Expression profiling and pharmacogenomics of muscle and muscle disease

Parallel technologies are emerging for the study of DNA (single nucleotide polymorphism genotyping and association studies), and RNA (microarrays and expression profiling). Muscle tissue has many intrinsic features that make it the tissue of choice to model the application of these newly emerging technologies. Well-preserved human biopsies are readily available both from volunteers undergoing specific muscle training protocols and from neuromuscular disease patients. Furthermore, the rapid adaptation of muscle to environmental cues (e.g. exercise, conditioning and weightlessness) makes it possible to conduct time series data in humans (molecular cause and effect). Muscle is also important in drug metabolism and adverse events, and the application of single nucleotide polymorphism association studies in muscle pharmacogenomics is a field of expected future growth.     

Statins and muscle pain

ABSTRACT

Introduction: Statins remain among the most frequently prescribed drugs and constitute a cornerstone in the prevention of cardiovascular disease. However, muscle symptoms are often reported from patients on statins. Muscle symptoms are frequently reported as adverse events associated with statin therapy.

Areas covered: In the present narrative review, statin-associated muscle pain is discussed. It elucidates potential mechanisms and possible targets for management.

Expert opinion: In general, the evidence in support of muscle pain caused by statins is in some cases equivocal and not particularly strong. Reported symptoms are difficult to quantify. Rarely is it possible to establish a causal link between statins and muscle pain. In randomized controlled trials, statins are well tolerated, and muscle-pain related side-effects is similar to placebo. There are also nocebo effects of statins. Exchange of statin may be beneficial although all statins have been associated with muscle pain. In some patients reduction of dose is worth trying, especially in primary prevention Although the benefits of statins outweigh potential risks in the vast majority of cases, careful clinical judgment may be necessary in certain cases to manage potential side effects on an individual basis.     

Emerging drugs for treating skeletal muscle injury and promoting muscle repair

Introduction: Musculoskeletal injuries represent a major global public health problem and muscle injury contributes significantly to the burden of disability and suffering. Drugs that can attenuate muscle trauma and/or hasten muscle repair to restore function can help reduce the economic burden and alleviate personal suffering and financial hardship.

Areas covered: This review provides an update on some emerging drugs with therapeutic potential for muscle injury including those that could attenuate damage or improve regeneration. Although there are few (if any) drugs in development specifically for muscle injury, there are numerous drugs in development for cardiovascular complications, such as ischemia-reperfusion, that might also have efficacy for promoting regeneration after similar events in skeletal muscle.

Expert opinion: Drugs in development for muscle wasting or inflammatory diseases should also be considered within the context of modulating the events associated with muscle degeneration and regeneration. More rigorous pre-clinical evaluations, especially of a drug's efficacy for improving function, would help minimize false leads and hasten development of effective approaches for treating muscle damage and promoting repair after injury.     

Emerging drugs for treating skeletal muscle injury and promoting muscle repair

INTRODUCTION: Musculoskeletal injuries represent a major global public health problem and muscle injury contributes significantly to the burden of disability and suffering. Drugs that can attenuate muscle trauma and/or hasten muscle repair to restore function can help reduce the economic burden and alleviate personal suffering and financial hardship. AREAS COVERED: This review provides an update on some emerging drugs with therapeutic potential for muscle injury including those that could attenuate damage or improve regeneration. Although there are few (if any) drugs in development specifically for muscle injury, there are numerous drugs in development for cardiovascular complications, such as ischemia-reperfusion, that might also have efficacy for promoting regeneration after similar events in skeletal muscle. EXPERT OPINION: Drugs in development for muscle wasting or inflammatory diseases should also be considered within the context of modulating the events associated with muscle degeneration and regeneration. More rigorous pre-clinical evaluations, especially of a drug's efficacy for improving function, would help minimize false leads and hasten development of effective approaches for treating muscle damage and promoting repair after injury.     

Leptin and vascular smooth muscle

Leptin has received extensive attention as an endogenously produced satiety factor. Although once considered to be solely derived from adipose tissue, it is now apparent that leptin can be produced by various tissues including those comprising the cardiovascular system such as blood vessels and cardiomyocytes. Moreover, leptin receptors (OBR) have been identified in cardiovascular tissues. The increased cardiovascular risk associated with obesity is well known and many of the effects of leptin appear to be compatible with its potential role as a contributing factor to increased cardiovascular morbidity associated with obesity. Evidence from both animal and human studies implicated leptin as a potential contributor to the increased incidence of cardiovascular morbidity associated with hyperleptinemic conditions. This review focuses on some of the complex vascular actions of leptin and the emerging role of leptin as a cardiovascular regulator in terms of normal homeostatic function, but particularly in cardiovascular pathology.     

