It is well established that resistance exercise (RE) is a potent stimulus for skeletal muscle hypertrophy. As a result, a plethora of research has been directed towards unravelling the complexity of mechanisms driving these muscular changes in order to establish how RE training variables might best be manipulated to optimize phenotypic adaptations, with important implications for athletic performance and prevention of a myriad of negative health complications (e.g. sarcopenia, metabolic diseases and rheumatoidand osteoarthritis). Major breakthroughs in the field have arisen from studies utilizing the muscle biopsy technique and arteriovenous catheterization in conjunction with the infusion of one or multiple stable amino acid (AA) isotope tracers. Measuring the rate of appearance and/or disappearance of isotopic tracer(s) in various skeletal muscle protein sub-fractions (predominantly myofibrillar or sarcoplasmic) or across the artery–vein has demonstrated that skeletal muscle mass is regulated via temporal fluctuations in muscle protein synthesis (MPS) and muscle protein breakdown (MPB) (Atherton & Smith, 2012). Individuals undertaking RE in the postabsorptive state mount a robust increase in the acute MPS response alongside elevated MPB rates, such that net protein balance (NPB) remains negative. However, when an adequate amount of high-quality protein is consumed in close proximity to the RE bout, the MPS response is potentiated and a positive NPB is achieved. Over time, the accumulation of periods of positive NPB leads to skeletal muscle protein accretion, manifested as increased muscle fibre cross-sectional area and an increased muscle mass. Although we are slowly beginning to understand the principle molecular and metabolic mechanisms underpinning muscle hypertrophy, a lot is yet to be discovered. Acute stable AA isotope infusion trials to assess MPS and MPB have proven extremely insightful; however, this method is not without limitations. First, it is extremely difficult to measure the true precursor (labelled tRNA) when using the precursor–product approach to calculate fractional synthesis rate. Second, and perhaps more importantly, this approach does not offer the opportunity to assess MPS in a free-living environment over an extended period (e.g. over the course of a training regimen) as extended AA isotope infusions lead to participant discomfort and are extremely costly. These limitations are important as it has been reported that a discord exists between the MPS response to an acute bout of RE (at the onset of training) and the chronic muscle remodelling that occurs over the course of prolonged RE training, thought to be due to the limited window in which exercise-induced MPS rates can be captured using stable AA isotope tracer infusions (Mitchell et al. 2014). Circumventing these issues to increase RE research validity is critical in order to understand the complex relationship between temporal fluctuations in MPS and long-term musc
阻力运动(RE)是骨骼肌肥大的有效刺激，这一点已经得到了很好的证实。因此，大量的研究一直致力于揭示驱动这些肌肉变化的复杂机制，以确定如何最好地操纵RE训练变量以优化表型适应，这对运动表现和预防无数负面健康并发症(例如肌肉减少症、代谢疾病、类风湿和骨关节炎)具有重要意义。该领域的重大突破来自于利用肌肉活检技术和动静脉导管置入结合输注一种或多种稳定氨基酸(AA)同位素示踪剂的研究。测量各种骨骼肌蛋白亚组分(主要是肌纤维或肌浆)或跨动静脉的同位素示踪剂的出现和/或消失率表明，骨骼肌质量是通过肌肉蛋白合成(MPS)和肌肉蛋白分解(MPB)的时间波动来调节的(Atherton & Smith, 2012)。在吸收后状态下进行RE的个体在MPB率升高的同时，急性MPS反应也会显著增加，因此净蛋白平衡(NPB)仍然为负。然而，当在RE回合附近摄入足量的高质量蛋白质时，MPS反应被增强，并实现阳性的NPB。随着时间的推移，NPB阳性周期的积累导致骨骼肌蛋白质的增加，表现为肌纤维横截面积的增加和肌肉质量的增加。虽然我们正在慢慢开始了解肌肉肥大的基本分子和代谢机制，但还有很多有待发现。急性稳定AA同位素输注试验评估MPS和MPB已被证明非常有见地;然而，这种方法并非没有局限性。首先，当使用前体产物方法计算分数合成速率时，很难测量真正的前体(标记的tRNA)。其次，也许更重要的是，这种方法不提供在长时间的自由生活环境中评估MPS的机会(例如，在训练方案的过程中)，因为长时间的AA同位素注入会导致参与者不适，而且成本极高。这些限制是很重要的，因为据报道，在急性RE发作(训练开始时)的MPS反应与在长时间RE训练过程中发生的慢性肌肉重塑之间存在不一致，这被认为是由于使用稳定的AA同位素示踪剂输注可以捕获运动诱导的MPS率的有限窗口(Mitchell et al. 2014)。为了了解MPS的时间波动与长期肌肉重构之间的复杂关系，规避这些问题以提高RE研究的有效性至关重要，并且可以通过结合使用氧化氘(D2O)来实现，氧化氘是近年来重新出现的同位素示踪剂。Damas及其同事最近在《生理学杂志》(The Journal of Physiology)上发表的一篇文章(2016)试图解决同位素示踪剂研究的主要局限性之一，调查了在RE训练过程中自由生活环境中MPS的长期发病率。在一项精心设计的研究中，10名年轻的未受过训练的男性接受了为期10周，每周两次的下肢RE训练计划。每次训练包括三组，每组9-12次重复，直到意志疲劳。在第一次、第五次和最后一次RE训练后48小时内，使用口服D2O测量肌原纤维蛋白合成率(MyoPS)。此外，通过z波段流直接评估肌肉损伤，通过血浆肌酸激酶(CK)、主观酸痛和最大膝关节伸肌力量间接评估肌肉损伤。通过纤维和股外侧肌横截面积(fCSA和VL CSA)的变化来评估肥厚。正如预期的那样，作者证明MyoPS在第一次训练后24和48小时升高，尽管在第五次也是最后一次训练后这种反应有所减弱。这些观察结果为在持续RE训练过程中运动诱导的MPS率的改进提供了支持。间接肌肉损伤指标符合预期模式，在第一次训练后，CK和主观疼痛增加，膝关节伸肌力量下降，而在第五次和最后一次训练后，只有疼痛增加。第一次训练后肌肉损伤(z波段流)显著大于训练前基础水平，随后逐渐降低。因此，re诱导的MyoPS率和肌肉损伤指数似乎在长期训练过程中消退。
{"title":"Mechanisms of resistance exercise‐induced muscle hypertrophy: ‘You can't make an omelette without breaking eggs’","authors":"Benoit Smeuninx, James McKendry","doi":"10.1113/JP273343","DOIUrl":"https://doi.org/10.1113/JP273343","url":null,"abstract":"It is well established that resistance exercise (RE) is a potent stimulus for skeletal muscle hypertrophy. As a result, a plethora of research has been directed towards unravelling the complexity of mechanisms driving these muscular changes in order to establish how RE training variables might best be manipulated to optimize phenotypic adaptations, with important implications for athletic performance and prevention of a myriad of negative health complications (e.g. sarcopenia, metabolic diseases and rheumatoidand osteoarthritis). Major breakthroughs in the field have arisen from studies utilizing the muscle biopsy technique and arteriovenous catheterization in conjunction with the infusion of one or multiple stable amino acid (AA) isotope tracers. Measuring the rate of appearance and/or disappearance of isotopic tracer(s) in various skeletal muscle protein sub-fractions (predominantly myofibrillar or sarcoplasmic) or across the artery–vein has demonstrated that skeletal muscle mass is regulated via temporal fluctuations in muscle protein synthesis (MPS) and muscle protein breakdown (MPB) (Atherton & Smith, 2012). Individuals undertaking RE in the postabsorptive state mount a robust increase in the acute MPS response alongside elevated MPB rates, such that net protein balance (NPB) remains negative. However, when an adequate amount of high-quality protein is consumed in close proximity to the RE bout, the MPS response is potentiated and a positive NPB is achieved. Over time, the accumulation of periods of positive NPB leads to skeletal muscle protein accretion, manifested as increased muscle fibre cross-sectional area and an increased muscle