Increased O<Subscript>2</Subscript> consumption in excitation–contraction coupling in hypertrophied rat heart slices related to increased Na<Superscript>+</Superscript>–Ca<Superscript>2+</Superscript> exchange activity

The goal of our study was to evaluate the origin of the increased O₂ consumption in electrically stimulated left ventricular slices of isoproterenol-induced hypertrophied rat hearts with normal left ventricular pressure. O₂ consumption per minute (mVO₂) of mechanically unloaded left ventricular slices was measured in the absence and presence of 1-Hz field stimulation. Basal metabolic mVO₂, i.e., mVO₂ without electrical stimulation, was significantly smaller, but mVO₂ for the total Ca²⁺ handling in excitation–contraction coupling (E–C coupling mVO₂), i.e., delta mVO₂ (=mVO₂ with stimulation − mVO₂ without stimulation), was significantly larger in the hypertrophied heart. Furthermore, the fraction of E–C coupling mVO₂ was markedly altered in the hypertrophied heart. Namely, mVO₂ consumed by sarcoplasmic reticulum Ca²⁺-ATPase (SERCA2) was depressed by 40%; mVO₂ consumed by the Na⁺/K⁺-ATPase (NKA)-Na⁺/Ca²⁺ exchange (NCX) coupling was increased by 100%. The depressed mVO₂ consumption by SERCA2 was supported by lower protein expressions of phosphorylated-Ser¹⁶ phospholamban and SERCA2. The increase in NKA–NCX coupling mVO₂ was supported by marked augmentation of NCX current. However, the increase in NCX current was not due to the increase in NCX1 protein expression, but was attributable to attenuation of the intrinsic inactivation mechanisms. The present results demonstrated that the altered origin of the increased E–C coupling mVO₂ in hypertrophy was derived from decreased SERCA2 activity (1ATP: 2Ca²⁺) and increased NCX activity coupled to NKA activity (1ATP: Ca²⁺). Taken together, we conclude that the energetically less efficient Ca²⁺ extrusion pathway evenly contributes to Ca²⁺ handling in E–C coupling in the present hypertrophy model.     

Compartmentalized cAMP/PKA signalling regulates cardiac excitation–contraction coupling

The sympathetic control over excitation–contraction coupling (ECC) is mediated by the cAMP/PKA signalling pathway. However, in the myocyte, the same signalling pathway is responsible for triggering a plethora of diverse intracellular functions the control of which must be independent of the regulation of ECC. Here we discuss what are the molecular mechanisms leading to selective modulation of ECC in cardiac myocytes with a particular focus on the role of spatial confinement of PKA subsets and the compartmentalization of cAMP.     

Chronic neural adaptation induced by long-term resistance training in humans

While it is known that resistance training causes changes in the central nervous system (CNS) in the initial stages of training, there have been few studies of cumulative or sustained neural adaptation to resistance training beyond the initial periods. To further investigate this we compared the electromyographic (EMG) response to transcranial magnetic stimulation (TMS) during voluntary contractions of ten subjects who have been training for more than 2 years, resistance-training (RT) group, and ten subjects that have never participated in resistance training (NT). The active motor threshold for biceps brachii was obtained during voluntary elbow flexion at 10% of maximal voluntary contraction (MVC). TMS was also delivered at 100% of the maximal stimulator output while the participants exerted forces ranging from 10 to 90% of MVC. Evoked force, motor-evoked potential (MEP) amplitude and latency from biceps brachii was recorded for each condition to explore changes in corticospinal excitability. The evoked force was significantly lower in the RT group in comparison with the NT group between 30 and 70% of MVC intensity (P<0.05). At 90% of MVC, nine subjects from the RT group showed an absence in the evoked force while this occurred in only five subjects from the NT group. The MEP amplitude and latency changed significantly (P<0.001) with increasing levels of contraction, without significant difference between groups. These results indicate that changes in the CNS are sustained in the log-term practices of resistance training and permit a higher voluntary activation at several intensities of the MVC.     

