MARKERS OF MUSCLE INJURY FOLLOWING ECCENTRIC EXERCISE

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 各种各样的药物都有可能导致肌肉损伤，作为一种副作用。一种罕见的副作用可能在药物进行有效性测试时无法识别，可能只有在药物上市并有更多人使用后才会显现。这在一定程度上是因为临床试验中纳入的受试者数量有限，但也可能反映了这样一个事实，即开药的人往往有医疗条件或伴随的药物，这可能使他们比研究中的受试者更容易受到副作用的影响。因此，在开发可能导致肌肉毒性的药物时，进行有助于识别肌肉损伤发生的敏感测试将是有用的。该项目的目的是确定潜在的肌肉损伤的新标记物，这些标记物可能有助于在药物开发和测试过程中监测肌肉毒性。这将通过在接下来的72小时内让志愿者进行偏心运动并在特定的时间点抽取血液样本来诱导轻微的肌肉损伤来实现。偏心运动是一种在紧张状态下伸展肌肉的运动，是常见日常活动的组成部分，如走下楼梯或放下物体。做超过习惯的偏心运动的量或强度可能会导致运动后一两天的延迟性肌肉酸痛，而且通常与肌肉酶(如肌酸磷酸酶，CPK)渗入血液，以及对肌肉进行显微镜检查时出现肌肉纤维损伤的迹象有关。因此，离心运动是肌肉损伤的一个公认的生理学模型。为了从代表健康和慢性疾病的一系列受试者中抽取样本，我们将使用这个模型来研究正常志愿者和临床稳定的糖尿病患者。糖尿病受试者被选为服用多种药物的代表性临床人群。这些受试者将进一步包括服用和不服用公认具有潜在肌肉影响的常见药物类别的人，即HMG-CoA还原酶抑制剂(他汀类)。通过这种方式，具有潜在混杂因素的广泛的受试者将在相对较小的研究队列中被代表。将在先前研究的基础上，通过分析静脉血样本中可能反映肌肉损伤的某些分子，以及更一般的蛋白质组学调查方法，寻找肌肉损伤的新标记物，这种方法描述了样本中蛋白质和蛋白质片段的整个群体。 受试者将到研究中心进行连续5次的参观。在第一次，他们将同意，有筛查病史，并提取第一个血液样本。在第二个练习中，他们将被教导使用手持重物进行屈肘练习(二头肌卷曲)，并将用每只手臂做一系列三组10个动作的升降动作。运动后一小时将采集血样。第三次、第四次和第五次访问将在运动后24、48和72小时进行，包括抽血和使用视觉模拟评分评估肌肉酸痛。受试者的不适和风险主要是预期的肌肉酸痛和抽血。肌肉酸痛预计是轻微的，类似于剧烈地做其他手臂活动(如练习网球发球或在花园工作)20或30分钟所引起的体验。这项研究的总抽血量约为100毫升。还有其他可能的风险，如关节损伤或严重的肌肉损伤/疼痛，但这些可能性要小得多。这对受试者没有任何好处。对社会的好处是，有可能开发出在新药开发和测试期间进行安全监测的更好方法。我们认为，这种潜在的益处证明了人类受试者面临的适度风险是合理的。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. A wide variety of drugs have the potential to cause injury to muscle as a side effect. A side effect that happens infrequently may not be identified while a drug is undergoing testing for effectiveness, and may only become apparent after the drug is on the market and many more people have used it. This is due in part to the limited number of subjects included in clinical trials, but may also reflect the fact that people prescribed drugs often have medical conditions or concomitant medications that could make them more susceptible to side effects than the subjects in the research studies. In the development of drugs that might have potential to cause muscle toxicity, it would therefore be useful to have sensitive tests that would help to identify the occurrence of muscle damage. The purpose of this project is to identify potential new markers of muscle damage that might be helpful in monitoring for muscle toxicity during the course of drug development and testing. This will be done by inducing a mild form of muscle damage in volunteers by having them do eccentric exercise and drawing blood samples at specific time points over the next 72 hours. Eccentric exercise is exercise that involves muscles elongating while under tension, and is a component of common everyday activities like walking down stairs or lowering an object. Doing an amount or intensity of eccentric exercise that is more than what someone is used to doing can cause delayed muscle soreness a day or two after the exercise and is often associated with leakage of muscle enzymes (like creatinine phosphokinase, CPK) into the blood, and signs of muscle fiber damage on microscopic examination of the muscle. Eccentric exercise is thus a well established physiologic model of muscle injury. In order to sample responses from a range of subjects representing both health and chronic disease, we will use this model to study both normal volunteers and clinically stable patients with diabetes. Diabetic subjects were selected as a representative clinical population taking a variety of medications. These subjects will further be selected to include those taking and not taking a common class of drugs recognized to have potential muscle effects, namely the HMG-CoA reductase inhibitors (statins). In this way a broad range of subjects with potential confounding factors will be represented within a relatively small study cohort. Novel markers of muscle injury will be sought by assaying venous blood samples for certain molecules that are likely to reflect muscle damage based on prior research, and also by a more general proteomics survey approach, which describes the entire population of proteins and protein fragments in the samples. Subjects will come to the research center for a series of 5 visits. On the first, they will give consent, have a screening medical history, and have the first blood sample drawn. On the second they will be taught to perform elbow flexion exercise (biceps curls) using hand held weights, and will do a series of three sets of 10 lifting and lowering movements with each arm. A blood sample will be obtained one hour after the exercise. The third, fourth, and fifth visits will be at 24, 48, and 72 hours after exercise and will include blood draw and assessment of muscle soreness using a visual analog scale. The discomforts and risks to subjects are primarily the intended muscle soreness and the blood draw. The muscle soreness is anticipated to be mild, similar to what would be experienced as a result of vigorously doing other arm activities (like practicing tennis serves or working in the garden) that one is unaccustomed to for 20 or 30 minutes. The total amount of blood drawn for the study will be approximately 100 ml. There are other possible risks, such as joint injury or severe muscle injury/soreness, but these are far less likely. There is no benefit to the subjects. The benefit to society is the potential for developing better ways of conducting safety monitoring during the development and testing of new drugs. We feel this potential benefit justifies the modest risks to human subjects.