mass. Although we are slowly beginning to understand the principle molecular and metabolic mechanisms underpinning muscle hypertrophy, a lot is yet to be discovered. Acute stable AA isotope infusion trials to assess MPS and MPB have proven extremely insightful; however, this method is not without limitations. First, it is extremely difficult to measure the true precursor (labelled tRNA) when using the precursor–product approach to calculate fractional synthesis rate. Second, and perhaps more importantly, this approach does not offer the opportunity to assess MPS in a free-living environment over an extended period (e.g. over the course of a training regimen) as extended AA isotope infusions lead to participant discomfort and are extremely costly. These limitations are important as it has been reported that a discord exists between the MPS response to an acute bout of RE (at the onset of training) and the chronic muscle remodelling that occurs over the course of prolonged RE training, thought to be due to the limited window in which exercise-induced MPS rates can be captured using stable AA isotope tracer infusions (Mitchell et al. 2014). Circumventing these issues to increase RE research validity is critical in order to understand the complex relationship between temporal fluctuations in MPS and long-term musc","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"31 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87525655","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
That the endothelium governs vasodilatation in healthy humans and animals is well established. Indeed, impaired endothelium-dependent dilatation (EDD) is diagnostic of vascular dysfunction. Through the generation of diffusible autacoids, e.g. nitric oxide (NO) and metabolites of arachidonic acid, an increase in luminal shear stress leads to relaxation of vascular smooth muscle and is integral to flow-dependent dilatation. In humans, manipulating arterial blood flow (i.e. shear stress) is a non-invasive diagnostic tool for evaluating endothelial function as vessel diameter and blood flow velocity are monitored using ultrasound. A second pathway for EDD involves the initiation of hyperpolarization by endothelial cells and the transmission of electrical charge through myoendothelial gap junctions to evoke smooth muscle relaxation (Bagher & Segal, 2011). While endothelium-dependent hyperpolarization (EDH) has been well characterized in small resistance arteries and arterioles of animals, there is a dearth of evidence for EDH in governing blood flow in humans. This gap in translating findings from animal studies to humans is attributable to the invasive nature of recording membrane potential in the vascular wall after surgical exposure. Thus, elucidating EDH signalling as a pathway for EDD in humans has been difficult. In this issue of The Journal of Physiology a new study by Hearon et al. (2016), applying mechanistic insight gleaned from animal models, has coupled clever experimental design with established protocols in human subjects to shed new light on a role for EDH in functional sympatholysis, i.e. the ability of exercising skeletal muscle to attenuate sympathetic vasoconstriction. By manipulating both the intensity of rhythmic handgrip contractions and signalling pathways for vasodilatation, Hearon and co-workers tested whether stimulating EDD – independent of NO and prostaglandins – enhanced the ability of active skeletal muscle to attenuate sympathetic vasoconstriction induced by α1-adrenoreceptor (α1AR) activation. Key to these experiments was the judicious application of agonists whose actions have been well defined using isolated vessel preparations in which membrane potential and calcium signalling were rigorously evaluated (Tran et al. 2012). Thus, as shown in resistance arteries, acetylcholine (ACh) stimulates the opening of smalland intermediate-conductance calcium-activated K+ channels (SKCa and IKCa, respectively) in endothelial cells to initiate hyperpolarization, which is transmitted directly (through myoendothelial gap junctions) into surrounding smooth muscle cells to promote vasodilatation (Crane et al. 2003). As the electrical signal is conducted along the endothelium, the vasodilator response is coordinated within the resistance network (Bagher & Segal, 2011). Studies of the microcirculation in anaesthetized hamsters have shown that conducted vasodilatation can attenuate sympathetic vasoconstriction (Kurjiaka & Segal, 1995) an
这些发现共同使作者得出结论，在轻度强度运动中引起的edh样信号的增强减弱了通过α1AR激活介导的血管收缩(图1,Hearon et al. 2016)。由于无法直接评估膜电位，人体EDH的研究(包括在休息和运动时)仍然受到限制。然而，这些新发现支持了这一假设
{"title":"Enhanced functional sympatholysis through endothelial signalling in healthy young men and women","authors":"S. Segal","doi":"10.1113/JP273454","DOIUrl":"https://doi.org/10.1113/JP273454","url":null,"abstract":"That the endothelium governs vasodilatation in healthy humans and animals is well established. Indeed, impaired endothelium-dependent dilatation (EDD) is diagnostic of vascular dysfunction. Through the generation of diffusible autacoids, e.g. nitric oxide (NO) and metabolites of arachidonic acid, an increase in luminal shear stress leads to relaxation of vascular smooth muscle and is integral to flow-dependent dilatation. In humans, manipulating arterial blood flow (i.e. shear stress) is a non-invasive diagnostic tool for evaluating endothelial function as vessel diameter and blood flow velocity are monitored using ultrasound. A second pathway for EDD involves the initiation of hyperpolarization by endothelial cells and the transmission of electrical charge through myoendothelial gap junctions to evoke smooth muscle relaxation (Bagher & Segal, 2011). While endothelium-dependent hyperpolarization (EDH) has been well characterized in small resistance arteries and arterioles of animals, there is a dearth of evidence for EDH in governing blood flow in humans. This gap in translating findings from animal studies to humans is attributable to the invasive nature of recording membrane potential in the vascular wall after surgical exposure. Thus, elucidating EDH signalling as a pathway for EDD in humans has been difficult. In this issue of The Journal of Physiology a new study by Hearon et al. (2016), applying mechanistic insight gleaned from animal models, has coupled clever