights into the network pathophysiology underlying neurological symptoms. Here we review recent neuroimaging studies using functional resting-state correlations, effective connectivity models or graph theoretical analyses to investigate changes in neural motor networks and recovery after stroke. The data demonstrate that network disturbances after stroke occur not only in the vicinity of the lesion but also between remote cortical areas in the affected and unaffected hemisphere. The reorganization of motor networks encompasses a restoration of interhemispheric functional coherence in the resting state, particularly between the primary motor cortices. Furthermore, reorganized neural networks feature strong excitatory interactions between fronto-parietal areas and primary motor cortex in the affected hemisphere, suggesting that greater top-down control over primary motor areas facilitates motor execution in the lesioned brain. In addition, there is evidence that motor recovery is accompanied by a more random network topology with reduced local information processing. In conclusion, Stroke induces changes in functional and effective connectivity within and across hemispheres which relate to motor impairments and recovery thereof. Connectivity analyses may hence provide new insights into the pathophysiology underlying neurological deficits and may be further used to develop novel, neurobiologically informed treatment strategies.
TL;DR: Exercise rapidly and transiently regulates several miRNA species potentially involved in the regulation of skeletal muscle regeneration, gene transcription and mitochondrial biogenesis.
Abstract: Key points
• The discovery of microRNAs (miRNAs) has established new mechanisms that control health, but little is known about the regulation of skeletal muscle miRNAs in response to exercise.
• This study investigated components of the miRNA biogenesis pathway (Drosha, Dicer and Exportin-5), muscle enriched miRNAs, (miR-1, -133a, -133b and 206), and several miRNAs dysregulated in muscle myopathies, and showed that 3 h following an acute exercise bout, Drosha, Dicer and Exportin-5, as well as miR-1, -133a, -133-b and miR-181a were all increased, while miR-9, -23a, -23b and -31 were decreased.
• Short-term training increased miR-1 and miR-29b, while miR-31 remained decreased.
• Negative correlations were observed between miR-9 and HDAC4 protein, miR-31 and HDAC4 protein and between miR-31 and NRF1 protein, 3 h after exercise.
• miR-31 binding to the HDAC4 and NRF1 3′ untranslated region (UTR) reduced luciferase reporter activity.
• Exercise rapidly and transiently regulates several miRNA species potentially involved in the regulation of skeletal muscle regeneration, gene transcription and mitochondrial biogenesis.
Abstract The identification of microRNAs (miRNAs) has established new mechanisms that control skeletal muscle adaptation to exercise. The present study investigated the mRNA regulation of components of the miRNA biogenesis pathway (Drosha, Dicer and Exportin-5), muscle enriched miRNAs, (miR-1, -133a, -133b and -206), and several miRNAs dysregulated in muscle myopathies (miR-9, -23, -29, -31 and -181). Measurements were made in muscle biopsies from nine healthy untrained males at rest, 3 h following an acute bout of moderate-intensity endurance cycling and following 10 days of endurance training. Bioinformatics analysis was used to predict potential miRNA targets. In the 3 h period following the acute exercise bout, Drosha, Dicer and Exportin-5, as well as miR-1, -133a, -133-b and -181a were all increased. In contrast miR-9, -23a, -23b and -31 were decreased. Short-term training increased miR-1 and -29b, while miR-31 remained decreased. Negative correlations were observed between miR-9 and HDAC4 protein (r=−0.71; P= 0.04), miR-31 and HDAC4 protein (r =−0.87; P= 0.026) and miR-31 and NRF1 protein (r =−0.77; P= 0.01) 3 h following exercise. miR-31 binding to the HDAC4 and NRF1 3′ untranslated region (UTR) reduced luciferase reporter activity. Exercise rapidly and transiently regulates several miRNA species in muscle. Several of these miRNAs may be involved in the regulation of skeletal muscle regeneration, gene transcription and mitochondrial biogenesis. Identifying endurance exercise-mediated stress signals regulating skeletal muscle miRNAs, as well as validating their targets and regulatory pathways post exercise, will advance our understanding of their potential role/s in human health.
