BACKGROUND & AIMS: :Skeletal muscle injury and regeneration are closely associated with an inflammatory reaction that is usually characterized by sequential recruitment of neutrophils and monocytes or macrophages. Selective macrophage depletion models have shown that macrophages are essential for complete regeneration of muscle fibers after freeze injuries, toxin injuries, ischemia-reperfusion, and hindlimb unloading and reloading. Although there is growing evidence that macrophages possess major myogenic capacities, it is not known whether the positive effects of macrophages can be optimized to stimulate muscle regrowth. We used in vivo and in vitro mouse models of atrophy to investigate the effects of stimulating macrophages with macrophage colony-stimulating factor (M-CSF) on muscle regrowth. When atrophied soleus muscles were injected intramuscularly with M-CSF, we observed a 1.6-fold increase in macrophage density and a faster recovery in muscle force (20%), combined with an increase in muscle fiber diameter (10%), after 7 days of reloading, compared with PBS-injected soleus muscles. Furthermore, coculture of atrophied myotubes with or without bone marrow-derived macrophages (BMDM) and/or M-CSF revealed that the combination of BMDMs and M-CSF was required to promote myotube growth (15%). More specifically, M-CSF promoted the anti-inflammatory macrophage phenotype, which in turn decreased protein degradation and MuRF-1 expression by 25% in growing myotubes. These results indicate that specific macrophage subsets can be stimulated to promote muscle cell regrowth after atrophy.

背景与目标： 骨骼肌损伤和再生与炎症反应密切相关，炎症反应通常以中性粒细胞和单核细胞或巨噬细胞的连续募集为特征。选择性巨噬细胞耗竭模型表明，巨噬细胞对于冷冻损伤，毒素损伤，缺血再灌注以及后肢卸载和重新加载后的肌纤维完全再生至关重要。尽管越来越多的证据表明巨噬细胞具有主要的肌源性能力，但尚不清楚是否可以优化巨噬细胞的积极作用以刺激肌肉再生。我们使用体内和体外萎缩小鼠模型来研究巨噬细胞集落刺激因子 (m-csf) 刺激巨噬细胞对肌肉再生的影响。当肌注m-csf肌注萎缩的比目鱼肌时，与注射PBS的比目鱼肌相比，在重装7天后，我们观察到巨噬细胞密度增加了1.6倍，肌力恢复更快 (20%)，并增加了肌纤维直径 (10%)。此外，具有或不具有骨髓来源的巨噬细胞 (BMDM) 和/或m-csf的萎缩肌管的共培养表明，需要BMDMs和m-csf的组合来促进肌管生长 (15%)。更具体地，m-csf促进抗炎巨噬细胞表型，这反过来通过25% 在生长的肌管中降低蛋白质降解和MuRF-1表达。这些结果表明，萎缩后可以刺激特定的巨噬细胞亚群以促进肌细胞再生。

BACKGROUND & AIMS: :Smooth muscle cells (SMC) make up the muscular portion of the gastrointestinal (GI) tract from the distal oesophagus to the internal anal sphincter. Coordinated contractions of these cells produce the motor patterns of GI motility. Considerable progress was made during the last 20 years to understand the basic mechanisms controlling excitation-contraction (E-C) coupling. The smooth muscle motor is now understood in great molecular detail, and much has been learned about the mechanisms that deliver and recover Ca2+ during contractions. The majority of Ca2+ that initiates contractions comes from the external solution and is supplied by voltage-dependent Ca2+ channels (VDCC). VDCC are regulated largely by the effects of K+ and non-selective cation conductances (NSCC) on cell membrane potential and excitability. Ca2+ entry is supplemented by release of Ca2+ from IP(3) receptor-operated stores and by mechanisms that alter the sensitivity of the contractile apparatus to changes in cytoplasmic Ca2+. Molecular studies of the regulation of smooth muscle have been complicated by the plasticity of SMC and difficulties in culturing these cells without dramatic phenotypic changes. Major questions remain to be resolved regarding the details of E-C coupling in human GI smooth muscles. New discoveries regarding molecular expression that give GI smooth muscle their unique properties, the phenotypic changes that occur in SMC in GI motor disorders, tissue engineering approaches to repair or replace defective muscular regions, and molecular manipulations of GI smooth muscles in animals models and in cell culture will be topics for exciting investigations in the future.