游离骨骼肌自体移植的肌纤维型分布、组织化学及组织形态学实验研究

目的研究实验动物游离骨骼肌自体移植的肌纤维型分布、组织化学及组织形态学变化。方法肌肉移植分为两期 :第一期去除支配移植肌的神经 ,第二期 3周后行肌肉移植。肌肉标本取材于手术时及术后 6周、10周 ,以肌球蛋白ATP酶染色 (pH9 4)将肌纤维分为Ⅰ型和Ⅱ型。组织化学和组织形态学分别用相应方法检测。超微结构用电镜观察。结果桡侧腕屈肌中Ⅰ型肌纤维百分率从移植后 6周时的 11 0 0± 1 80增加到 10周的 19 82± 2 38;股薄肌中Ⅰ型肌纤维百分率从移植后6周时的 10 91± 1 80增加到 10周的 15 48± 2 0 0。肌肉移植后 6周时两块移植肌中Ⅰ型肌纤维分布差异无显著意义 (P >0 0 5 ) ,10周时差异有显著性意义 (P <0 0 1)。组织化学从正常变化转为去神经后 3周时降低或消失 ,肌肉移植后又逐渐恢复。组织形态学为肌肉移植后通过肌细胞再生逐渐恢复。结论同型肌纤维游离骨骼肌自体移植后Ⅰ型肌纤维分布多于不同型肌纤维骨骼肌移植 ,功能恢复亦为同型肌纤维骨骼肌移植优于不同型肌纤维骨骼肌移植。目的研究实验动物游离骨骼肌自体移植的肌纤维型分布、组织化学及组织形态学变化。方法肌肉移植分为两期 :第一期去除支配移植肌的神经 ,第二期 3周后行肌肉移植。肌肉标本取材于手术时及术后 6周、10周 ,以     

Vascular smooth muscle serotonin and alpha-adrenoceptors

Rat isolated perfused tail arteries were used to investigate interactions between serotonin receptors and alpha-adrenoceptors. Ketanserin was shown to be a potent serotonin antagonist (pA2 = 9.17, s.e.m. = 0.06, n = 6) which also antagonized phenylephrine (pA2 = 7.47, s.e.m. = 0.10, n = 4) and noradrenaline (pA2 = 7.55, s.e.m. = 0.14, n = 6). Ketanserin reduced the maximal response to serotonin but not to phenylephrine or noradrenaline. Prazosin antagonized phenylephrine (pA2 = 9.60, s.e.m. = 0.12, n = 5) and noradrenaline (pA2 = 9.14, s.e.m. = 0.11, n = 6) and had no effect on maximal responses. Prazosin reduced the maximal response to serotonin but did not displace the dose-response curve. These results are interpreted to indicate the existence of separate, but overlapping, serotonin and alpha-adrenoceptors.     

家兔不同形态肌肉的肌梭分布情况

目的探究家兔不同形态肌肉的肌梭分布。方法肌构筑法和HE染色法。结果家兔胸大肌为一扇形的阔肌,肌重11．21g,肌梭密度为12．98个／g,但各部位的肌梭密度不同,横行纤维中部最高(21．68个／g),斜行纤维以远端为高;跖肌是一羽肌,肌重3．94g,肌梭密度为16．94个／g,内侧部近端最高(47．71个／g),外侧部以中部密度最高(19．77个／g);趾长伸肌为长肌,肌重2．20g,肌梭密度26．24个／g,其肌腹中部密度最高(44．76个／g)。结论不同形态肌的肌肉的梭分布与肌纤维排列有关;不同形态的肌肉或同一块肌肉,肌梭分布不均匀;小肌较大肌、伸肌较屈肌有更高的肌梭密度。     

The smooth muscle and airway hyperresponsiveness

Airway hyperresponsiveness, excessive airway narrowing caused by stimuli that normally elicit limited or no response, is one of the cardinal features of asthma. The length-dependence of smooth muscle contractility has been recognized for decades, and it forms an essential foundation for many aspects of the physiological regulation of airway contractility in vivo. This review summarizes the structural and functional alterations of airway smooth muscle in asthma and chronic obstructive pulmonary disease, that underlie pathophysiological conditions of airway hyperresponsiveness.     

Physical exercise and binding of digoxin to skeletal muscle — Effect of muscle activation frequency

Summary Ten healthy subjects who had ingested 0.5 mg digoxin daily for at least 10 days, performed a 1-hour bicycle exercise test on two occasions, 24 h after the latest dose, with the same work load but at two different pedalling rates, 40 and 80 rpm. During exercise the mean digoxin concentration in the thigh muscle increased by 8% at 40 rpm (n.s.) and by 29% at 80 rpm (p<0.01). The serum digoxin concentration decreased by 39% at both pedalling rates (p<0.001). The results suggest that the increase in skeletal muscle digoxin concentration during exercise is related to the neuromuscular activation frequency. The digoxin concentration in erythrocytes was measured in 16 healthy subjects before and 1 minute after a 1-hour bicycle exercise test. The erythrocyte digoxin concentration decreased by 12% (p<0.01) during the exercise indicating that the increased uptake of digoxin in skeletal muscle during exercise influences the digoxin concentration in other tissues.     

Effect of methylated bepridil on slow action potentials in cardiac muscle and vascular smooth muscle

The anti-anginal agent bepridil blocks slow Ca2+ channels in a variety of tissues. Since bepridil accumulates inside cells, the possibility exists that bepridil acts, at least partially, from inside the cell. To test this possibility, we examined the effects of a quaternary ammonium analog of bepridil, methylated bepridil, which presumably would enter the cells less readily, on the Ca2+-dependent slow action potentials of guinea pig papillary muscles (in 25 mM [K+]0) and rabbit pulmonary arteries (in tetraethylammonium chloride). In cardiac muscle, methylated bepridil had little effect on the slow action potentials at low stimulation frequencies (0.5 Hz), but at higher frequencies (1.0 and 2.0 Hz) the slow action potentials were depressed and/or the muscle was unable to follow each stimulation. These effects are similar to those obtained with bepridil, but bepridil was more potent than methylated bepridil. In vascular smooth muscle cells, methylated bepridil inhibited the slow action potentials at a somewhat lower dose than bepridil. We conclude that, in cardiac muscle, bepridil probably has two sites of action, one outside the cell (presumably on or associated with the slow Ca2+ channel) and a second site inside the cell. On the other hand, in vascular smooth muscle cells, bepridil may act only on an external site.