TL;DR: ET and SIT were equally effective at decreasing arterial stiffness and increasing skeletal muscle capillarisation and eNOS content, suggesting that both training modes improve skeletal muscle microvascular and macrovascular function.
Abstract: Sprint interval training (SIT) has been proposed as a time efficient alternative to endurance training (ET) for increasing skeletal muscle oxidative capacity and improving certain cardiovascular functions. In this study we sought to make the first comparisons of the structural and endothelial enzymatic changes in skeletal muscle microvessels in response to ET and SIT. Sixteen young sedentary males (age 21 ± SEM 0.7 years, BMI 23.8 ± SEM 0.7 kg m(-2)) were randomly assigned to 6 weeks of ET (40-60 min cycling at ∼65% , 5 times per week) or SIT (4-6 Wingate tests, 3 times per week). Muscle biopsies were taken from the m. vastus lateralis before and following 60 min cycling at 65% to measure muscle microvascular endothelial eNOS content, eNOS serine(1177) phosphorylation, NOX2 content and capillarisation using quantitative immunofluorescence microscopy. Whole body insulin sensitivity, arterial stiffness and blood pressure were also assessed. ET and SIT increased skeletal muscle microvascular eNOS content (ET 14%; P < 0.05, SIT 36%; P < 0.05), with a significantly greater increase observed following SIT (P < 0.05). Sixty minutes of moderate intensity exercise increased eNOS ser(1177) phosphorylation in all instances (P < 0.05), but basal and post-exercise eNOS ser(1177) phosphorylation was lower following both training modes. All microscopy measures of skeletal muscle capillarisation (P < 0.05) were increased with SIT or ET, while neither endothelial nor sarcolemmal NOX2 was changed. Both training modes reduced aortic stiffness and increased whole body insulin sensitivity (P < 0.05). In conclusion, in sedentary males SIT and ET are effective in improving muscle microvascular density and eNOS protein content.
TL;DR: A novel mechanism for the training‐induced improvements in IMTG breakdown and insulin sensitivity is suggested, and it is shown that SIT is an alternative, time‐efficient training strategy that induces similar beneficial metabolic adaptations.
Abstract: Intramuscular triglyceride (IMTG) utilization is enhanced by endurance training (ET) and is linked to improved insulin sensitivity. This study first investigated the hypothesis that ET-induced increases in net IMTG breakdown and insulin sensitivity are related to increased expression of perilipin 2 (PLIN2) and perilipin 5 (PLIN5). Second, we hypothesized that sprint interval training (SIT) also promotes increases in IMTG utilization and insulin sensitivity. Sixteen sedentary males performed 6 weeks of either SIT (4-6, 30 s Wingate tests per session, 3 days week(-1)) or ET (40-60 min moderate-intensity cycling, 5 days week(-1)). Training increased resting IMTG content (SIT 1.7-fold, ET 2.4-fold; P < 0.05), concomitant with parallel increases in PLIN2 (SIT 2.3-fold, ET 2.8-fold; P < 0.01) and PLIN5 expression (SIT 2.2-fold, ET 3.1-fold; P < 0.01). Pre-training, 60 min cycling at ∼65% pre-training decreased IMTG content in type I fibres (SIT 17 ± 10%, ET 15 ± 12%; P < 0.05). Following training, a significantly greater breakdown of IMTG in type I fibres occurred during exercise (SIT 27 ± 13%, ET 43 ± 6%; P < 0.05), with preferential breakdown of PLIN2- and particularly PLIN5-associated lipid droplets. Training increased the Matsuda insulin sensitivity index (SIT 56 ± 15%, ET 29 ± 12%; main effect P < 0.05). No training × group interactions were observed for any variables. In conclusion, SIT and ET both increase net IMTG breakdown during exercise and increase in PLIN2 and PLIN5 protein expression. The data are consistent with the hypothesis that increases in PLIN2 and PLIN5 are related to the mechanisms that promote increased IMTG utilization during exercise and improve insulin sensitivity following 6 weeks of SIT and ET.