背景与目标： : 平滑肌细胞 (SMC) 构成胃肠道 (GI) 从远端食道到肛门内括约肌的肌肉部分。这些细胞的协调收缩产生胃肠道运动的运动模式。在过去的20年中，在了解控制激发-收缩 (E-C) 耦合的基本机制方面取得了相当大的进展。平滑肌运动现在已经在分子上得到了很大的了解，并且已经了解了在收缩过程中传递和恢复Ca2的机制。引发收缩的大部分Ca2来自外部解决方案，并由电压相关的Ca2通道 (VDCC) 提供。VDCC在很大程度上受K和非选择性阳离子电导 (NSCC) 对细胞膜电位和兴奋性的影响。通过从IP(3) 受体操作的存储中释放Ca2以及通过改变收缩装置对细胞质Ca2变化的敏感性的机制来补充Ca2的进入。平滑肌调节的分子研究因SMC的可塑性和难以培养这些细胞而没有显着的表型变化而变得复杂。关于人类胃肠道平滑肌中E-C耦合的细节，仍有主要问题有待解决。关于赋予GI平滑肌独特特性的分子表达的新发现，在GI运动障碍中SMC中发生的表型变化，修复或替换有缺陷的肌肉区域的组织工程方法，在动物模型和细胞培养中，GI平滑肌的分子操纵将成为未来令人兴奋的研究的主题。

BACKGROUND & AIMS: :We tested the hypothesis that brief static contraction of the triceps surae muscle causes reflex-induced increases in plasma arginine vasopressin (AVP) in anesthetized cats. Arterial blood samples, for measurement of plasma AVP, were taken before and after 30 s of electrically stimulated static contraction performed at a low intensity (<20% of maximal; n = 5), a high intensity (>70% of maximal; n = 7), and a high intensity after denervation of the triceps surae (n = 5). The low intensity contraction protocol was repeated during alpha-adrenergic blockade (n = 7) to minimize potential baroreflex-induced inhibition of AVP release. Passive stretch of the triceps surae was conducted (n = 5) to determine effects of muscle mechanoreceptor stimulation on the release of AVP. Low intensity contraction had no effect on plasma AVP. During alpha-adrenergic blockade, this same contraction intensity caused this peptide to increase from 12.8 +/- 2.1 to 17.7 +/- 2.6 pg/ml. High intensity contraction caused an increase in AVP (13.2 +/- 3.5 to 26.1 +/- 6.6 pg/ml) that was abolished by denervation (14.4 +/- 3. 7 vs. 17.1 +/- 6.6 pg/ml). Passive stretch had no effect on plasma AVP. These findings suggest that brief static contraction causes increases in plasma AVP that are reflex in nature, intensity dependent, opposed by the arterial baroreflex, and probably unrelated to muscle mechanoreceptor activation.

背景与目标： : 我们测试了以下假设: 肱三头肌的短暂静态收缩会导致麻醉猫的血浆精氨酸加压素 (AVP) 反射引起的增加。在低强度 (<最大20%; n = 5)，高强度 (> 最大70%; n = 7) 电刺激静态收缩30 s之前和之后采集用于测量血浆AVP的动脉血样本，以及肱三头肌去神经后的高强度 (n = 5)。在 α-肾上腺素能阻断 (n = 7) 期间重复低强度收缩方案，以最大程度地减少压力反射诱导的AVP释放的潜在抑制。进行肱三头肌的被动拉伸 (n = 5)，以确定肌肉机械感受器刺激对AVP释放的影响。低强度收缩对血浆AVP没有影响。在 α-肾上腺素能阻断期间，该相同的收缩强度导致该肽从12.8 +/- 2.1增加到17.7 +/- 2.6 pg/ml。高强度收缩引起AVP的增加 (13.2 +/- 3.5至26.1 +/- 6.6 pg/ml)，其被去神经支配消除 (14.4 +/-3.7对17.1 +/- 6.6 pg/ml)。被动拉伸对血浆AVP没有影响。这些发现表明，短暂的静态收缩会导致血浆AVP的增加，这种增加本质上是反射性的，强度依赖性的，与动脉压力反射相反，并且可能与肌肉机械感受器的激活无关。

BACKGROUND & AIMS: :The efficacy of selective endothelin (ET) receptor antagonists may be limited by a functional interaction between the ET(A) and ET(B) receptors. This interaction, also termed "cross talk", is characterized by the dependency of the inhibition of an ET-1 response due to antagonism of one ET receptor subtype upon concomitant antagonism of the other ET receptor subtype. Although a reduction in ET(A)-ET(B) receptor cross talk would presumably increase the efficacy of selective ET receptor antagonists, an approach that accomplishes this aim is largely absent due to a lack of mechanistic understanding. Toward this goal, we evaluated the characteristics and potential dependencies of cross talk in smooth muscle. Smooth muscle was adopted as an exemplar not only because cross talk is widely reported in this tissue type, thereby allowing numerous comparisons, but also significant controversy surrounds the use of selective versus nonselective ET receptor antagonists in ET-1-related pathophysiologies involving smooth muscle. Based on this evaluation, we suggest that ET(A)-ET(B) receptor cross talk is a dynamic process directed by either or both ET receptor subtypes and expressed to varying magnitudes depending on the ET-1 and selective ET receptor antagonist concentrations, tone due to intraluminal pressure/stretch, agonists acting at receptors other than the ET(A)/ET(B) receptors, and endothelial/epithelial function. It is speculated that ET(A)-ET(B) receptor cross talk occurs through signal transduction pathways along with changes at the receptor level. Pharmacologic intervention of the signaling pathways could increase the therapeutic efficacy of ET receptor antagonists.

