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. It is well known that the muscles are highly adaptive to loading and use. Increased intensity and frequency of exercise stimulates muscle growth, while reduced activity leads to muscle loss. For the vast majority of people, the predominant loading of muscle occurs through normal weight bearing activities associated with daily living. A number of conditions lead to reduced activity or outright disuse of weight bearing muscles. Such conditions cause an adaptive loss of muscle. While not usually life threatening, such muscle deficits can make rehabilitation from illness take longer and be more difficult. Muscle loss can also increase the risk of injury to tendons and ligaments. Such problems are most notable for aged individuals who, with slowing and reduced activity, undergo muscle loss that occurs over a long period of time. This condition is called sarcopenia. For older individuals, sarcopenia can compound already existing weakness and frailty and increase the risk for accidental falls and injury. Disuse results from such conditions as limb casting following a bone fracture, bed rest from a debilitating injury, illness or recovery from surgery, partial or full paralysis from spinal cord injury, loss of muscle control from brain injury or stroke and even weightlessness associated with space flight, a problem of keen interest to the National Aeronautics and Space Administration. All of these conditions can lead to rapid and relatively large losses of muscle. Bed rest immobilization in healthy subjects is known to result in a state of accelerated muscle loss and is an effective way to model disuse. The model provides clear start and stop time points (in bed and out of bed, respectively) and allows study of muscle changes during both disuse and recovery phases. In addition, muscle loss can be studied in healthy subjects with the expectation that losses that result from bed rest will be fully recovered in the days and weeks following the bed rest phase. Bed rest causes relatively rapid decreases in muscle size and strength. While it seems clear that atrophy occurs in direct response to reduced use of muscles, the mechanism that gives rise to this loss is unclear. Recently, myostatin (GDF-8), a naturally occurring compound found predominantly in the skeletal muscle, has been shown to be a negative regulator of muscle size and strength. This means that when myostatin levels increase, muscle atrophy occurs and when myostatin levels decrease, muscle growth occurs. Mice that have been modified to produce no myostatin have dramatically increased muscle mass throughout their bodies as they grow. Myostatin may also play a key role in bed rest-induced muscle loss. Blocking myostatin in normal animals or humans may prove to be an effective method to protect against muscle atrophy and weakness. If so, then a drug that blocks myostatin may be effective in treating age-induced muscle loss, paralysis patients, bed-ridden patients and even patients with muscular dystrophy. The proposed study will look at the effects of 10 days of bed rest in normal subjects on myostatin levels. Muscle samples will be obtained through biopsy before, twice during and once after the bed rest period. Myostatin and other related compounds will be measured and compared with loss of muscle size and strength in individual subjects. It is hypothesized that myostatin levels will increase by two-fold during the bed rest period. A secondary goal of the study will be to look for markers of muscle loss in blood and urine that will make future studies easier to conduct. Results from the study are expected to lay the foundation for future clinical investigations where a drug to block myostatin and prevent muscle loss may be tested. If successfully developed, such a drug could improve the lives of millions of patients worldwide.
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