TL;DR: It is shown that motor learning robustly increases the economy of locomotion during split‐belt treadmill adaptation, and reductions in metabolic power scale with the magnitude of adaptation and are also associated with a reduction in muscle activity throughout the lower limbs.
Abstract: Many theories of motor control suggest that we select our movements to reduce energy use. However, it is unclear whether this process underlies short-term motor adaptation to novel environments. Here we asked whether adaptation to walking on a split-belt treadmill leads to a more economical walking pattern. We hypothesized that adaptation would be accompanied by a reduction in metabolic power and muscle activity and that these reductions would be temporally correlated. Eleven individuals performed a split-belt adaptation task where the belt speeds were set at 0.5 and 1.5 m s(-1). Adaptation was characterized by step length symmetry, which is the normalized difference in step length between the legs. Metabolic power was calculated based on expired gas analysis, and surface EMG was used to record the activity of four bilateral leg muscles (tibialis anterior, lateral gastrocnemius, vastus lateralis and biceps femoris). All participants initially walked with unequal step lengths when the belts moved at different speeds, but gradually adapted to take steps of equal length. Additionally, net metabolic power was reduced from early adaptation to late adaptation (early, 3.78 ± 1.05 W kg(-1); and late, 3.05 ± 0.79 W kg(-1); P < 0.001). This reduction in power was also accompanied by a bilateral reduction in EMG throughout the gait cycle. Furthermore, the reductions in metabolic power occurred over the same time scale as the improvements in step length symmetry, and the magnitude of these improvements predicted the size of the reduction in metabolic power. Our results suggest that increasing economy may be a key criterion driving locomotor adaptation.
TL;DR: Modelling the time course of fatigue development during and after an intense bout of self‐paced, high‐intensity dynamic exercise using various electrical stimulation parameters to assess neuromuscular function (NMF) changes suggests that the extent to which muscle fatigue is documented during exercise depends upon NMF assessment methodology.
Abstract: The time course of muscular fatigue that develops during and after an intense bout of self-paced dynamic exercise was characterized by using different forms of electrical stimulation (ES) of the exercising muscles. Ten active subjects performed a time trial (TT) involving repetitive concentric extension/flexion of the right knee using a Biodex dynamometer. Neuromuscular function (NMF), including ES and a 5 s maximal isometric voluntary contraction (MVC), was assessed before the start of the TT and immediately (<5 s) after each 20% of the TT had been completed, as well as 1, 2, 4 and 8 min after TT termination. The TT time was 347 ± 98 s. MVCs were 52% of baseline values at TT termination. Torque responses from ES were reduced to 33-68% of baseline using different methods of stimulation, suggesting that the extent to which peripheral fatigue is documented during exercise depends upon NMF assessment methodology. The major changes in muscle function occurred within the first 40% of exercise. Significant recovery in skeletal muscle function occurs within the first 1-2 min after exercise, showing that previous studies may have underestimated the extent to which peripheral fatigue develops during exercise.
TL;DR: To perform an unbiased comparison of WBSRs (but not necessarily core temperature) between different individuals/groups under conditions allowing full evaporation, future studies should consider using a fixed Ereq irrespective of the % incurred.