背景与目标： : 选择性内皮素 (ET) 受体拮抗剂的功效可能受到ET (a) 和ET(B) 受体之间功能相互作用的限制。这种相互作用，也称为 “串扰”，其特征在于由于一种ET受体亚型的拮抗作用而引起的ET-1反应的抑制对另一种ET受体亚型的伴随拮抗作用的依赖性。尽管ET (a)-ET(B) 受体串扰的减少可能会增加选择性ET受体拮抗剂的功效，但由于缺乏机理理解，基本上没有实现这一目标的方法。为此，我们评估了平滑肌中串扰的特征和潜在依赖性。平滑肌被用作示例，不仅因为在这种组织类型中广泛报道了串扰，从而允许进行大量比较，而且在涉及平滑肌的ET-1-related病理生理中使用选择性与非选择性ET受体拮抗剂也存在重大争议。基于此评估，我们建议ET(A)-ET(B) 受体串扰是由ET受体亚型之一或两者指导的动态过程，并根据ET-1和选择性ET受体拮抗剂的浓度表达为不同的幅度，由于腔内压力/拉伸，作用于ET(A)/ET(B) 受体以外的受体和内皮/上皮功能的激动剂。据推测，ET(A)-ET(B) 受体串扰是通过信号转导途径以及受体水平的变化而发生的。信号通路的药物干预可以提高ET受体拮抗剂的治疗效果。

BACKGROUND & AIMS: :This study compared the effects of fatigue on corticospinal responsiveness in the upper- and lower-limb muscles of the same participants. Seven healthy males performed a 2-min maximal voluntary isometric contraction of the elbow flexors or knee extensors on four separate days. Electromyographic responses were elicited by nerve stimulation (maximal M-wave) in all sessions and by transcranial magnetic stimulation (motor-evoked potential; silent period) and spinal tract stimulation (cervicomedullary or thoracic motor-evoked potentials; silent period) in one session each per limb. During sustained maximal voluntary contractions, motor-evoked potential area normalised to M-waves increased from baseline in biceps brachii (155 ± 55%) and rectus femoris (151 ± 44%) (both p ≤ 0.045). At the end of maximal voluntary contractions, spinal tract motor-evoked potential area normalised to M-waves was smaller than baseline in biceps brachii (74 ± 23%; p = 0.012) but not rectus femoris (108 ± 40%; p = 0.999). The ratio of motor-evoked potential to spinal tract-evoked potential areas increased dramatically from 90 to 115 s in biceps brachii (p = 0.001) but not in rectus femoris (p = 0.999). Silent period durations increased similarly in both muscles (p ≤ 0.008) after transcranial and spinal stimulation. Sustained maximal contractions elicit different neurophysiological adjustments in upper- and lower-limb muscles. Specifically, motoneuronal excitability was reduced in biceps brachii, but not in rectus femoris, and this reduction required greater compensatory adjustments from the motor cortex. Therefore, changes in cortical and spinal excitability during sustained maximal exercise are likely specific to the muscle performing the task.

背景与目标： : 这项研究比较乏力对同一参与者上肢和下肢肌肉皮质脊髓反应性的影响。七名健康男性在四个不同的日子里对肘部屈肌或膝伸肌进行了2分钟的最大自愿等距收缩。在所有会话中通过神经刺激 (最大M波) 以及经颅磁刺激 (运动诱发电位; 静默期) 和脊髓道刺激 (颈髓或胸腔运动诱发电位; 静默期) 引起肌电图反应每个肢体。在持续最大自愿收缩期间，肱二头肌 (155   ±   55%) 和股直肌 (151   ±   44%) (均p  ≤   0.045) 的运动诱发电位区域从基线增加到M波。在最大自愿性收缩结束时，肱二头肌 (74   ±   23%; P   =   0.012) 的脊髓道运动诱发电位面积标准化为M波，小于基线，而股直肌 (108   ±   40%; P   =   0.999)。肱二头肌 (p   =   0.001) 的运动诱发电位与脊髓束诱发电位区域的比率从90到115  s急剧增加，而股直肌 (p   =   0.999) 则没有。经颅和脊柱刺激后，两种肌肉的静默期持续时间相似地增加 (p  ≤   0.008)。持续的最大收缩会引起上肢和下肢肌肉的不同神经生理调节。具体来说，肱二头肌的运动神经元兴奋性降低，但股直肌却没有，这种降低需要运动皮层进行更大的补偿性调整。因此，持续最大运动期间皮质和脊柱兴奋性的变化可能是特定于执行任务的肌肉的。

BACKGROUND & AIMS: :Radix astragali is a popular traditional herbal medicine that provides significant protection against tissue injury in various models of oxidative stress-related diseases. In this study, we aimed to investigate whether administration of Radix astragali prevented atrophy in both slow- and fast-twitch muscles following cast immobilization. Twenty-seven 12-week-old male F344 rats were divided into three experimental groups: control (CON), immobilized (IM), and immobilized with Radix astragali administration (IM+AR). Rats in the IM and IM+AR groups were subjected to immobilization of both lower extremities using casting-tape for 14 days. Rats in the IM+AR group were orally administered a decoction of Radix astragali daily for 21 days beginning 7 days before cast immobilization. As expected, rats in the IM group showed significant decreases (P < 0.05) in soleus and plantaris muscle-to-body weight ratios by 74.3% and 70.5%, respectively, compared with those in the CON group. Administration of Radix astragali significantly reversed (+35.5%) the weight reduction observed in soleus muscle, but not in the plantaris muscle, compared with that in the IM group. Furthermore, administration of Radix astragali inhibited MuRF1 mRNA expression only in the soleus muscle during cast immobilization. Our results demonstrated that administration of Radix astragali suppressed the immobilization-induced reductions in skeletal muscle mass and expression of MuRF1 mRNA in slow-twitch soleus muscles, but not in fast-twitch plantaris muscles.