experimental design with established protocols in human subjects to shed new light on a role for EDH in functional sympatholysis, i.e. the ability of exercising skeletal muscle to attenuate sympathetic vasoconstriction. By manipulating both the intensity of rhythmic handgrip contractions and signalling pathways for vasodilatation, Hearon and co-workers tested whether stimulating EDD – independent of NO and prostaglandins – enhanced the ability of active skeletal muscle to attenuate sympathetic vasoconstriction induced by α1-adrenoreceptor (α1AR) activation. Key to these experiments was the judicious application of agonists whose actions have been well defined using isolated vessel preparations in which membrane potential and calcium signalling were rigorously evaluated (Tran et al. 2012). Thus, as shown in resistance arteries, acetylcholine (ACh) stimulates the opening of smalland intermediate-conductance calcium-activated K+ channels (SKCa and IKCa, respectively) in endothelial cells to initiate hyperpolarization, which is transmitted directly (through myoendothelial gap junctions) into surrounding smooth muscle cells to promote vasodilatation (Crane et al. 2003). As the electrical signal is conducted along the endothelium, the vasodilator response is coordinated within the resistance network (Bagher & Segal, 2011). Studies of the microcirculation in anaesthetized hamsters have shown that conducted vasodilatation can attenuate sympathetic vasoconstriction (Kurjiaka & Segal, 1995) an","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"521 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"78151672","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Exercise is widely known to lead to beneficial adaptions in whole body health, including improvements in indices of glucose homeostasis. During exercise, muscle contraction stimulates an increase in skeletal muscle glucose uptake in order to provide substrate for energy production. The provision of glucose to skeletal muscle is mediated by three factors: (1) the delivery of glucose to muscle; (2) the transport of glucose across the plasma membrane; and (3) the intracellular metabolism of glucose (Richter & Hargreaves, 2013). The delivery of glucose to working skeletal muscle is regulated by changes in blood flow and capillary recruitment, both of which increase with exercise. The transport of glucose across the plasma membrane is increased during exercise, which occurs by translocation of glucose transporter type 4 (GLUT4) from intracellular sites to the plasma membrane (sarcolemma and T-tubules), allowing for facilitated diffusion. Exercise increases the flux of glucose through glycolysis, and the enzyme hexokinase II (HKII) controls this process. Once inside the muscle cell, HKII phosphorylates glucose for commitment to glycolysis or for storage as glycogen. It is the coordination of delivery, transport and metabolism of glucose that leads to increases in glucose uptake during exercise (Richter & Hargreaves, 2013); however, the molecular mechanisms that mediate this process are not fully understood. Recently the Rho family GTPase Rac1 has emerged as having an important role in the regulation of skeletal muscle glucose uptake. Pioneering work from Drs Klip (JeBailey et al. 2004; Thong et al. 2007) and Ueda and Satoh (Ueda et al. 2010) revealed the role for Rac1 in this process, and a recent series of studies from Sylow and colleagues have further advanced our understanding. They found that Rac1 was required for insulin-induced ex vivo glucose uptake in murine soleus and extensor digitorum longus (EDL) muscles (Sylow et al. 2013a). Using pharmacological inhibition and an in vivo inducible muscle specific Rac1 knockout, they showed that Rac1 plays a critical role in electrically induced contraction-stimulated glucose transport (Sylow et al. 2013b). Finally, using a similar approach, they showed an attenuated response to stretch-induced glucose uptake in ex vivo soleus and EDL (Sylow et al. 2015). Despite this, the role of Rac1 in in vivo exercise-induced glucose uptake and GLUT4 translocation is not known. In a paper published in The Journal of Physiology, Sylow et al. (2016) demonstrate that Rac1 is a critical regulator of glucose uptake during exercise. To define the role of Rac1 in vivo, a Rac1 muscle-specific knockout (mKO) was established by breeding Rac1 floxed mice with mice carrying a muscle specific Cre recombinase. Rac1 mKO mice were induced at 10–14 weeks of age by a 3 week exposure to doxycycline in drinking water, followed by a 3 week washout period to reverse potential mitochondrial and gene expression changes induced by this treatme
众所周知，运动可以对全身健康产生有益的适应，包括改善葡萄糖稳态指标。在运动过程中，肌肉收缩刺激骨骼肌葡萄糖摄取的增加，从而为能量产生提供基质。向骨骼肌提供葡萄糖是由三个因素介导的:(1)向肌肉输送葡萄糖;(2)葡萄糖在质膜上的转运;(3)细胞内葡萄糖代谢(Richter & Hargreaves, 2013)。葡萄糖输送到工作的骨骼肌是由血流和毛细血管募集的变化来调节的，这两者都随着运动而增加。在运动过程中，葡萄糖通过质膜的运输增加，这是通过葡萄糖转运蛋白4型(GLUT4)从细胞内转运到质膜(肌膜和t小管)，从而促进扩散。运动通过糖酵解增加葡萄糖的通量，而己糖激酶II (HKII)控制着这一过程。一旦进入肌肉细胞，HKII将葡萄糖磷酸化，用于糖酵解或作为糖原储存。正是葡萄糖的输送、运输和代谢的协调导致运动过程中葡萄糖摄取增加(Richter & Hargreaves, 2013);然而，介导这一过程的分子机制尚不完全清楚。最近，Rho家族GTPase Rac1在骨骼肌葡萄糖摄取的调节中发挥了重要作用。Klip博士的开创性工作(JeBailey et al. 2004;Thong et al. 2007)和Ueda and Satoh (Ueda et al. 2010)揭示了Rac1在这一过程中的作用，Sylow及其同事最近的一系列研究进一步加深了我们的理解。他们发现，小鼠比目鱼和指长伸肌(EDL)肌肉中胰岛素诱导的离体葡萄糖摄取需要Rac1 (Sylow et al. 2013a)。通过药理抑制和体内诱导的肌肉特异性Rac1敲除，他们发现Rac1在电诱导收缩刺激的葡萄糖运输中起着关键作用(Sylow et al. 2013b)。最后，使用类似的方法，他们在离体比目鱼和EDL中显示出对拉伸诱导的葡萄糖摄取的减弱反应(Sylow et al. 2015)。尽管如此，Rac1在体内运动诱导的葡萄糖摄取和GLUT4易位中的作用尚不清楚。Sylow等人(2016)在《The Journal of Physiology》上发表的一篇论文中证明，Rac1是运动过程中葡萄糖摄取的关键调节因子。为了确定Rac1在体内的作用，通过将Rac1固定小鼠与携带肌肉特异性Cre重组酶的小鼠杂交，建立了Rac1肌肉特异性敲除(mKO)。在10-14周龄的Rac1 mKO小鼠中，通过在饮用水中暴露3周的强力霉素诱导，然后进行3周的洗脱期，以逆转该处理诱导的潜在线粒体和基因表达变化。与野生型(WT)对照相比，这导致比目鱼、腓肠肌和股四头肌全肌肉匀浆中Rac1的蛋白质含量降低了70-90%。这表明Rac1的肌肉敲除不完全，作者提出，通过Western blot分析检测到的残留Rac1蛋白含量是来自整个肌肉匀浆中非肌肉组织的污染。与整个肌肉相反，孤立的肌纤维制备可能表明完全的肌肉敲除。为了测试Rac1 mKO对运动性能的影响，我们进行了最大跑能力测试。这表明WT和Rac1 mKO小鼠的最大跑步速度相似。相比之下，当在糖原耗尽状态下进行该测试时，由单次运动诱导(30分钟，最大75%)。2.5 h恢复后，与WT小鼠相比，Rac1 mKO降低了最大跑步速度。与此同时，血糖也呈下降趋势，表明Rac1可能在运动诱导的葡萄糖摄取中发挥作用。为了验证这一假设，作者在65%最大强度的急性运动后测量了体内肌肉葡萄糖摄入量。Rac1 mKO对比目鱼肌和腓肠肌葡萄糖摄取的增加有减弱作用，对股四头肌的影响不显著。由于葡萄糖摄取受到运动强度的影响(Richter & Hargreaves, 2013)，他们在85% max下重复了这些实验。强度，并观察到Rac1 mKO小鼠葡萄糖摄取的类似衰减。总之，这些结果表明，尽管在Rac1 mKO小鼠中葡萄糖摄取受损，但这仅影响糖原耗尽状态下的运动能力。为了确定Rac1如何调节这一过程，他们评估了向肌肉提供葡萄糖的三个因素。