Abstract: Although the requirements for heat dissipation during exercise are determined by the necessity for heat balance, few studies have considered them when examining sweat production and its potential modulators. Rather, the majority of studies have used an experimental protocol based on a fixed percentage of maximum oxygen uptake (% ). Using multiple regression analysis, we examined the independent contribution of the evaporative requirement for heat balance (Ereq) and % to whole-body sweat rate (WBSR) during exercise. We hypothesised that WBSR would be determined by Ereq and not by % . A total of 23 males performed two separate experiments during which they exercised for 90 min at different rates of metabolic heat production (200, 350, 500 W) at a fixed air temperature (30°C, n = 8), or at a fixed rate of metabolic heat production (290 W) at different air temperatures (30, 35, 40°C, n = 15 and 45°C, n = 7). Whole-body evaporative heat loss was measured by direct calorimetry and used to calculate absolute WBSR in grams per minute. The conditions employed resulted in a wide range of Ereq (131-487 W) and % (15-55%). The individual variation in non-steady-state (0-30 min) and steady-state (30-90 min) WBSR correlated significantly with Ereq (P < 0.001). In contrast, % correlated negatively with the residual variation in WBSR not explained by Ereq, and marginally increased (∼2%) the amount of total variability in WBSR described by Ereq alone (non-steady state: R(2) = 0.885; steady state: R(2) = 0.930). These data provide clear evidence that absolute WBSR during exercise is determined by Ereq, not by % . Future studies should therefore use an experimental protocol which ensures a fixed Ereq when examining absolute WBSR between individuals, irrespective of potential differences in relative exercise intensity.
TL;DR: It is shown that inhibition of mammalian target of rapamycin complex 1 or 2 markedly decreases the activity of key placental amino acid transporters in cultured primary human placental cells, mediated by modulating the movement of specific transporter isoforms between the cell interior and the plasma membrane.
Abstract: Abnormal fetal growth increases the risk for perinatal complications and predisposes for the development of obesity, diabetes and cardiovascular disease later in life. Emerging evidence suggests that changes in placental amino acid transport directly contribute to altered fetal growth. However, the molecular mechanisms regulating placental amino acid transport are largely unknown. Here we combined small interfering (si) RNA-mediated silencing approaches with protein expression/localization and functional studies in cultured primary human trophoblast cells to test the hypothesis that mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) regulate amino acid transporters by post-translational mechanisms. Silencing raptor (inhibits mTORC1) or rictor (inhibits mTORC2) markedly decreased basal System A and System L amino acid transport activity but had no effect on growth factor-stimulated amino acid uptake. Simultaneous inhibition of mTORC1 and 2 completely inhibited both basal and growth factor-stimulated amino acid transport activity. In contrast, mTOR inhibition had no effect on serotonin transport. mTORC1 or mTORC2 silencing markedly decreased the plasma membrane expression of specific System A (SNAT2, SLC38A2) and System L (LAT1, SLC7A5) transporter isoforms without affecting global protein expression. In conclusion, mTORC1 and mTORC2 regulate human trophoblast amino acid transporters by modulating the cell surface abundance of specific transporter isoforms. This is the first report showing regulation of amino acid transport by mTORC2. Because placental mTOR activity and amino acid transport are decreased in human intrauterine growth restriction our data are consistent with the possibility that dysregulation of placental mTOR plays an important role in the development of abnormal fetal growth.
TL;DR: The data suggest that modulation of fast‐spiking interneuron activity may represent a new therapeutic strategy to prevent generalization of focal epilepsies.
Abstract: In different animal models of focal epilepsy, seizure-like ictal discharge propagation is transiently opposed by feedforward inhibition. The specific cellular source of this signal and the mechanism by which inhibition ultimately becomes ineffective are, however, undefined. We used a brain slice model to study how focal ictal discharges that were repetitively evoked from the same site, and at precise times, propagate across the cortex. We used Ca2+ imaging and simultaneous single/dual cell recordings from pyramidal neurons (PyNs) and different classes of interneurons in rodents, including G42 and GIN transgenic mice expressing the green fluorescence protein in parvalbumin (Pv)-fast spiking (FS) and somatostatin (Som) interneurons, respectively. We found that these two classes of interneurons fired intensively shortly after ictal discharge generation at the focus. The inhibitory barrages that were recorded in PyNs occurred in coincidence with Pv-FS, but not with Som interneuron burst discharges. Furthermore, the strength of inhibitory barrages increased or decreased in parallel with increased or decreased firing in Pv-FS interneurons but not in Som interneurons. A firing impairment of Pv-FS interneurons caused by a membrane depolarization was found to precede ictal discharge onset in neighbouring pyramidal neurons. This event may account for the collapse of local inhibition that allows spatially defined clusters of PyNs to be recruited into propagating ictal discharges. Our study demonstrates that Pv-FS interneurons are a major source of the inhibitory barrages that oppose ictal discharge propagation and raises the possibility that targeting Pv-FS interneurons represents a new therapeutic strategy to prevent the generalization of human focal seizures.
