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.
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