背景与目标： : 黄芪是一种流行的传统草药，在各种氧化应激相关疾病模型中提供对组织损伤的显着保护。在这项研究中，我们旨在研究黄芪的给药是否可以预防石膏固定后缓慢和快速抽搐肌肉的萎缩。将27只12周龄雄性F344大鼠分为三个实验组: 对照组 (CON)，固定化 (IM) 和固定化黄芪给药 (IM AR)。IM和IM AR组的大鼠使用流延胶带固定两个下肢14天。IM AR组的大鼠在石膏固定前7天开始每天口服黄芪汤21天。正如预期的那样，与CON组相比，IM组大鼠比目鱼肌和plantaris的肌肉重量比分别显着降低了74.3% 和70.5% (P <0.05)。与IM组相比，黄芪的给药显着逆转 (35.5%) 比目鱼肌中观察到的重量减少，但在plant肌中没有。此外，黄芪的给药仅在石膏固定期间抑制比目鱼肌中的MuRF1 mRNA表达。我们的结果表明，黄芪的给药抑制了固定诱导的慢抽搐比目鱼肌骨骼肌质量的减少和MuRF1 mRNA的表达，但抑制了快抽搐的plant肌。

BACKGROUND & AIMS: :1. The influence of perinatal and pubertal gonadal androgens on acetylcholinesterase (AChE) activity was studied in the hormone-sensitive levator ani (LA) and extensor digitorum longus (EDL) muscles of adult male rats (105 days). 2. The hormone was withdrawn by gonadectomy at various ages and the effects on AChE and weight were compared with those induced by chronic denervation of both muscles from adult rats. 3. Gonadectomy of infantile (2-30 days) rats prevented LA muscle growth, and reduced total AChE activity to values similar to those found in denervated muscles (15% of control). The EDL muscles were slightly affected and only in rats castrated on the 2nd postnatal day. 4. When the rats were castrated at puberty (45 days), LA muscle weight and total AChE activity were reduced to 20% and 18% of control values, respectively. 5. Gonadectomy of adult (60 and 75 days) rats led to atrophy of the LA muscle (to 29% of control) and reduced the total AChE activity (to 40% of control). 6. AChE activity per unit weight was reduced by 30% in rats castrated from 5 to 20 days of age, and increased by 30% in both LA and EDL muscles from rats castrated in adulthood. Gonadectomy before puberty prevented total AChE in the LA from increasing above the levels detected in chronically denervated muscles. 7. Gonadectomy after puberty reduced total AChE of the LA but never to the extent caused by muscle denervation. 8. It is concluded that testosterone regulates AChE in the LA by early priming of the motoneuron and by pubertal stimulation of enzyme synthesis, the synthesis being dependent on intact innervation.

背景与目标： : 1。在成年雄性大鼠 (105天) 的激素敏感性提ani (LA) 和趾长伸肌 (EDL) 肌肉中研究了围产期和青春期性腺雄激素对乙酰胆碱酯酶 (AChE) 活性的影响。2.在不同年龄的性腺切除术中停用激素，并将其对疼痛和体重的影响与成年大鼠两种肌肉慢性去神经支配引起的影响进行比较。3.婴儿 (2-30天) 大鼠的性腺切除术可防止LA肌肉生长，并将总AChE活性降低至与失神经肌肉相似的值 (对照15%)。EDL肌肉受到轻微影响，仅在出生后第二天cast割的大鼠中。4.当大鼠在青春期 (45天) 去势时，LA肌肉重量和总AChE活性分别降低至对照值的20% 和18%。5.成年 (60和75天) 大鼠的性腺切除术导致LA肌肉萎缩 (至对照29%) 并降低总AChE活性 (至对照40%)。6.在5至20日龄的大鼠中，每单位重量的AChE活性因30% 而降低，而在成年后被阉割的大鼠的LA和EDL肌肉中，每单位重量的AChE活性因30% 而增加。青春期前的性腺切除术可防止LA的总疼痛增加到慢性失神经肌肉中检测到的水平以上。7.青春期后的性腺切除术减少了LA的总疼痛，但从未达到由肌肉神经支配引起的程度。8.结论是，睾丸激素通过运动神经元的早期启动和青春期刺激酶合成来调节LA中的AChE，该合成取决于完整的神经支配。