TL;DR: GLUT5‐ and GLUT2‐mediated fructose effects on intestinal electrolyte transporters, hepatic uric acid metabolism, as well as renal and cardiomyocyte function, may play a role in fructose‐induced hypertension and the development of non‐alcoholic fatty liver disease.
Abstract: Fructose intake has increased dramatically since humans were hunter-gatherers, probably outpacing the capacity of human evolution to make physiologically healthy adaptations. Epidemiological data indicate that this increasing trend continued until recently. Excessive intakes that chronically increase portal and peripheral blood fructose concentrations to >1 and 0.1 mm, respectively, are now associated with numerous diseases and syndromes. The role of the fructose transporters GLUT5 and GLUT2 in causing, contributing to or exacerbating these diseases is not well known. GLUT5 expression seems extremely low in neonatal intestines, and limited absorptive capacities for fructose may explain the high incidence of malabsorption in infants and cause problems in adults unable to upregulate GLUT5 levels to match fructose concentrations in the diet. GLUT5- and GLUT2-mediated fructose effects on intestinal electrolyte transporters, hepatic uric acid metabolism, as well as renal and cardiomyocyte function, may play a role in fructose-induced hypertension. Likewise, GLUT2 may contribute to the development of non-alcoholic fatty liver disease by facilitating the uptake of fructose. Finally, GLUT5 may play a role in the atypical growth of certain cancers and fat tissues. We also highlight research areas that should yield information needed to better understand the role of these GLUTs in fructose-induced diseases.
TL;DR: Insight into the dysfunction and dysregulation of the cardiac sodium channel in the setting of SCN5A mutations identified in patients with these inherited arrhythmia syndromes would enable improved diagnosis, risk stratification and treatment strategies, and enable a major next step in research related to cardiac Sodium channel disease.
Abstract: Over the last two decades, an increasing number of SCN5A mutations have been described in patients with long QT syndrome type 3 (LQT3), Brugada syndrome, (progressive) conduction disease, sick sinus syndrome, atrial standstill, atrial fibrillation, dilated cardiomyopathy, and sudden infant death syndrome (SIDS). Combined genetic, electrophysiological and molecular studies have provided insight into the dysfunction and dysregulation of the cardiac sodium channel in the setting of SCN5A mutations identified in patients with these inherited arrhythmia syndromes. However, risk stratification and patient management is hindered by the reduced penetrance and variable disease expressivity in sodium channelopathies. Furthermore, various SCN5A-related arrhythmia syndromes are known to display mixed phenotypes known as cardiac sodium channel overlap syndromes. Determinants of variable disease expressivity, including genetic background and environmental factors, are suspected but still largely unknown. Moreover, it has become increasingly clear that sodium channel function and regulation is more complicated than previously assumed, and the sodium channel may play additional, as of yet unrecognized, roles in cardiac structure and function. Development of cardiac structural abnormalities secondary to SCN5A mutations has been reported, but the clinical relevance and underlying mechanisms are unclear. Increased insight into these issues would enable a major next step in research related to cardiac sodium channel disease, ultimately enabling improved diagnosis, risk stratification and treatment strategies.
TL;DR: It is argued that the influence of vagal stimulation on ventricular myocardial action potential refractory period, duration, force and rhythm is evidence that vagal fibres have close apposition to myocardia, supported by clear evidence of accentuated antagonism between sympathetic activity and vagal activity in the ventricle.