Comparison of the electromyographic activity in the upper trapezius and biceps brachii muscle in subjects with muscular disorders: a pilot study

The aim of the present study was to investigate the extent to which work-related muscular disorders of the upper trapezius affect the activity of other pain-free muscles, in particular in the biceps brachii. Two groups of female subjects (age >43 years) participated in the study: seven affected subjects with self-reported disorders in the shoulder/neck region (cases) and nine healthy subjects (control group). Multi-channel electromyography (EMG) and force were recorded during maximum voluntary contractions (MVC) and during 6 min sustained contractions (at 30% MVC) of the upper trapezius and biceps brachii on the dominant side. From the EMG signals, the root mean square (RMS), median frequency (MDF) and single motor unit (MU) conduction velocity (CV) were estimated. From the force signal, the coefficient of variation was calculated. All data are presented as mean values and standard deviation. Differences between the cases and controls were found in the MVC force of the upper trapezius, which was lower in cases [253 (70) N] than in controls [357 (75) N], while the coefficient of variation of force during the sustained contraction was increased [cases 5.5 (2.2); controls 4.1 (1.9)]. The RMS (normalized to the RMS at MVC) during the 6 min sustained contractions was significantly lower in the cases than in the controls for both the upper trapezius and the biceps brachii. A tendency towards a smaller increase in the RMS with fatigue was only found in the trapezius muscle [slope: cases 6.5 (14.1) %/min, controls 10.2 (12.9) %/min]. No differences were found between the two subject groups with respect to the MDF and single MU CV in both muscles. While the lower RMS for the trapezius muscles of the cases may reflect changes at the local level, as well as in motor control, the lower biceps activity indicates a change in the central control strategies of the primarily unaffected muscle. Indications for a changed fatigability of the muscle were only found in the trapezius.     

Myosin-based contraction is not necessary for cardiac c-looping in the chick embryo

During the initial phase of cardiac looping, known as c-looping, the heart bends and twists into a c-shaped tube with the convex outer curvature normally directed toward the right side of the embryo. Despite intensive study for more than 80 years, the biophysical mechanisms that drive and regulate looping remain poorly understood, although some investigators have speculated that differential cytoskeletal contraction supplies the driving force for c-looping. The purpose of this investigation was to test this hypothesis. To inhibit contraction, embryonic chick hearts at stages 10-12 (10-16 somites, 33-48 h) were exposed to the myosin inhibitors 2,3-butanedione monoxime (BDM), ML-7, Y-27632, and blebbistatin. Experiments were conducted in both whole embryo culture and, to focus on bending alone, isolated heart culture. Measurements of heart stiffness and phosphorylation of the myosin regulatory light chains showed that BDM, Y-27632, and blebbistatin significantly reduced myocardial contractility, while ML-7 had a lesser effect. None of these drugs significantly affected looping during the studied stages. These results suggest that active contraction is not required for normal c-looping of the embryonic chick heart between stages 10 and 12.     

Isometric muscle torque in children 5 to 15 years of age: normative data

OBJECTIVE: To establish reference values of arm and leg muscle strength as measured by isometric torque production in healthy children. DESIGN: Measurement of isometric muscle strength in healthy children. SETTING: Public school. PARTICIPANTS: Healthy children (N=149; 76 boys, 73 girls) ages 5 to 15 years. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Isometric torque values of 12 arm and leg muscle groups of healthy children as measured by a handheld dynamometer. RESULTS: Normative data were obtained for children 5 to 15 years of age. There was an increase in torque with age and weight and a strong correlation with both age and weight. There were few differences between boys and girls. Equations for predicted torque taking into account age, weight, and sex were calculated. The agreement between examiners was excellent. CONCLUSIONS: Studies on growing children require comparison to healthy (normal) children to assess the amount of deviation from normal and to be able to draw conclusions of change over time. The reference values for torque in combination with a predicted value based on the child's age, weight, and sex make it possible to compare over time and between subjects and provide a tool for evaluation of physical status and efficacy of therapy.     