BACKGROUND & AIMS: :Na/Ca exchange is the dominant calcium (Ca) efflux mechanism in cardiac myocytes. Although our knowledge of exchanger function (NCX1 in the heart) was originally established using biochemical and electrophysiological tools such as cardiac sarcolemmal vesicles and the giant patch technique [1-4], many advances in our understanding of the physiological/pathophysiological roles of NCX1 in the heart have been obtained using a suite of genetically modified mice. Early mouse studies focused on modification of expression levels of NCX1 in the ventricles, with transgenic overexpressors, global NCX1 knockout (KO) mice (which were embryonic lethal if homozygous), and finally ventricular-specific NCX1 KO [5-12]. We found, to our surprise, that ventricular cardiomyocytes lacking NCX1 can survive and function by engaging a clever set of adaptations to minimize Ca entry, while maintaining contractile function through an increase in excitation-contraction (EC) coupling gain [5,6,13]. Having studied ventricular NCX1 ablation in detail, we more recently focused on elucidating the role of NCX1 in the atria through altering NCX1 expression. Using a novel atrial-specific NCX1 KO mouse, we found unexpected changes in atrial cell morphology and calcium handling, together with dramatic alterations in the function of sinoatrial node (SAN) pacemaker activity. In this review, we will discuss these findings and their implications for cardiac disease.

背景与目标： : Na/Ca交换是心肌细胞中主要的钙 (Ca) 流出机制。尽管我们对交换器功能 (心脏NCX1) 的了解最初是使用生化和电生理工具 (例如心脏肌膜囊泡和巨型贴片技术) 建立的 [1-4]，使用一组转基因小鼠，我们对NCX1在心脏中的生理/病理生理作用的理解取得了许多进展。早期的小鼠研究集中在脑室中NCX1的表达水平的修饰，转基因过表达，全球NCX1基因敲除 (KO) 小鼠 (如果纯合子是胚胎致死性的)，最后是心室特异性NCX1 KO [5-12]。令我们惊讶的是，我们发现缺乏NCX1的心室心肌细胞可以通过参与一组巧妙的适应来最小化Ca的进入而存活和发挥功能，同时通过增加兴奋-收缩 (EC) 耦合增益来维持收缩功能 [5,6，13]。在详细研究了心室NCX1消融之后，我们最近着重于通过改变NCX1表达来阐明NCX1在心房中的作用。使用新型的心房特异性NCX1 KO小鼠，我们发现心房细胞形态和钙处理的意外变化，以及窦房结 (SAN) 起搏器活动功能的显着变化。在这篇综述中，我们将讨论这些发现及其对心脏病的影响。

BACKGROUND & AIMS: :Repeated stimulation of unfatigued rodent fast-twitch skeletal muscle accelerates the kinetics of tension relaxation through an unknown mechanism. This effect varies with muscle type and stimulation parameters, and has been observed at physiological temperatures for submaximal but not maximal contractions. The purpose of this study was to compare relaxation kinetics of C57BL/6 mouse lumbrical muscles ex vivo from maximal isometric force (500 Hz for 20 ms) when evoked before (pre) and after (post) an intervening tetanic contraction at 37°C. During post contractions, we noted significant increases in the rate of tension decline during both the slow linear phase and the fast exponential phase of relaxation, as well as a reduced duration of the slow phase of relaxation compared with pre contractions (all P<0.05). This is the first demonstration of enhanced slow and fast relaxation phases from maximal isometric tension induced by prior stimulation in intact muscle at a physiological temperature.

背景与目标： : 反复刺激未疲劳的啮齿动物快速抽搐骨骼肌通过未知机制加速张力松弛的动力学。这种效果随肌肉类型和刺激参数而变化，并且在生理温度下观察到亚最大收缩而不是最大收缩。这项研究的目的是比较C57BL/6小鼠腰肌在体外的最大等轴测力 (500 hz，持续20  ms) 的松弛动力学，当在37 °C的介入强直收缩之前 (前) 和之后 (后) 诱发时。在收缩后期间，我们注意到在松弛的缓慢线性阶段和快速指数阶段期间，张力下降的速率显着增加，并且与收缩前相比，松弛的缓慢阶段的持续时间减少 (所有P<0.05)。这是在生理温度下由完整肌肉的先前刺激引起的最大等距张力增强的慢速和快速松弛阶段的首次证明。