Abstract: There is continuing belief that cardiac parasympathetic postganglionic fibres are sparse or absent from the ventricles. This review of the literature shows that the supposition is a myth. Early studies considered that fine silver-stained fibres coursing amongst ventricle myocardial cells were most likely cardiac parasympathetic postganglionic fibres. The conclusions were later supported by acetyl cholinesterase staining using a method that appeared not to be associated with noradrenaline nerve fibres. The conclusion is critically examined in the light of several recent histological studies using the acetyl cholinesterase method and also a more definitive technique (CHAT), that suggest a widespread location of parasympathetic ganglia and a relatively dense parasympathetic innervation of ventricular muscle in a range of mammals including man. The many studies demonstrating acetylcholine release in the ventricle on vagal nerve stimulation and a high density of acetylcholine M2 receptors is in accord with this as are tests of ventricular performance from many physiological studies. Selective control of cardiac functions by anatomically segregated parasympathetic ganglia is discussed. It is argued that the influence of vagal stimulation on ventricular myocardial action potential refractory period, duration, force and rhythm is evidence that vagal fibres have close apposition to myocardial fibres. This is supported by clear evidence of accentuated antagonism between sympathetic activity and vagal activity in the ventricle and also by direct effects of vagal activity independent of sympathetic activity. The idea of differential control of atrial and ventricular physiology by vagal C and vagal B preganglionic fibres is examined as well as differences in chemical phenotypes and their function. The latter is reflected in medullary and supramedullary control. Reference is made to the importance of this knowledge to understanding the normal physiology of cardiac autonomic control and significance to pathology.
TL;DR: N nanoparticle tracking analysis was able to track an increase in exosomal aquaporin 2 concentration following desmopressin treatment of a kidney cell line, a rodent model and a patient with central diabetes insipidus, indicating potential for rapid characterization and quantification of exosomes in human urine.
Abstract: Exosomes are vesicles that are released from the kidney into urine. They contain protein and RNA from the glomerulus and all sections of the nephron and represent a reservoir for biomarker discovery. Current methods for the identification and quantification of urinary exosomes are time consuming and only semi-quantitative. Nanoparticle tracking analysis (NTA) counts and sizes particles by measuring their Brownian motion in solution. In this study, we applied NTA to human urine and identified particles with a range of sizes. Using antibodies against the exosomal proteins CD24 and aquaporin 2 (AQP2), conjugated to a fluorophore, we could identify a subpopulation of CD24- and AQP2-positive particles of characteristic exosomal size. Extensive pre-NTA processing of urine was not necessary. However, the intra-assay variability in the measurement of exosome concentration was significantly reduced when an ultracentrifugation step preceded NTA. Without any sample processing, NTA tracked exosomal AQP2 upregulation induced by desmopressin stimulation of kidney collecting duct cells. Nanoparticle tracking analysis was also able to track changes in exosomal AQP2 concentration that followed desmopressin treatment of mice and a patient with central diabetes insipidus. When urine was stored at room temperature, 4°C or frozen, nanoparticle concentration was reduced; freezing at -80°C with the addition of protease inhibitors produced the least reduction. In conclusion, with appropriate sample storage, NTA has potential as a tool for the characterization and quantification of extracellular vesicles in human urine.
TL;DR: The main study finding was the observation of a less marked muscle mass recovery after immobilisation in elderly compared to young individuals that was paralleled by an elevation in myogenic precursor cell content in young individuals only, whereas the elderly failed to demonstrate any change inMyogenic precursor cells.
