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The investigators propose that low-intensity exercise and supplementing daily meals with leucine or whey will independently and synergistically reduce the deleterious effects of inactivity on skeletal muscle and facilitate recovery during rehabilitation.
The loss of muscle mass and function in older adults during bed rest is facilitated by defects in the regulation of muscle protein metabolism, including an impaired ability to mount an anabolic response to a mixed nutrient meal. The investigators propose that low-intensity exercise and supplementing daily meals with leucine or whey will independently and synergistically reduce the deleterious effects of inactivity on skeletal muscle and facilitate recovery during rehabilitation. Metabolic measures will include: a) nutrient and exercise-specific markers of translation initiation; b) skeletal muscle protein synthesis; and c) a novel breath test of glucose tolerance. Morphologic and functional measures will include: a) muscle mass and body composition; b) muscle strength and function; and c) motor activation. The investigators will test the following hypotheses in older men and women (65-80 years) during 7 days of bed rest followed by 7 days of inpatient rehabilitation:
This translational project will provide mechanistic and practical insight into strategies to reduce the negative consequences of physical inactivity and promote rehabilitation in aging muscle. Our novel, minimally invasive and clinically interventions have direct application for older hospitalized patients at risk of accelerated muscle loss and diminished functional capacity.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Control | No Intervention | Control bed rest group | |
| Leucine | Experimental | Leucine will be administered in mixed meal 3 times a day at 0.06g/kg lean body mass/meal |
|
| Exercise | Experimental | Daily bouts of low intensity, bed-based exercise for 30 min/day @ 70% of stress test determined maximal heart rate. |
|
| Leucine + Exercise | Experimental | Leucine (0.06 g/kg lean body mass/meal, 3 meal/day) and exercise daily bouts of low intensity, bed-based exercise for 30 min/day @ 70% of stress test determined maximal heart rate. |
|
| Whey protein | Experimental | 22 g of whey isolate 3x a day (with meals) |
|
| Whey protein + exercise | Experimental |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Leucine | Dietary Supplement |
| ||
| Exercise |
| Measure | Description | Time Frame |
|---|---|---|
| Change in lean leg mass from baseline following seven days of bed rest and seven days of rehabilitation. (Morphologic primary measure) | The lower body musculature is primarily affected by physical inactivity (19). Lean leg mass will be determined by segmental dual energy x-ray absorptiometry (iDXA:General Electric, Lunar, Madison, WI). The whole body scan will be divided in sub-regions for analysis. | Study day 3, 11, 18, 39 |
| Change in stair climbing power test from baseline following seven days of bed rest and seven days of rehabilitation (Primary functional outcome) | Loss of leg muscle power occurs during prolonged bed rest (-14.4+4 % in 10 days)and is a key factor contributing to impaired mobility, balance and functional capacity. Climbing power will be calculated as the time to ascend 10 steps [Power = (Distance/Time) x Body Weight]. | Study day 3, 11, 18, 39 |
| Change in mixed muscle fractional synthesis rate (FSR) from baseline following seven days of bed rest and seven days of rehabilitation (Primary metabolic outcome) | Mixed muscle FSR will be calculated by measuring the direct incorporation of a stable isotope of phenylalanine into protein using the precursor-product model. | Study day 4, 11, 18 |
| Measure | Description | Time Frame |
|---|---|---|
| Change in cell signaling from baseline following seven days of bed rest and seven days of rehabilitation (Secondary metabolic measure) | We will examine protein content and phosphorylation status of key exercise and nutrient sensitive signaling proteins in the mammalian target of rapamycin. | Study day 4, 11, 18 |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Doug Paddon-Jones, Ph.D. | University of Texas | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Unversity of Texas Medical Branch | Galveston | Texas | 77555 | United States |
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| ID | Term |
|---|---|
| D007930 | Leucine |
| D015444 | Exercise |
| D000067816 | Whey Proteins |
| ID | Term |
|---|---|
| D000597 | Amino Acids, Branched-Chain |
| D000596 | Amino Acids |
| D000602 | Amino Acids, Peptides, and Proteins |
| D000601 | Amino Acids, Essential |
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22 g whey isolate 3x day (with meals) and daily bouts of low intensity, bed-based exercise for 30 min/day @ 70% of stress test determined maximal heart rate
|