BACKGROUND & AIMS: :The cell adhesion molecule N-CAM is localized to the adult neuromuscular junction but is also expressed in the extrajunctional membrane of denervated muscles concurrent with extrajunctional acetylcholine receptors. Here we used N-CAM immunohistochemistry to determine whether we could detect early denervation in hindlimb muscles of the G93A transgenic mouse model of amyotrophic lateral sclerosis (ALS). In denervated wild type mouse muscles, N-CAM immunoreactivity on the sarcolemma of all fiber types and within the sarcoplasm of only type IIA fibers was detected at day 2: approximately 30% of the muscle fibers in cross-section were fully circumscribed by N-CAM immunoreactivity and approximately 25% of fibers were incompletely circumscribed. The proportion of the latter fibers remained constant over the next 8 days as the proportions of the former fibers increased exponentially. Thereafter, fully circumscribed muscle fibers increased to a maximum by 30 days with a concomitant fall in the incompletely circumscribed fibers. Hence, early muscle denervation was detected by the incomplete circumscription of fiber membranes by N-CAM immunoreactivity with full circumscription and intracellular localization indicating more long-term denervation. In the G93A transgenic mouse, rapid denervation of fast-twitch muscles was readily detected by a corresponding proportion of muscle fibers in cross-section with positive N-CAM immunoreactivity. The proportions of incompletely and completely circumscribed muscle fibers corresponded well with the rate of decline in intact motor units and reduced muscle contractile forces. Progressively more fully circumscribed muscle fibers became evident with age. We conclude that the N-CAM immunoreactivity on muscle fiber membranes in muscle cross-sections provides a sensitive means of detecting early muscle fiber denervation.

背景与目标： : 细胞粘附分子N-CAM定位于成人神经肌肉接头，但也与接头外乙酰胆碱受体同时在失神经支配肌肉的结外膜中表达。在这里，我们使用N-CAM免疫组织化学来确定是否可以检测到肌萎缩性侧索硬化症 (ALS) G93A转基因小鼠模型后肢肌肉的早期去神经支配。在失神经的野生型小鼠肌肉中，在第2天检测到对所有纤维类型的肌膜和仅IIA型纤维的肌浆内的N-CAM免疫反应性: 横截面中大约30% 的肌肉纤维被N-CAM免疫反应性完全限制，并且大约25% 的纤维不完全限制。后一种纤维的比例在接下来的8天内保持恒定，因为前一种纤维的比例呈指数增长。此后，完全外接的肌肉纤维增加到最大30天，同时不完全外接的纤维也随之下降。因此，通过N-CAM免疫反应性通过纤维膜的不完全外接检测到早期肌肉去神经，并具有完全外接和细胞内定位，表明更长期的去神经。在G93A转基因小鼠中，通过具有正N-CAM免疫反应性的横截面中相应比例的肌纤维很容易检测到快速抽动肌肉的快速去神经。不完全和完全外接的肌肉纤维的比例与完整运动单位的下降速度和肌肉收缩力的降低非常吻合。随着年龄的增长，逐渐变得更加完全限制的肌肉纤维。我们得出的结论是，肌肉横截面中肌纤维膜上的N-CAM免疫反应性提供了检测早期肌纤维去神经支配的敏感手段。

BACKGROUND & AIMS: :Paraspinal muscle fatigability during various trunk extension tests has been widely investigated by electromyography (EMG), and its task-dependency is established recently. Hip extensor muscle fatigability during the Sorensen test has been reported. The aim of the present experiments was to evaluate the task-dependency of back and hip extensor muscle fatigue during two variants of the Sorensen test. We hypothesized that the rate of muscular fatigue of the hip and back extensor muscles varies according to the test position. Twenty healthy young males with no history of low back pain volunteered to participate in this cross-sectional study. They were asked to perform two body weight-dependent isometric back extension tests (S1 = Sorensen test; S2 = modified Sorensen on a 45 degrees Roman chair). Surface EMG activity of the paraspinal muscles (T10 and L5 levels) and hip extensor muscles (gluteus maximus; biceps femoris) was recorded, and muscular fatigue was assessed through power spectral analysis of the EMG data by calculating the rate of median power frequency change. We observed hip extensor muscle fatigue simultaneously with paraspinal muscle fatigue during both Sorensen variants. However, only L5 level EMG fatigue indices showed a task-dependency effect between S1 and S2. Hip extensor muscles appear to contribute to load sharing of the upper body mass during both Sorensen variants, but to a different extent because L5 level fatigue differs between the Sorensen variants. Our findings suggest that task-dependency has to be considered when EMG variables are compared between two types of lumbar muscle-fatiguing tasks.

背景与目标： : 肌电图 (EMG) 已广泛研究了各种躯干伸展测试过程中的脊柱旁肌肉疲劳能力，并且最近建立了其任务依赖性。已经报道了Sorensen测试期间的髋伸肌易疲劳性。本实验的目的是评估Sorensen测试的两个变体中背部和髋部伸肌乏力的任务依赖性。我们假设髋部和背部伸肌的肌肉乏力率根据测试位置而变化。20名没有腰痛病史的健康年轻男性自愿参加了这项横断面研究。他们被要求进行两次体重相关的等距背部伸展测试 (S1 = Sorensen测试; S2 = 在45度罗马椅上修改后的Sorensen)。记录椎旁肌 (T10和L5水平) 和髋伸肌 (臀大肌; 股二头肌) 的表面EMG活动，并通过计算中值功率频率变化率，通过EMG数据的功率谱分析评估肌肉乏力。在两个Sorensen变体中，我们同时观察到了髋关节伸肌乏力和椎旁肌乏力。但是，只有L5级EMG乏力指数在S1和s2之间显示出任务依赖性效应。在两个Sorensen变体中，髋关节伸肌似乎都有助于上半身质量的负荷分担，但程度不同，因为Sorensen变体之间的L5水平乏力有所不同。我们的发现表明，在比较两种类型的腰肌疲劳任务之间的EMG变量时，必须考虑任务依赖性。