Different pharmacological properties of the optical isomers of MN9202, a novel 1,4‐dihydropyridine Ca2+ channel modulator,in rat ventricular myocytes

1. We have shown previously that 1,4‐dihydro‐2,6‐dimethyl‐4‐(3‐nitrophenyl)‐3,5‐pyridinedicarboxylic acid pentyl methyl ester (MN9202), a new 1,4‐dihydropyridine Ca²⁺ channel modulator, has significant hypotensive effects and favourable pharmacokinetic characteristics. As a chiral molecule, MN9202 has two optical isomers. The aim of the present study was to evaluate the pharmacological properties of the two enantiomers. 2. The two enantiomers, S‐(?)‐ and R‐(+)‐MN9202, were obtained by HPLC. At 1 μmol/L, both racemic MN9202 and S‐(?)‐MN9202 decreased the contractility of rat ventricular myocytes by 54.0 and 64.4%, respectively, compared with control, whereas R‐(+)‐MN9202 enhanced cell shortening by 10.1%. At 1 μmol/L, racemic MN9202 markedly reduced calcium transient (CaT) and L‐type Ca²⁺ channel current (I_Ca,L) by 60.0 and 50.7%, respectively, whereas the reductions in CaT and I_Ca,L produced by 1 μmol/L S‐(?)‐MN9202 were greater still (62.2 and 65.7%, respectively). In contrast, 1 μmol/L R‐(+)‐MN9202 increased CaT and I_Ca,L by 11.4 and 10.6%, respectively. Furthermore, findings from kinetics studies of I_Ca,L revealed that the steady state inactivation curve of I_Ca,L was shifted towards a hyperpolarizing potential by S‐(?)‐MN9202, but towards a depolarizing potential by R‐(+)‐MN9202. These results demonstrate different effects of R‐(+)‐MN9202 and S‐(?)‐MN9202. 3. In conclusion, the findings of the present study suggest that the chirality of MN9202 results in opposing pharmacological properties of its two enantiomers: S‐(?)‐MN9202 may be responsible for the therapeutic effects of racemic MN9202, whereas R‐(+)‐MN9202 contributes to it unwanted effects. The findings of the present study also indicate that MN9202 may be used as a new probe with which to investigate the structure–function relationships of Ca²⁺ channels.     

Telithromycin blocks neuromuscular transmission and inhibits nAChR currents in vitro

Telithromycin, a ketolide antibiotic, is reported to exacerbate myasthenia gravis, potentially leading to respiratory failure and death. However, telithromycin is not associated with neuromuscular effects in animal toxicity studies. The objective of this study was to examine the effect of telithromycin on the neuromuscular junction in the isolated rat phrenic nerve-diaphragm preparation and to investigate its postsynaptic effects on the muscle-like nicotinic acetylcholine (ACh) receptors expressed on human TE671 cells. Telithromycin decreased the twitch contraction force of the rat diaphragm muscle in response to phrenic nerve stimulation in a concentration-dependent manner with an IC₅₀ of 22.3 μM and a maximal inhibition of ∼70%. The trans-membrane current from the ACh receptors expressed in the TE671 neuromedulloblastoma cells was recorded in the whole-cell patch-clamp configuration. When applied to the TE671 cells, telithromycin caused a dose-dependent inhibition of the nicotinic ACh current with an IC₅₀ of 3.5 μM and maximal inhibition of nearly 100%. These results indicate that telithromycin inhibits postsynaptic nicotinic ACh receptors in vitro and partially blocks neuromuscular transmission in the isolated rat phrenic nerve-diaphragm preparation. Based on these findings, we propose that exacerbation of myasthenia gravis reported in some patients taking telithromycin results in part from postsynaptic neuromuscular transmission block.     

前交叉韧带重建后韧带力学转归的研究

目的探讨前交叉韧带（ACL）重建中等距与非等距移植对韧带转归的力学变化。方法选取雄性日本大白兔60只,体重2 500~3 000 g,分成等距移植组（A组）、非等距移植组（B组）。术后3、6和12周每组处死10只,观察比较A组与B组韧带的组织学变化,并且行移植韧带的力学测试。结果 3、6和12周A组与B组韧带的组织学及力学性能均有所改善,但同期A组明显优于B组,差异均有显著性（P（0.05）。结论在ACL重建中应该采用等距移植,由此可以有利于ACL的力学功能的恢复。