{"title":"Rac1 is a novel regulator of exercise‐induced glucose uptake","authors":"W. Peppler, R. MacPherson","doi":"10.1113/JP272929","DOIUrl":"https://doi.org/10.1113/JP272929","url":null,"abstract":"Exercise is widely known to lead to beneficial adaptions in whole body health, including improvements in indices of glucose homeostasis. During exercise, muscle contraction stimulates an increase in skeletal muscle glucose uptake in order to provide substrate for energy production. The provision of glucose to skeletal muscle is mediated by three factors: (1) the delivery of glucose to muscle; (2) the transport of glucose across the plasma membrane; and (3) the intracellular metabolism of glucose (Richter & Hargreaves, 2013). The delivery of glucose to working skeletal muscle is regulated by changes in blood flow and capillary recruitment, both of which increase with exercise. The transport of glucose across the plasma membrane is increased during exercise, which occurs by translocation of glucose transporter type 4 (GLUT4) from intracellular sites to the plasma membrane (sarcolemma and T-tubules), allowing for facilitated diffusion. Exercise increases the flux of glucose through glycolysis, and the enzyme hexokinase II (HKII) controls this process. Once inside the muscle cell, HKII phosphorylates glucose for commitment to glycolysis or for storage as glycogen. It is the coordination of delivery, transport and metabolism of glucose that leads to increases in glucose uptake during exercise (Richter & Hargreaves, 2013); however, the molecular mechanisms that mediate this process are not fully understood. Recently the Rho family GTPase Rac1 has emerged as having an important role in the regulation of skeletal muscle glucose uptake. Pioneering work from Drs Klip (JeBailey et al. 2004; Thong et al. 2007) and Ueda and Satoh (Ueda et al. 2010) revealed the role for Rac1 in this process, and a recent series of studies from Sylow and colleagues have further advanced our understanding. They found that Rac1 was required for insulin-induced ex vivo glucose uptake in murine soleus and extensor digitorum longus (EDL) muscles (Sylow et al. 2013a). Using pharmacological inhibition and an in vivo inducible muscle specific Rac1 knockout, they showed that Rac1 plays a critical role in electrically induced contraction-stimulated glucose transport (Sylow et al. 2013b). Finally, using a similar approach, they showed an attenuated response to stretch-induced glucose uptake in ex vivo soleus and EDL (Sylow et al. 2015). Despite this, the role of Rac1 in in vivo exercise-induced glucose uptake and GLUT4 translocation is not known. In a paper published in The Journal of Physiology, Sylow et al. (2016) demonstrate that Rac1 is a critical regulator of glucose uptake during exercise. To define the role of Rac1 in vivo, a Rac1 muscle-specific knockout (mKO) was established by breeding Rac1 floxed mice with mice carrying a muscle specific Cre recombinase. Rac1 mKO mice were induced at 10–14 weeks of age by a 3 week exposure to doxycycline in drinking water, followed by a 3 week washout period to reverse potential mitochondrial and gene expression changes induced by this treatme","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"18 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90014758","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The recent resurgence of biomedical interest in non-shivering thermogenesis has been fuelled by key discoveries, including the following: there is active brown adipose tissue (BAT) in adult humans; brown adipocytes and skeletal muscle cells have common cellular origins; and uncoupling protein-1 (UCP1)-expressing beige adipocytes emerge in white adipose tissue depots following stimulation, for example, by chronic cold exposure, exercise, or peroxisome proliferator-activated receptor-γ (PPARγ) agonists. While there has never been any question of the importance of UCP1 in thermogenesis, a role in this realm for UCP3 has not been clearly demonstrated. UCP1-deficient mice are cold-intolerant (Enerbäck et al. 1997), and develop obesity if housed at thermoneutrality (Feldmann et al. 2009). Shortly after the initial characterizations of the UCP1 knockout mouse, the UCP3 knockout mouse was produced and characterized. Given that UCP3 is expressed in brown adipose and skeletal muscle, it was anticipated that the UCP3 knockout mouse would have a number of physiological and metabolic deficiencies. Surprisingly the whole-body phenotypic characteristics unveiled were minimal, even though there was lower mitochondrial proton leak and increased oxidative stress in skeletal muscle. However, additional metabolic studies of UCP3 in vivo and in vitro revealed its roles in facilitating fatty acid oxidation and minimizing reactive oxygen species (ROS) emission (e.g. Bezaire et al. 2005), and indicated that UCP3 functions in a negative feedback loop in mitochondrial ROS emission (Echtay et al. 2003; Mailloux et al. 2011). Important in the interpretation of these findings is that UCP1 is expressed at exceptionally high levels ( 10% of mitochondrial protein) in BAT, a tissue that is ideally ‘poised’, both biochemically and anatomically, for thermoregulatory thermogenesis. In contrast, UCP3 is expressed at much lower levels in BAT and skeletal muscle, compared to UCP1 in BAT. Physiological thermogenic processes can be categorized as either obligatory or facultative. Obligatory forms are associated with the basal thermogenic processes occurring when the animal is resting in a post-absorptive and thermoneutral state. The latter comprise an animal’s basal metabolic rate. Another form of obligatory thermogenesis is the thermic effect of food. Facultative forms of thermogenesis are those associated with additional energy demanding functions (i.e. beyond the obligatory), and include shivering and non-shivering thermogenesis, non-exercise
最近对非寒颤产热的生物医学兴趣的复苏受到了一些关键发现的推动，包括:成年人中存在活跃的棕色脂肪组织(BAT);棕色脂肪细胞和骨骼肌细胞有共同的细胞起源;和表达解偶联蛋白-1 (UCP1)的米色脂肪细胞在受到刺激后出现在白色脂肪组织库中，例如，通过慢性冷暴露、运动或过氧化物酶体增殖物激活受体-γ (PPARγ)激动剂。虽然从未有人质疑UCP1在产热中的重要性，但UCP3在这一领域的作用尚未得到明确证明。缺乏ucp1的小鼠不耐冷(Enerbäck et al. 1997)，如果置于热中性环境中，会发生肥胖(Feldmann et al. 2009)。在对UCP1基因敲除小鼠进行初步表征后不久，又产生了UCP3基因敲除小鼠并进行了表征。鉴于UCP3在棕色脂肪和骨骼肌中表达，预计UCP3敲除小鼠将存在许多生理和代谢缺陷。令人惊讶的是，尽管骨骼肌中线粒体质子泄漏较低，氧化应激增加，但揭示的全身表型特征却很少。然而，UCP3在体内和体外的其他代谢研究揭示了它在促进脂肪酸氧化和减少活性氧(ROS)排放方面的作用(例如Bezaire等人，2005)，并表明UCP3在线粒体ROS排放的负反馈回路中起作用(Echtay等人，2003;Mailloux et al. 2011)。对这些发现的重要解释是，UCP1在BAT中以异常高的水平表达(线粒体蛋白的10%)，BAT是一种理想的“平衡”组织，在生物化学和解剖学上都是热调节产热的。相比之下，UCP3在BAT和骨骼肌中的表达水平远低于UCP1在BAT中的表达水平。生理性产热过程可分为强制性和兼性两类。强制性形式与动物在吸收后和热中性状态下休息时发生的基础产热过程有关。后者包括动物的基础代谢率。另一种形式的强制性产热是食物的热效应。兼性产热形式是那些与额外的能量需求功能(即超出强制性)相关的形式，包括颤抖和非颤抖产热，非运动