BACKGROUND & AIMS: :The purpose of current study was to clarify the influence of preceding muscle activity on the force production and movement-related cortical potential (MRCP) during superimposed ballistic contractions. The participants performed the ballistic force production at 40 % of maximum voluntary contraction (MVC) using the isometric abduction force of the metacarpophalangeal joint of the index finger. They were asked to match the peak of force curve with a horizontal target line displayed on the computer monitor. We compared the MRCP amplitude during force exertion detected from Fz, C4, C3, Cz and Pz electrodes during ballistic force production with (active condition) and without (resting condition) preceding muscle activity. The results showed that the MRCP amplitudes of Fz, C4, C3 and Cz electrodes were significantly smaller for the active condition than the resting condition. This was the case even though the peak force values during both conditions were identical. This result suggests that the facilitation of spinal motoneuron excitability by preceding muscle activity could reduce the required central motor command to produce the identical force level. In addition, we examined the MRCP amplitude during ballistic force production of the active condition without a visually displayed target. In this condition, the participants had to perform the force production based on aiming point of target force level (40 %MVC). As a result, the mean of peak force without a visual target was 54 %MVC, which overshot the aiming force level. However, the MRCP amplitudes of five electrodes during the 54 %MVC force production in the active condition were equivalent to the case of the 40 %MVC force production in the resting condition. These results suggest that the MRCP amplitude is consistent with participants' sense of effort involved in the force production, rather than the actual produced force level.

背景与目标： : 当前研究的目的是阐明叠加弹道收缩过程中先前的肌肉活动对力产生和与运动相关的皮质电位 (MRCP) 的影响。参与者使用食指掌指关节的等距外展力在最大自愿收缩 (MVC) 40% 时产生弹道力。他们被要求将力曲线的峰值与计算机监视器上显示的水平目标线匹配。我们比较了在弹道力产生期间从Fz，C4，C3，Cz和Pz电极检测到的力施加期间的MRCP振幅 (活动状态) 和没有 (静息状态) 之前的肌肉活动。结果表明，活动状态下Fz，C4，C3和Cz电极的MRCP幅度明显小于静止状态。即使两种情况下的峰值力值相同，情况也是如此。该结果表明，通过先前的肌肉活动促进脊髓运动神经元的兴奋性可能会降低产生相同力水平所需的中央运动命令。此外，我们在没有视觉显示目标的情况下检查了活动状态的弹道力产生期间的MRCP振幅。在这种情况下，参与者必须根据目标力水平的瞄准点 (40% MVC) 进行力产生。结果，没有视觉目标的峰值力的平均值为54% MVC，超过了瞄准力水平。但是，在活动条件下产生54% MVC力的过程中，五个电极的MRCP幅度等于在静止条件下产生40% MVC力的情况。这些结果表明，MRCP振幅与参与者参与力产生的努力感相一致，而不是实际产生的力水平。

BACKGROUND & AIMS: :The regulation of fatty acid utilization during muscle contraction and exercise remains to be fully elucidated. Evidence suggests that the metabolic responses of skeletal muscle induced by the contraction-induced changes in energy demand are mediated by the activation of a multitude of intracellular signaling cascades. This review addresses the roles played by 3 intracellular signaling cascades of interest in the regulation of fatty acid uptake and oxidation in contracting skeletal muscle; namely, the AMP-activated protein kinase (AMPK), calcium/calmodulin-dependent protein kinases (CaMKs), and the extracellular signal-regulated kinase 1 and 2 (ERK1/2) signaling cascades. Data delineating the potential role of AMPK in cross-talk with CaMKII, CaMK kinase (CaMKK), and ERK1/2 are presented. Collectively, data show that in perfused rodent muscle, regulation of fatty acid uptake and oxidation occurs via (i) CaMKII signaling via both AMPK-dependent and -independent cascades, (ii) CaMKK signaling via both AMPK-dependent and -independent cascades, (iii) AMPK signaling in a time- and intensity-dependent manner, and (iv) ERK1/2 signaling in an intensity-dependent manner.

背景与目标： : 肌肉收缩和运动过程中脂肪酸利用的调节仍有待充分阐明。证据表明，由收缩引起的能量需求变化引起的骨骼肌的代谢反应是由多种细胞内信号级联的激活介导的。这篇评论讨论了3个感兴趣的细胞内信号级联在收缩骨骼肌中调节脂肪酸摄取和氧化中的作用; 即AMP激活的蛋白激酶 (AMPK)，钙/钙调蛋白依赖性蛋白激酶 (CaMKs)，和细胞外信号调节激酶1和2 (ERK1/2) 信号级联。提供了描述AMPK在与CaMKII，CaMK激酶 (CaMKK) 和ERK1/2串扰中的潜在作用的数据。总的来说，数据表明，在灌注的啮齿动物肌肉中，脂肪酸吸收和氧化的调节是通过 (i) AMPK依赖性和非依赖性级联的CaMKII信号传导，(ii) AMPK依赖性和非依赖性级联的CaMKK信号传导，(iii) 以时间和强度依赖的方式进行AMPK信号传导，以及 (iv) 以强度依赖的方式进行ERK1/2信号传导。