Abstract: Recovery of skeletal muscle mass from immobilisation-induced atrophy is faster in young than older individuals, yet the cellular mechanisms remain unknown. We examined the cellular and molecular regulation of muscle recovery in young and older human subjects subsequent to 2 weeks of immobility-induced muscle atrophy. Retraining consisted of 4 weeks of supervised resistive exercise in 9 older (OM: mean age) 67.3, range 61-74 yrs) and 11 young (YM: mean age 24.4, range 21-30 yrs) males. Measures of myofibre area (MFA), Pax7-positive satellite cells (SCs) associated with type I and type II muscle fibres, as well as gene expression analysis of key growth and transcription factors associated with local skeletal muscle milieu, were performed after 2 weeks immobility (Imm) and following 3 days (+3d) and 4 weeks (+4wks) of retraining. OM demonstrated no detectable gains in MFA (vastus lateralis muscle) and no increases in number of Pax7-positive SCs following 4wks retraining, whereas YM increased their MFA (P < 0.05), number of Pax7-positive cells, and had more Pax7-positive cells per type II fibre than OM at +3d and +4wks (P < 0.05). No age-related differences were observed in mRNA expression of IGF-1Ea, MGF, MyoD1 and HGF with retraining, whereas myostatin expression levels were more down-regulated in YM compared to OM at +3d (P < 0.05). In conclusion, the diminished muscle re-growth after immobilisation in elderly humans was associated with a lesser response in satellite cell proliferation in combination with an age-specific regulation of myostatin. In contrast, expression of local growth factors did not seem to explain the age-related difference in muscle mass recovery.
TL;DR: It is suggested that short‐wavelength visible light exposures may be more efficient than traditional high‐intensity white light exposures for treatment of circadian rhythm sleep disorders.
Abstract: The photic resetting response of the human circadian pacemaker depends on the timing of exposure, and the direction and magnitude of the resulting shift is described by a phase response curve (PRC). Previous PRCs in humans have utilized high-intensity polychromatic white light. Given that the circadian photoreception system is maximally sensitive to short-wavelength visible light, the aim of the current study was to construct a PRC to blue (480 nm) light and compare it to a 10,000 lux white light PRC constructed previously using a similar protocol. Eighteen young healthy participants (18-30 years) were studied for 9-10 days in a time-free environment. The protocol included three baseline days followed by a constant routine (CR) to assess initial circadian phase. Following this CR, participants were exposed to a 6.5 h 480 nm light exposure (11.8 I¼W cm-2, 11.2 lux) following mydriasis via a modified Ganzfeld dome. A second CR was conducted following the light exposure to re-assess circadian phase. Phase shifts were calculated from the difference in dim light melatonin onset (DLMO) between CRs. Exposure to 6.5 h of 480 nm light resets the circadian pacemaker according to a conventional type 1 PRC with fitted maximum delays and advances of -2.6 h and 1.3 h, respectively. The 480 nm PRC induced â�¼75% of the response of the 10,000 lux white light PRC. These results may contribute to a re-evaluation of dosing guidelines for clinical light therapy and the use of light as a fatigue countermeasure. © 2012 The Physiological Society.
TL;DR: It is concluded that ion channels and associated proteins are important players in different types of genetic and acquired epilepsies.
Abstract: Genetic mutations causing dysfunction of both voltage- and ligand-gated ion channels make a major contribution to the cause of many different types of familial epilepsy. Key mechanisms comprise defective Na(+) channels of inhibitory neurons, or GABA(A) receptors affecting pre- or postsynaptic GABAergic inhibition, or a dysfunction of different types of channels at axon initial segments. Many of these ion channel mutations have been modelled in mice, which has largely contributed to the understanding of where and how the ion channel defects lead to neuronal hyperexcitability. Animal models of febrile seizures or mesial temporal epilepsy have shown that dendritic K(+) channels, hyperpolarization-activated cation channels and T-type Ca(2+) channels play important roles in the generation of seizures. For the latter, it has been shown that suppression of their function by pharmacological mechanisms or in knock-out mice can antagonize epileptogenesis. Defects of ion channel function are also associated with forms of acquired epilepsy. Autoantibodies directed against ion channels or associated proteins, such as K(+) channels, LGI1 or NMDA receptors, have been identified in epileptic disorders that can largely be included under the term limbic encephalitis which includes limbic seizures, status epilepticus and psychiatric symptoms. We conclude that ion channels and associated proteins are important players in different types of genetic and acquired epilepsies. Nevertheless, the molecular bases for most common forms of epilepsy are not yet clear, and evidence to be discussed indicates just how much more we need to understand about the complex mechanisms that underlie epileptogenesis.