{"title":"Drugs and bugs: turning on the heat through UCP1 and UCP3","authors":"M. Harper","doi":"10.1113/JP273485","DOIUrl":"https://doi.org/10.1113/JP273485","url":null,"abstract":"The recent resurgence of biomedical interest in non-shivering thermogenesis has been fuelled by key discoveries, including the following: there is active brown adipose tissue (BAT) in adult humans; brown adipocytes and skeletal muscle cells have common cellular origins; and uncoupling protein-1 (UCP1)-expressing beige adipocytes emerge in white adipose tissue depots following stimulation, for example, by chronic cold exposure, exercise, or peroxisome proliferator-activated receptor-γ (PPARγ) agonists. While there has never been any question of the importance of UCP1 in thermogenesis, a role in this realm for UCP3 has not been clearly demonstrated. UCP1-deficient mice are cold-intolerant (Enerbäck et al. 1997), and develop obesity if housed at thermoneutrality (Feldmann et al. 2009). Shortly after the initial characterizations of the UCP1 knockout mouse, the UCP3 knockout mouse was produced and characterized. Given that UCP3 is expressed in brown adipose and skeletal muscle, it was anticipated that the UCP3 knockout mouse would have a number of physiological and metabolic deficiencies. Surprisingly the whole-body phenotypic characteristics unveiled were minimal, even though there was lower mitochondrial proton leak and increased oxidative stress in skeletal muscle. However, additional metabolic studies of UCP3 in vivo and in vitro revealed its roles in facilitating fatty acid oxidation and minimizing reactive oxygen species (ROS) emission (e.g. Bezaire et al. 2005), and indicated that UCP3 functions in a negative feedback loop in mitochondrial ROS emission (Echtay et al. 2003; Mailloux et al. 2011). Important in the interpretation of these findings is that UCP1 is expressed at exceptionally high levels ( 10% of mitochondrial protein) in BAT, a tissue that is ideally ‘poised’, both biochemically and anatomically, for thermoregulatory thermogenesis. In contrast, UCP3 is expressed at much lower levels in BAT and skeletal muscle, compared to UCP1 in BAT. Physiological thermogenic processes can be categorized as either obligatory or facultative. Obligatory forms are associated with the basal thermogenic processes occurring when the animal is resting in a post-absorptive and thermoneutral state. The latter comprise an animal’s basal metabolic rate. Another form of obligatory thermogenesis is the thermic effect of food. Facultative forms of thermogenesis are those associated with additional energy demanding functions (i.e. beyond the obligatory), and include shivering and non-shivering thermogenesis, non-exercise","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"4 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87206727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
D. Blondin, A. Daoud, T. Taylor, H. Tingelstad, V. Bézaire, D. Richard, A. Carpentier, A. W. Taylor, M. Harper, C. Aguer, F. Haman
Muscle‐derived thermogenesis during acute cold exposure in humans consists of a combination of cold‐induced increases in skeletal muscle proton leak and shivering. Daily cold exposure results in an increase in brown adipose tissue oxidative capacity coupled with a decrease in the cold‐induced skeletal muscle proton leak and shivering intensity. Improved coupling between electromyography‐determined muscle activity and whole‐body heat production following cold acclimation suggests a maintenance of ATPase‐dependent thermogenesis and decrease in skeletal muscle ATPase independent thermogenesis. Although daily cold exposure did not change the fibre composition of the vastus lateralis, the fibre composition was a strong predictor of the shivering pattern evoked during acute cold exposure.
{"title":"Four‐week cold acclimation in adult humans shifts uncoupling thermogenesis from skeletal muscles to brown adipose tissue","authors":"D. Blondin, A. Daoud, T. Taylor, H. Tingelstad, V. Bézaire, D. Richard, A. Carpentier, A. W. Taylor, M. Harper, C. Aguer, F. Haman","doi":"10.1113/JP273395","DOIUrl":"https://doi.org/10.1113/JP273395","url":null,"abstract":"Muscle‐derived thermogenesis during acute cold exposure in humans consists of a combination of cold‐induced increases in skeletal muscle proton leak and shivering. Daily cold exposure results in an increase in brown adipose tissue oxidative capacity coupled with a decrease in the cold‐induced skeletal muscle proton leak and shivering intensity. Improved coupling between electromyography‐determined muscle activity and whole‐body heat production following cold acclimation suggests a maintenance of ATPase‐dependent thermogenesis and decrease in skeletal muscle ATPase independent thermogenesis. Although daily cold exposure did not change the fibre composition of the vastus lateralis, the fibre composition was a strong predictor of the shivering pattern evoked during acute cold exposure.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"93 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"74370559","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Reaching movements can be perturbed by vestibular input, but the function of this response is unclear. Here, we applied galvanic vestibular stimulation concurrently with real body movement while subjects maintained arm position either fixed in space or fixed with respect to their body. During the fixed‐in‐space conditions, galvanic vestibular stimulation caused large changes in arm trajectory consistent with a compensatory response to maintain upper‐limb accuracy in the face of body movement. Galvanic vestibular stimulation responses were absent during the body‐fixed task, demonstrating task dependency in vestibular control of the upper limb. The results suggest that the function of vestibular‐evoked arm movements is to maintain the accuracy of the upper limb during unpredictable body movement, but only when reaching in an earth‐fixed reference frame.