BACKGROUND & AIMS: :BMS-A78277 (1) is a 5,10-dihydrobenzo[beta][1,8]naphthyridine-N-oxide compound that resides in a class of novel non-nucleoside reverse transcriptase inhibitors (NNRTIs), displaying improved activity against clinically relevant mutants of HIV-1 and possessing pharmacokinetic profiles amenable to once-daily dosing. In the course of investigating the nonclinical metabolism of 1, a circulating metabolite specific to the cynomolgus monkey was identified and subsequently characterized as the carboxyindole metabolite 2. The present investigation describes the biotransformation of this NNRTI in cynomolgus monkey, one which results in a net ring contraction of 1. The use of mass spectrometry and high field NMR analysis aided in the structural characterization of metabolite 2, the source of which originated from the urine and bile of cynomolgus monkeys receiving oral doses of 1. Preparation of a synthetic standard of 2 not only provided ultimate structural confirmation but also afforded ample material for biological testing. The metabolism of 1 was investigated in monkey hepatocytes and hepatic subcellular fractions. While microsomes were incapable of generating metabolite 2, incubation of 1 in monkey S9 fractions as well as hepatocytes resulted in measurable levels of the carboxyindole metabolite. Consequently, incubation of 1 in monkey hepatocytes, which were suspended in media containing (18)O-labeled water, resulted in the incorporation of (18)O into the carboxyindole metabolite, 2. These data implicate a mechanism involving the bioactivation of 1 to an electrophilic intermediate that upon hydrolysis undergoes a concerted ring contraction, resulting in the formation of 2. Previously confined to discussions regarding the metabolism of natural products and select aliphatic heterocycles, the present investigation extends the discussion of metabolism-mediated ring contraction to aromatics such as the present naphthyridine compound, 1.

背景与目标： : BMS-A78277 (1) 是5,10-二氢苯并 [β][1,8] 萘啶-N-氧化物化合物，其位于一类新型非核苷类逆转录酶抑制剂 (NNRTIs) 中，显示出针对临床相关HIV-1突变体的改进活性，并具有适于每日一次给药的药代动力学特征。在研究1的非临床代谢的过程中，鉴定了食蟹猴特有的循环代谢物，并随后将其表征为羧酸吲哚代谢物2。本研究描述了这种NNRTI在食蟹猴中的生物转化，导致净环收缩为1。质谱和高场NMR分析的使用有助于代谢物2的结构表征，其来源来自食蟹猴的尿液和胆汁，口服剂量为1。合成标准2的制备不仅提供了最终的结构确认，而且为生物测试提供了充足的材料。在猴肝细胞和肝亚细胞级分中研究了1的代谢。虽然微粒体无法产生代谢物2，但在猴子S9级分和肝细胞中孵育1会导致可测量的羧酸吲哚代谢物水平。因此，将1悬浮在含有 (18)O标记的水的培养基中，在猴肝细胞中孵育，导致 (18)O掺入羧基吲哚代谢物2中。这些数据暗示了一种机制，该机制涉及1对亲电中间体的生物活化，该中间体在水解后会经历协同的环收缩，从而形成2。以前仅限于有关天然产物和某些脂肪族杂环的代谢的讨论，本研究将代谢介导的环收缩的讨论扩展到芳烃，例如本萘啶化合物1。

BACKGROUND & AIMS: BACKGROUND:The impact of vitamin D3 (VD3) on obesity has been reported in the past. Our study was aimed at investigating the possible mechanisms by which VD3 affects obesity induced by a high fat diet. METHODS:Eight-week-old C57BL/6 J male mice were fed a normal- or high-fat diet for 9 weeks and were treated with a gavage of vehicle (corn oil) or cholecalciferol (50 μg/kg, daily). Body weight, white adipose tissue weight, blood lipid and glucose levels were measured. In addition, we investigated the expression of 1,25(OH)2D3 (calcitriol)/VDR-regulated genes involved in energy and lipid metabolism, such as of uncoupling protein 3 (UCP3), by using qRT-PCR in the liver, adipose tissue, skeletal muscle and C2C12, L6, and H-EMC-SS cells. We also measured UCP3 promoter transcription in the same cell lines using a Dual Luciferase Assay. Furthermore, we analyzed the binding site consensus sequences of VDR on the UCP3 promoter. RESULTS:Mice consuming a high-fat diet treated with cholecalciferol had lower body weight and adipose tissue weight and higher expression of UCP3 compared to the other treatment groups. Changes in the expression of genes correlated with calcitriol/VDR. Luciferase activity was dose-dependently associated with calcitriol/VDR levels. We confirmed the functional VDR binding site consensus sequences at -2200, -1561, -634, and +314 bp in the UCP3 promoter region. CONCLUSION:We suggest that VD3/VDR inhibits weight gain by activating UCP3 in the muscles.

背景与目标：