| Skewed | No Intervention | Protein intake is distributed similar to typical American diet with low protein intake at breakfast, intermediate at lunch and high at dinner. |
| Behavioral |
|
| Whey protein | Dietary Supplement |
|
| Change in hormones and cytokines from baseline following seven days of bed rest and seven days of rehabilitation (Secondary Metabolic measure) |
Analysis will be performed on existing blood and tissue samples collected for primary metabolic analysis. Serum concentrations of insulin, testosterone, and hsCRP will be analyzed. Serum and muscle tissue concentrations of cytokines and biomarkers, including tumor necrosis factor-alpha (TNF-a), interleukin (IL)-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, granulocyte-macrophage colony-stimulating factor (GM-CSF), and interferon-gamma (IFN-γ) will also be assessed. |
| Study day 3, 11, 18 |
| Change in quantitative real-time polymerase chain reaction (PCR) analysis of MAFbx/Atrogin, MuRF1 and Ubiquitin from baseline following seven days of bed rest and seven days of rehabilitation (Secondary metabolic measure) | Total RNA from skeletal muscle will be isolated and ratios for Atrogin-1/GAPDH, MuRF1/GAPDH and Ubiquitin/GAPDH will be calculated from a portion of the 1st and 3rd muscle biopsy from each study. | Study day 4, 18 |
| Change in protein abundance of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB) and Actin Fragments from baseline following seven days of bed rest and seven days of rehabilitation. (Secondary metabolic measure) | The activation of NF-κB and actin fragment will be measured pre-and post bed rest and rehabilitation from portions of the 1st and 3rd muscle biopsy taken during each stable isotopic study. Data will also be used to asses muscle protein catabolism. | Study day 3, 18 |
| Change in muscle fiber cross sectional area and fiber typing from baseline following seven days of bed rest and seven days of rehabilitation(secondary morphologic measure) | To provide mechanistic insight into gross changes in muscle mass and volume, microscopic assessment of muscle fiber cross sectional area (CSA), fiber type and satellite cell activation will be performed using standard techniques. | Study day 4, 11, 18 |
| Change in motor activation from baseline following seven days of bed rest and seven days of rehabilitation (secondary functional measure) | Surface Electromyography (sEMG) will be collected using a Myomonitor IV wireless EMG system (Delsys, Inc., Boston, MA) to assess neuromuscular factors contributing to force production and fatigue in the vastus lateralis during maximal and submaximal isometric muscle contractions. We will determine degree of neuromuscular activation, fatigue, and rate of EMG activation with measures of root mean square (RMS) EMG, median frequency, and integrated EMG. | Study day 3, 11, 18, 39 |
| Physical activity monitoring post-bed rest (Secondary functional measure) | Physical activity throughout the study (primarily the post-bed rest/rehabilitation periods) will be used to monitor compliance and obtain a descriptive assessment of prescribed and spontaneous physical activity (StepWatch Activity Monitor; SAM, Cyma Inc., Seattle, WA). | Study day 11-18 |
| Change in muscle strength and fatigue from baseline following seven days of bed rest and seven days of rehabilitation (secondary functional outcome) | Isokinetic and isometric knee extension torque production are standard, readily comparable tests of muscle function. Tests will be performed on a dynamometer (Biodex, Systems-4, Shirley, NY). The peak of the three maximal attempts will be recorded for strength measures while a 20-repetition protocol will be used to assess fatigue. | Study day 3, 11, 18, 39 |
| Change in whole body physical function from baseline following seven days of bed rest and seven days of rehabilitation (secondary functional outcome) | Whole body physical function: We previously reported that the Short Physical Performance Battery (SPPB), and five-item physical performance test (5 minute walk, 50 foot walk, 5 step test, functional reach, and floor transfer) lacked the sensitivity to detect changes in older adults following bed rest. However, given the ease of administration, the clinical relevance of these measures and the fact that this will be only the 2nd bed rest study in older adults, we propose to include these tests a secondary/exploratory measure. | Study day 3, 11, 18, 39 |
| D009043 | Motor Activity |
| D009068 | Movement |
| D009142 | Musculoskeletal Physiological Phenomena |
| D055687 | Musculoskeletal and Neural Physiological Phenomena |
| D008894 | Milk Proteins |
| D000080224 | Animal Proteins, Dietary |
| D004044 | Dietary Proteins |
| D011506 | Proteins |
| D000067796 | Whey |
| D008892 | Milk |
| D003611 | Dairy Products |
| D005502 | Food |
| D000066888 | Diet, Food, and Nutrition |
| D010829 | Physiological Phenomena |
| D019602 | Food and Beverages |