{"title":"Vestibular feedback maintains reaching accuracy during body movement","authors":"Craig P Smith, R. Reynolds","doi":"10.1113/JP273125","DOIUrl":"https://doi.org/10.1113/JP273125","url":null,"abstract":"Reaching movements can be perturbed by vestibular input, but the function of this response is unclear. Here, we applied galvanic vestibular stimulation concurrently with real body movement while subjects maintained arm position either fixed in space or fixed with respect to their body. During the fixed‐in‐space conditions, galvanic vestibular stimulation caused large changes in arm trajectory consistent with a compensatory response to maintain upper‐limb accuracy in the face of body movement. Galvanic vestibular stimulation responses were absent during the body‐fixed task, demonstrating task dependency in vestibular control of the upper limb. The results suggest that the function of vestibular‐evoked arm movements is to maintain the accuracy of the upper limb during unpredictable body movement, but only when reaching in an earth‐fixed reference frame.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"10 1","pages":"1339 - 1349"},"PeriodicalIF":0.0,"publicationDate":"2016-11-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"84350920","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Pei-Chi Yang, J. Moreno, Mao-Tsuen Jeng, X. Wehrens, S. Noskov, C. Clancy
We appreciate Williams et al. (2016) taking the time to comment on our recently published study (Yang et al. 2016). In their letter, the authors question the ‘usefulness’ of the computational modelling and simulation approaches that we used in part because as they state, ‘The blocking parameters used in Yang et al. (2016) are based on values reported in Hilliard et al. (2010) and subsequent publications from the same group.’ This statement does not reflect the careful process that we actually used in building our modelling approaches, where we rather considered the full range of experimentally measured IC50 values for flecainide interaction that have been reported in multiple studies. In addition to the assumption of IC50 = 0 μM (i.e. no interaction with RyR) as reported by the Williams group (Bannister et al. 2015), we reported the following in our paper (Yang et al. 2016): ‘Isoproterenol-stimulated Ca2+ waves in CASQ2 knockout (KO) CASQ2(−/−) mice were inhibited by flecainide with an IC50 of 2.0 ± 0.2 μM (Hwang et al. 2011), while other experimental preparations measured an IC50 range from 2 to 17 μM (Brunton et al. 2010; Hilliard et al. 2010; Hwang et al. 2011; Mehra et al. 2014) . . . We also predicted cases for variable flecainide IC50 = 3, 4, and 5 μM shown in Fig. 1.’ The model simulations led to the predictions that IC50 values above 5 μM are too low to show therapeutic benefit to normalize the catecholaminergic polymorphic ventricular tachycardia (CPVT) phenotype. An alternative interpretation is that the concentration of flecainide near the receptor is considerably higher than in the bulk water compartments, a possibility supported by our physics-based approach (Fig. 5 in Yang et al. 2016) that shows accumulation of flecainide on the membrane surface and very favourable conditions for neutral flecainide in the hydrophobic core of the membrane. Detailed investigations into membrane partitioning of drugs are ongoing in our group. The point of the simulations in our study was to make predictions about the necessary and sufficient targets of flecainide and the range of IC50 that would allow for normalization of the CPVT phenotype since the experimental literature has shown such variety in reported values. When we started the investigation reported in Yang et al. (2016), we had no preconceived intent or notion about the results. The predictions are the resulting outputs of the model, and suggest that Na+ channel block alone is not sufficient to prevent the CPVT phenotype. The critical point here is that the disparity in sensitivity of the dose–response for flecainide interaction with the RyR depends on the experimental approach being used. This issue has been the subject of discussion by others (Steele et al. 2013; Sikkel et al. 2013b; Smith & MacQuaide, 2015). Williams et al. describe their recent work in their letter. It is important to mention, however, the numerous other studies that report alternative data and explanations. Some in nati
我们感谢Williams et al.(2016)花时间评论我们最近发表的研究(Yang et al. 2016)。在他们的信中，作者质疑我们使用的计算建模和模拟方法的“有用性”，部分原因是正如他们所说，“Yang等人(2016)使用的阻塞参数是基于Hilliard等人(2010)和同一组后续出版物中报告的值。”“这种说法并没有反映出我们在建立模型方法时实际使用的仔细过程，我们考虑的是在多个研究中报告的氟氯胺相互作用的全部实验测量IC50值。”除了IC50 = 0μM的假设(即不与RyR)据威廉姆斯集团(班尼斯特et al . 2015年),我们在论文报告以下(杨et al . 2016年):“Isoproterenol-stimulated Ca2 +波CASQ2淘汰赛(KO) CASQ2(−−)老鼠被氟卡尼的IC50 2.0±0.2μM(黄et al . 2011年),而其他实验准备测定IC50范围从2到17μM(勃氏et al . 2010;Hilliard et al. 2010;Hwang et al. 2011;Mehra et al. 2014)…如图1所示，我们还预测了可变氟氯胺IC50 = 3、4和5 μM的病例。模型模拟预测，IC50值高于5 μM太低，无法显示治疗效果，无法使儿茶酚胺能多态性室性心动过速(CPVT)表型正常化。另一种解释是，受体附近的flecainide浓度明显高于大水隔室，我们基于物理的方法支持了这种可能性(Yang等人2016年的图5)，该方法显示了flecainide在膜表面的积累，以及在膜疏水核心中中性flecainide的非常有利条件。我们小组正在对药物的膜分配进行详细的研究。在我们的研究中，模拟的目的是预测flecainide的必要和充分的靶点，以及IC50的范围，这将允许CPVT表型正常化，因为实验文献已经显示了报道值的多样性。当我们开始Yang et al.(2016)报道的调查时，我们对结果没有先入为主的意图或概念。预测是模型的结果输出，并表明仅Na+通道阻断不足以阻止CPVT表型。这里的关键点是氟氯胺与RyR相互作用的剂量反应灵敏度的差异取决于所使用的实验方法。这个问题已经被其他人讨论过(Steele et al. 2013;Sikkel et al. 2013;Smith & MacQuaide, 2015)。Williams等人在信中描述了他们最近的工作。然而，重要的是要提到，许多其他研究报告了不同的数据和解释。一些天然肌细胞在细胞浆[Ca2+]和[Na+]被固定的实验条件下，显示出flecainide对自发Ca2+释放(即Ca2+波)的非常明显的影响，表明flecainide对ryr2介导的肌浆网(SR) Ca2+释放有直接作用(Savio-Galimberti & Knollmann, 2015;Hilliard et al.， 2010;Galimberti & Knollmann, 2011)。此外，在天然肌细胞中，flecainide不抑制生理Ca2+电流诱导的SR Ca2+释放，而只抑制自发性SR Ca2+释放，这发生在舒张[Ca2+](即100 nM)的环境中(Hilliard等人，2010)。这样的条件很难使用纳入人工双层的RyR2通道来建模，因此Williams等人的研究小组从未对其进行过测试。其他研究表明氟氯胺在临床CPVT中有明显的益处，但在其他Na+通道阻滞剂的实验中没有(Watanabe et al. 2009;Hwang et al. 2011;van der Werf et al. 2011)。Williams等人在包含磷脂酰乙醇胺(PE)双层的实验模型中进行了单通道实验，表明flecainide不会通过结合RyR2成孔结构域的细胞质区域内的一个位点来阻断离子电流。然而，我们论文中的其他数据和基于物理的计算方法表明，亲脂性药物通路可能是关键的，并且是药物与膜蛋白靶点(如RyR2)相互作用的重要组成部分。我们在研究中进行的平均力计算的潜力表明，脂相中的氟氯胺浓度可能大大高于双分子层研究中预期的浓度。卡维地洛是另一种非常疏水/亲脂的药物，在单通道实验中与RyR2相互作用而不阻断单一电导。脂质体分配实验表明，高达90%的卡维地洛分子是脂相定位的(Cheng et al. 1996)。
{"title":"Reply from Pei‐Chi Yang, Jonathan D. Moreno, Mao‐Tsuen Jeng, Xander H. T. Wehrens, Sergei Noskov and Colleen E. Clancy","authors":"Pei-Chi Yang, J. Moreno, Mao-Tsuen Jeng, X. Wehrens, S. Noskov, C. Clancy","doi":"10.1113/JP273143","DOIUrl":"https://doi.org/10.1113/JP273143","url":null,"abstract":"We appreciate Williams et al. (2016) taking the time to comment on our recently published study (Yang et al. 2016). In their letter, the authors question the ‘usefulness’ of the computational modelling and simulation approaches that we used in part because as they state, ‘The blocking parameters used in Yang et al. (2016) are based on values reported in Hilliard et al. (2010) and subsequent publications from the same group.’ This statement does not reflect the careful process that we actually used in building our modelling approaches, where we rather considered the full range of experimentally measured IC50 values for flecainide interaction that have been reported in multiple studies. In addition to the assumption of IC50 = 0 μM (i.e. no interaction with RyR) as reported by the Williams group (Bannister et al. 2015), we reported the following in our paper (Yang et al. 2016): ‘Isoproterenol-stimulated Ca2+ waves in CASQ2 knockout (KO) CASQ2(−/−) mice were inhibited by flecainide with an IC50 of 2.0 ± 0.2 μM (Hwang et al. 2011), while other experimental preparations measured an IC50 range from 2 to 17 μM (Brunton et al. 2010; Hilliard et al. 2010; Hwang et al. 2011; Mehra et al. 2014) . . . We also predicted cases for variable flecainide IC50 = 3, 4, and 5 μM shown in Fig. 1.’ The model simulations led to the predictions that IC50 values above 5 μM are too low to show therapeutic benefit to normalize the catecholaminergic polymorphic ventricular tachycardia (CPVT) phenotype. An alternative interpretation is that the concentration of flecainide near the receptor is considerably higher than in the bulk water compartments, a possibility supported by our physics-based approach (Fig. 5 in Yang et al. 2016) that shows accumulation of flecainide on the membrane surface and very favourable conditions for neutral flecainide in the hydrophobic core of the membrane. Detailed investigations into membrane partitioning of drugs are ongoing in our group. The point of the simulations in our study was to make predictions about the necessary and sufficient targets of flecainide and the range of IC50 that would allow for normalization of the CPVT phenotype since the experimental literature has shown such variety in reported values. When we started the investigation reported in Yang et al. (2016), we had no preconceived intent or notion about the results. The predictions are the resulting outputs of the model, and suggest that Na+ channel block alone is not sufficient to prevent the CPVT phenotype. The critical point here is that the disparity in sensitivity of the dose–response for flecainide interaction with the RyR depends on the experimental approach being used. This issue has been the subject of discussion by others (Steele et al. 2013; Sikkel et al. 2013b; Smith & MacQuaide, 2015). Williams et al. describe their recent work in their letter. It is important to mention, however, the numerous other studies that report alternative data and explanations. Some in nati","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"24 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"87516322","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
It has been known for more than a century that bile acids and gallstones may represent an aetiological factor in acute pancreatitis (AP). Importantly, while bile is responsible for around 40% of AP, its aetiological role in the chronic form of the disease (CP) is close to zero. Only 4% of patients suffering from CP have gallstones, and it is still not clear whether this is only an association or whether bile or gallstones play any pathophysiological role in the development of the chronic inflammation. In this issue of The Journal of Physiology, Ferdek et al. have offered the first explanation for this phenomenon at the cellular level (Ferdek et al. 2016). They have shown for the first time that bile acids elicit dramatic necrosis in pancreatic stellate cells (PSCs) but not in pancreatic acinar cells (PACs). In the presence of calcium, sodium cholate induces 73% necrosis in PSCs but only around 10% in PACs, suggesting that the PSC, the key player in the extracellular matrix in the pancreas, is the cell type most endangered by bile (Ferdek et al. 2016). Since the effects of bile acids on pancreatic ductal cells (PDCs) have also been characterized, the chronological events in how bile acids affect the exocrine pancreas and induce acute but not chronic pancreatitis can be followed (Fig. 1).
一个多世纪以来，人们已经知道胆汁酸和胆结石可能是急性胰腺炎(AP)的病因之一。重要的是，虽然胆汁约占AP的40%，但其在慢性形式的疾病(CP)中的病因作用接近于零。只有4%的CP患者有胆结石，目前尚不清楚这是否只是一种关联，或者胆汁或胆结石是否在慢性炎症的发展中起任何病理生理作用。在本期的《生理学杂志》中，Ferdek等人首次从细胞水平上解释了这一现象(Ferdek et al. 2016)。他们首次证明胆汁酸会引起胰腺星状细胞(PSCs)的剧烈坏死，但不会引起胰腺腺泡细胞(PACs)的剧烈坏死。在钙存在的情况下，胆酸钠诱导73%的PSCs坏死，但在PACs中仅诱导10%左右的坏死，这表明胰腺细胞外基质中的关键角色PSC是最受胆汁威胁的细胞类型(Ferdek et al. 2016)。由于胆汁酸对胰腺导管细胞(PDCs)的影响也已被表征，因此可以跟踪胆汁酸如何影响外分泌胰腺并诱导急性而非慢性胰腺炎的时间顺序事件(图1)。
{"title":"Bile as a key aetiological factor of acute but not chronic pancreatitis: a possible theory revealed","authors":"P. Hegyi","doi":"10.1113/JP273108","DOIUrl":"https://doi.org/10.1113/JP273108","url":null,"abstract":"It has been known for more than a century that bile acids and gallstones may represent an aetiological factor in acute pancreatitis (AP). Importantly, while bile is responsible for around 40% of AP, its aetiological role in the chronic form of the disease (CP) is close to zero. Only 4% of patients suffering from CP have gallstones, and it is still not clear whether this is only an association or whether bile or gallstones play any pathophysiological role in the development of the chronic inflammation. In this issue of The Journal of Physiology, Ferdek et al. have offered the first explanation for this phenomenon at the cellular level (Ferdek et al. 2016). They have shown for the first time that bile acids elicit dramatic necrosis in pancreatic stellate cells (PSCs) but not in pancreatic acinar cells (PACs). In the presence of calcium, sodium cholate induces 73% necrosis in PSCs but only around 10% in PACs, suggesting that the PSC, the key player in the extracellular matrix in the pancreas, is the cell type most endangered by bile (Ferdek et al. 2016). Since the effects of bile acids on pancreatic ductal cells (PDCs) have also been characterized, the chronological events in how bile acids affect the exocrine pancreas and induce acute but not chronic pancreatitis can be followed (Fig. 1).","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"37 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"90606399","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
L. Bozi, Luiz R G Bechara, A. F. dos Santos, Juliane C Campos
Mitochondria are critical organelles involved in adenosine triphosphate (ATP) synthesis, reactive oxygen species generation, ion homeostasis, aldehyde metabolism and programmed cell death. Loss of mitochondrial integrity is sufficient to establish pathological conditions such as cardiovascular diseases. In an attempt to ensure the maintenance of mitochondrial functionality, eukaryotic cells developed an integrated quality control system. This mitochondrial quality control machinery works in different levels of surveillance: (1) the antioxidant enzymes protect the organelle against oxygen-mediated toxicity, (2) the ubiquitin–proteasome system as well as the mitochondrial proteases and chaperones ensure the proteostasis by refolding or degrading damaged mitochondrial proteins, and (3) the interconnected processes of mitochondrial dynamics (fusion and fission) and mitophagy controls mitochondrial size, shape and clearance (Sugiura et al. 2014). More recently, a study by Cadete et al. (2016) published in The Journal of Physiology provides evidence that mitochondrial-derived vesicles (MDVs) are also involved in the maintenance of cardiac mitochondrial homeostasis. Although the results are associative, the well-conducted experiments complemented by the relevant findings make this work attractive, opening a new field of investigation in cardiac mitochondrial physiology. MDVs are generated by selective incorporation of mitochondrial cargo into small vesicles (70–150 nm of diameter) which transit to the lysosome for subsequent degradation (Sugiura et al. 2014). Despite it being a conserved mechanism from bacteria to mammals, the presence of MDVs and their physiological relevance in various cells types, including cardiomyocytes, needs to be clarified. In