CLINICAL TRIAL: INSULIN AND SARCOPENIA IN THE ELDERLY (CYCLE NO, 2)
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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 fundamental cause of and contributor to disability in older people is the involuntary loss of muscle mass and strength (sarcopenia), which eventually reduces function , thus increasing risk of falls and vulnerability to injury. Our general hypothesis is that nutritional factors and inactivity play significant roles in the development of sarcopenia. Thus, age-specific prolonged interventions including nutritional manipulations and/or exercise may help to reduce, stabilize, or even reverse the loss of muscle mass and strength with age. Our goal is to establish if specific interventions that can acutely increase muscle protein synthesis can also effectively translate into increased muscle mass and/or performance in older sedentary people, thus preventing frailty and promoting physical independence. To this end we will use stable isotope methodologies to measure muscle protein metabolism and contrast enhanced ultrasound to measure muscle perfusion, in order to determine if the treatments' acute effects can predict their chronic impact on muscle mass and function. Furthermore, we will also determine if chronic treatment leads to metabolic and/or vascular adaptations that may explain the measured changes in muscle mass and function. If we confirm that this type of supplementation can effectively improve muscle mass and strength in sedentary older subjects, it will be possible to test efficient supplements not only in frail elderly, but also in cases where caloric restriction is necessary or desirable, and where physical frailty is a potential risk (e.g., older obese and/or diabetic subjects, sarcopenic obesity).
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. In both selenium and vitamin E, the strongest evidence for their potential roles in preventing prostate cancer comes from secondary findings of two randomized, placebo-controlled clinical trials. The development of these two supplements has arrived at the stage where a randomized, placebo-controlled intervention is needed to test the primary hypothesis regarding these supplements' prostate cancer chemoprevention effects. Data indicate that activities of selenium and vitamin E are complementary and that the two supplements act synergistically to inhibit carcinogenesis. This evidence makes the 2 x 2 factorial design for simultaneously testing both supplements a particularly attractive option for the confirmatory Phase III trial. We hypothesize that Vit E &/or Selenium Supplements would prevent or decrease Prostate Cancer. The aims are to assess the effect of selenium and vitamin E alone and in combination on the clinical incidence of prostate cancer. Study duration will be twelve years, with a five-year uniform accrual period and a minimum of seven years of treatment. Participants will receive study medication until a common point in time (the entire length of the trial is between seven and twelve years depending on when the participant was randomized. The study will help evaluate the therapeutic efficacy of this intervention on prostate cancer
I
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. Muscle mass and function progressively decline with aging. This process has been termed sarcopenia, and is associated with increased risk of falls and vulnerability to injury, especially bone fracture, which increase the risk of functional dependence. Our preliminary results suggest that there is a change in the response of muscle protein synthesis to insulin in the elderly, which can compromise the positive effect of amino acids on muscle protein gain. Our goal is to determine the mechanisms underlying the age-related insulin resistance of muscle proteins, which will allow us to define specific interventions to target this defect and provide the scientific basis for the prevention and treatment of sarcopenia.
Subjects will be assigned randomly to any of the following groups: for 18-35 years old the possible groups are the following: insulin alone, insulin with L-NMMA, L-NMMA alone; meal; for 65 or older the possible groups will be the following: insulin alone, insulin with sodium nitroprusside; insulin with exercise; meal alone; meal with sodium nitroprusside; meal with exercise. We will measure the rate of metabolism, exchange, or turnover of amino acids in the body. Overall, we believe that this proposal will allow us to better delineate the changes in muscle metabolism with aging, thus providing a solid scientific basis for future intervention to prevent and treat muscle loss with aging (sarcopenia).
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. Our studies in the past have focused on the short term effects of exercise and amino acids in sedentary subjects. We would like to expand our research to include recreationally active middle aged people looking at the effect of essential amino acid on muscle growth. We hypothesize that long-term nutritional supplementation with essential amino acids will grow muscle and increase strength in healthy, trained middle-aged people. We will determine if long-term nutritional supplementation with essential amino acids can grow muscle and increase strength in healthy, trained middle aged people.
Enrolled subjects will be randomized to receive supplement or a placebo (i.e. like a sugar pill ) every day for one year. They will be tested every four months to check for muscle growth, strength testing, and safety of the supplements. At the end of the year all tests will be performed again to get the final results. This pilot study will serve to determine feasibility and safety of a nutritional intervention for muscle growth in trained middle-aged persons, and will allow us to collect preliminary data for a larger clinical trial to determine the optimal dose and composition of nutritional supplements for the prevention of muscle weakness and loss with aging.
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. Rapamycin (mTOR) signaling pathway plays a significant role in stimulating translation initiation and muscle protein synthesis. Though both muscular contraction and hypoxia have been demonstrated to acutely up regulate AMPK activity, effect of hypoxia per se on muscle protein turnover is unknown. Additionally, recent studies have shown that hypoxia can up-regulate the mTOR signaling pathway through a transcription factor called hypoxia-inducible factor-1 (HIF1). Hypoxia induced angiogenesis and cardiac cell growths have been linked to HIF1; therefore, resistance exercise combined with restricted venous blood flow may further stimulate mTOR signaling pathway through HIF1.
The specific aims are to: 1) to determine which component(s) of the mTOR signaling pathway are modified with muscular contraction combined with local hypoxia in older men. 2) To determine whether blood flow restriction during low-intensity exercise produces a larger increase in muscle protein synthesis than regular resistance exercise alone in older men. We will study groups of 24 older (60 yrs and above yrs) men after an overnight fast. The protocol is designed to study the modulations in mixed muscle protein fractional synthetic rate (FSR) and total protein content and phosphorylation status of components of the mTOR signaling pathway involved in translation initiation (mTOR, p70S6K, eIF2B, HIFs and AMPK) at rest and after low intensity resistance exercise with or without vascular occlusion. These studies will provide insight into the cellular mechanisms responsible for the enhanced hypertrophic effect of resistance exercise combined with reduced muscular blood flow.
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. The focus of this project is to explore how muscles grow. Muscle wasting is a common phenomenon in many conditions, such as cancer, AIDS, trauma, sepsis, kidney failure, and is also particularly prevalent in the elderly. Specific aims are to: (1) determine the magnitude of the short-term response of muscle growth to feeding when the food is given before or after a bout of resistance exercise. (2) determine the magnitude of the short-term response of muscle growth to food that provides an amount of energy that either matches or exceeds the amount of energy used during the exercise. (3) determine the differences between women and men in the short-term response of muscle growth to weight lifting alone and in combination with feeding when ingested before or after a bout of weight lifting exercise. The procedures include the use of femoral catheters, weight lifting exercise, blood and breath collection and taking muscle biopsies. During each experiment we will be continuously infusing stable isotopes. Stable isotopes are not radioactive and can be given safely to humans. These stable isotopes allow us to be able to measure short-term muscle growth in humans. These studies will provide insight into the mechanisms that regulate human muscle growth, and will be utilized as a basis from which to develop interventions for improving muscle growth in conditions such as aging, trauma, cancer, and AIDS.
