MARKERS OF MUSCLE INJURY FOLLOWING ECCENTRIC EXERCISE

该子项目是利用 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 中心，不一定是研究者的机构。 各种各样的药物都有可能导致肌肉损伤作为副作用。 一种不常发生的副作用在药物进行有效性测试时可能无法被发现，只有在药物上市和更多人使用后才可能变得明显。这部分是由于临床试验中纳入的受试者数量有限，但也可能反映出这样一个事实，即处方药的人往往有医疗条件或伴随用药，这可能使他们更容易受到副作用的影响。比研究中的受试者更有效。 因此，在开发可能导致肌肉毒性的药物时，进行有助于确定肌肉损伤发生的敏感试验将是有用的。 该项目的目的是确定潜在的肌肉损伤的新标志物，这些标志物可能有助于在药物开发和测试过程中监测肌肉毒性。 这将通过让志愿者做离心运动并在接下来的72小时内的特定时间点抽取血液样本来诱导他们轻微的肌肉损伤来完成。 离心运动是指肌肉在紧张状态下伸长的运动，是下楼梯或放下物体等常见日常活动的一部分。 做离心运动的量或强度超过某人习惯做的运动可能会导致运动后一两天延迟肌肉酸痛，并且通常与肌肉酶（如肌酐磷酸激酶，CPK）泄漏到血液中有关，以及肌肉显微镜检查时肌纤维损伤的迹象。 因此，离心运动是肌肉损伤的良好建立的生理模型。 为了从代表健康和慢性疾病的一系列受试者中采样响应，我们将使用该模型研究正常志愿者和临床稳定的糖尿病患者。 选择糖尿病受试者作为服用各种药物的代表性临床人群。 将进一步选择这些受试者，包括服用和未服用公认具有潜在肌肉效应的常见药物类别（即HMG-CoA还原酶抑制剂（他汀类药物））的受试者。 通过这种方式，具有潜在混杂因素的广泛受试者将在相对较小的研究队列中代表。 肌肉损伤的新标志物将通过测定静脉血样本中可能反映肌肉损伤的某些分子来寻找，这些分子基于先前的研究，并且还通过更一般的蛋白质组学调查方法来寻找，该方法描述了样本中的整个蛋白质和蛋白质片段群体。 受试者将前往研究中心进行5次访视。 在第一次，他们将给予同意，有一个筛选病史，并有第一个血液样本提取。 在第二天，他们将被教导使用手持重物进行肘部弯曲运动（二头肌卷曲），并将用每只手臂做一系列的三组10个升降动作，运动后一小时将采集血液样本。 第三、第四和第五次访视将在运动后24、48和72小时进行，包括抽血和使用视觉模拟量表评估肌肉酸痛。 受试者的不适和风险主要是预期的肌肉酸痛和抽血。 肌肉酸痛预计是温和的，类似于剧烈做其他手臂活动（如练习网球发球或在花园里工作）的结果，一个人不习惯20或30分钟。 本研究抽取的血液总量约为100 ml。 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。 对受试者没有任何益处。 对社会的好处是在新药开发和测试期间开发更好的安全监测方法的潜力。 我们认为这种潜在获益证明了对人类受试者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.