an attempt to characterize the role of MDVs in heart physiology, Cadete et al. (2016) used both in vitro and in vivo approaches. The authors first showed the presence of MDVs in H9C2 myoblasts (a cardiac cell line). It is worth mentioning that their innovative approach of switching the cell energy substrate from glucose to galactose, in order to stimulate the mitochondrial metabolism, helped the authors to identify MDVs under normal conditions. MDVs were identified by their apparent size and selective enrichment for mitochondrial markers from both matrix (PDH – pyruvate dehydrogenase) and outer membrane (TOM20 – translocase of the outer membrane) at baseline. A further increase in MDVs along with a hyperfused mitochondrial network was detected upon mild oxidative stress. Under severe oxidative stress myoblasts accumulated both PDH-enriched vesicles and fragmented mitochondria. Using another stress condition, authors demonstrated that doxorubicin-induced stress increased MDV formation within 30 min without affecting mitochondrial morphology and bioenergetics in myoblasts. Interestingly, PDH and TOM20-enriched vesicles gradually declined in the following 6 h, while the mitochondrial network became fragmented
有趣的是，与mdv相比，阿霉素处理的小鼠心脏中含有线粒体的自噬体数量更少，而对照组小鼠心脏中没有发现自噬体。基于这些发现，作者认为MDVs是心脏细胞中一个活跃的、生理相关的线粒体质量控制元件。MDV形成、运输和传递到溶酶体的机制仍然知之甚少。因此，MDVs的生理作用难以确定。有两个证据支持作者关于线粒体质量控制系统中MDV转运到溶酶体的说法。首先，MDV蛋白货物根据线粒体应激的性质被选择性地结合。例如，全局细胞氧化应激诱导携带线粒体外膜蛋白的MDVs。另一方面，细胞器内的氧化应激导致mdv携带线粒体复合体III亚基(Sugiura et al. 2014)。第二个证据是MDV转运到溶酶体需要有丝分裂相关
{"title":"Mitochondrial‐derived vesicles: a new player in cardiac mitochondrial quality control","authors":"L. Bozi, Luiz R G Bechara, A. F. dos Santos, Juliane C Campos","doi":"10.1113/JP273124","DOIUrl":"https://doi.org/10.1113/JP273124","url":null,"abstract":"Mitochondria are critical organelles involved in adenosine triphosphate (ATP) synthesis, reactive oxygen species generation, ion homeostasis, aldehyde metabolism and programmed cell death. Loss of mitochondrial integrity is sufficient to establish pathological conditions such as cardiovascular diseases. In an attempt to ensure the maintenance of mitochondrial functionality, eukaryotic cells developed an integrated quality control system. This mitochondrial quality control machinery works in different levels of surveillance: (1) the antioxidant enzymes protect the organelle against oxygen-mediated toxicity, (2) the ubiquitin–proteasome system as well as the mitochondrial proteases and chaperones ensure the proteostasis by refolding or degrading damaged mitochondrial proteins, and (3) the interconnected processes of mitochondrial dynamics (fusion and fission) and mitophagy controls mitochondrial size, shape and clearance (Sugiura et al. 2014). More recently, a study by Cadete et al. (2016) published in The Journal of Physiology provides evidence that mitochondrial-derived vesicles (MDVs) are also involved in the maintenance of cardiac mitochondrial homeostasis. Although the results are associative, the well-conducted experiments complemented by the relevant findings make this work attractive, opening a new field of investigation in cardiac mitochondrial physiology. MDVs are generated by selective incorporation of mitochondrial cargo into small vesicles (70–150 nm of diameter) which transit to the lysosome for subsequent degradation (Sugiura et al. 2014). Despite it being a conserved mechanism from bacteria to mammals, the presence of MDVs and their physiological relevance in various cells types, including cardiomyocytes, needs to be clarified. In an attempt to characterize the role of MDVs in heart physiology, Cadete et al. (2016) used both in vitro and in vivo approaches. The authors first showed the presence of MDVs in H9C2 myoblasts (a cardiac cell line). It is worth mentioning that their innovative approach of switching the cell energy substrate from glucose to galactose, in order to stimulate the mitochondrial metabolism, helped the authors to identify MDVs under normal conditions. MDVs were identified by their apparent size and selective enrichment for mitochondrial markers from both matrix (PDH – pyruvate dehydrogenase) and outer membrane (TOM20 – translocase of the outer membrane) at baseline. A further increase in MDVs along with a hyperfused mitochondrial network was detected upon mild oxidative stress. Under severe oxidative stress myoblasts accumulated both PDH-enriched vesicles and fragmented mitochondria. Using another stress condition, authors demonstrated that doxorubicin-induced stress increased MDV formation within 30 min without affecting mitochondrial morphology and bioenergetics in myoblasts. Interestingly, PDH and TOM20-enriched vesicles gradually declined in the following 6 h, while the mitochondrial network became fragmented","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"133 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"75989310","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
The membrane‐associated guanylate kinase (MAGUK) family of synaptic scaffolding proteins anchor glutamate receptors at CNS synapses. MAGUK removal via RNAi‐mediated knockdown in the CA1 hippocampal region in immature animals causes rapid and lasting reductions in glutamatergic transmission. In mature animals, the same manipulation has little acute effect. The hippocampal dentate gyrus, a region with ongoing adult neurogenesis, is sensitive to MAGUK loss in mature animals, behaving like an immature CA1. Over long time courses, removal of MAGUKs in CA1 causes reductions in glutamatergic transmission, indicating that synapses in mature animals require MAGUKs for anchoring glutamate receptors, but are much more stable. These results demonstrate regional and developmental control of synapse stability and suggest the existence of a sensitive period of heightened hippocampal plasticity in CA1 of pre‐adolescent rodents, and in dentate gyrus throughout maturity.
{"title":"Membrane‐associated guanylate kinase dynamics reveal regional and developmental specificity of synapse stability","authors":"Jonathan M. Levy, R. Nicoll","doi":"10.1113/JP273147","DOIUrl":"https://doi.org/10.1113/JP273147","url":null,"abstract":"The membrane‐associated guanylate kinase (MAGUK) family of synaptic scaffolding proteins anchor glutamate receptors at CNS synapses. MAGUK removal via RNAi‐mediated knockdown in the CA1 hippocampal region in immature animals causes rapid and lasting reductions in glutamatergic transmission. In mature animals, the same manipulation has little acute effect. The hippocampal dentate gyrus, a region with ongoing adult neurogenesis, is sensitive to MAGUK loss in mature animals, behaving like an immature CA1. Over long time courses, removal of MAGUKs in CA1 causes reductions in glutamatergic transmission, indicating that synapses in mature animals require MAGUKs for anchoring glutamate receptors, but are much more stable. These results demonstrate regional and developmental control of synapse stability and suggest the existence of a sensitive period of heightened hippocampal plasticity in CA1 of pre‐adolescent rodents, and in dentate gyrus throughout maturity.","PeriodicalId":22512,"journal":{"name":"The Japanese journal of physiology","volume":"1 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2016-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"83653513","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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