Dynamic Proteomics and Integrated Rates of Muscle Protein Synthesis During an Acute Period of Loading and Unloading

Study Overview
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Brief Summary
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Skeletal muscle plays several different roles in the promotion and maintenance of health and well-being. The loss of muscle mass that occurs with aging, chronic muscle wasting diseases, and physical inactivity puts people at an increased risk of frailty and becoming insulin resistant, and therefore imposes a significant burden on health care spending. Resistance exercise participation has proven particularly effective for increasing muscle mass and strength. This effectiveness can be used by health care practitioners in a rehabilitation setting to promote the recovery of individuals who have undergone involuntary periods of muscular unloading (i.e. limb immobilization caused by a sports injury or reconstructive surgery). However, there is large variability in the amount of muscle mass and strength that people gain following participation in resistance exercise. Some individuals fail to increase the size of their muscle (low responders) whereas others show vary large increases in muscle size (high responders) in response to the same resistance training program. People also show differences in the amount of muscle tissue they lose when they have a limb immobilized. To circumvent variability across individuals, the investigators utilized a within-person paired Hypertrophy and Atrophy ('HYPAT') strategy that reduced response heterogeneity by  40% (Available at: https://ssrn.com/abstract=3445673). Specifically, one leg performed resistance training for 10 weeks to induce hypertrophy, whereas the other leg underwent single-leg immobilization for 2 weeks to induce atrophy. The primary goal of the study will be to gain insight into the molecular responses to an acute period of single-leg immobilization and resistance exercise (8 days). The investigators will use an integrated systems biology approach to monitor the individual rates of over one hundred different muscle proteins.

Official Title
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Dynamic Proteomics and Integrated Rates of Muscle Protein Synthesis During an Acute Period of Hypertrophy and Atrophy (HYPAT) in Young, Healthy Men

Conditions
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Proteomics, Exercise, Atrophy, Disuse, Hypertrophy

Intervention / Treatment
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* Procedure: Knee bracing
* Other: Unilateral Resistance Exercise Training


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy males, between the ages of 18 and 30 y Body Mass Index between 18.5 and 30.0 kg/m2 Able and willing to provide informed consent Exclusion Criteria: A history of neuromuscular disorders or muscle/bone wasting diseases. Any acute or chronic illness, cardiac, pulmonary, liver, or kidney abnormalities, uncontrolled hypertension, insulin-dependent or insulin-independent diabetes, or the presence of any other metabolic disease - all of which will be determined via a medical history screening questionnaire. The use of any medications known to affect protein metabolism (glucocorticoids, non-steroidal anti-inflammatory medication, or prescription strength acne medication, etc.). A (family) history of thrombosis. The use of anticoagulant medications. Consumption of tobacco-containing products. Excessive alcohol consumption (>21 units/wk). History of bleeding diathesis, platelet or coagulation disorders, or anti-platelet/anticoagulation therapy. Exercise participation >2 days/wk (structured resistance and/or aerobic-type exercise)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 30 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: In a randomized fashion, one participant will have one leg assigned to unilateral immobilization, and the other leg will undergo unilateral resistance exercise training, for 8 days.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Unilateral Immobilization<br>One leg will undergo 14 days of single-leg immobilization, by means of a removable knee brace. | Procedure: Knee bracing<br>* Participants will have one leg immobilized, by means of a removable Don Joy Knee Brace. Participants will be expected to keep the knee brace on for 14 days, completely prevent weight bearing on the immobilized leg, and use crutches.<br>|
| Experimental: Unilateral Resistance Exercise<br>One leg will undergo 4 sessions of unilateral resistance exercise, over the course of 8 days. Specifically, participants will be asked to perform leg press and leg extension. | Other: Unilateral Resistance Exercise Training<br>* Participants will perform resistance training on 4 occasions throughout an 8 day time period.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Dynamic Proteomics | The investigators will use deuterated water and skeletal muscle biopsies, paired with sensitive Gas Chromatography-Mass Spectrometry techniques to calculate the individual synthesis rate of over one hundred different skeletal muscle proteins. | Baseline, Day 5, Day 9 and Day 14 (Post) | 
| Change in Integrated Rates of Muscle Protein Synthesis | The investigators will use deuterated water and skeletal muscle biopsies to calculate the cumulative synthesis of skeletal muscle proteins. | Baseline, Day 5, Day 9 and Day 14 (Post) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Lean Mass Using Dual X-Ray Absorptiometry | The change in lean mass (kg) will be assessed throughout the intervention using dual X-Ray absorptiometry at baseline, Day 4, and Day 8 (Post) of the intervention | Baseline, Day 5 and Day 14 (Post) | 
| Change in Muscle Strength using an Isokinetic Dynamometer | Muscle strength will be analyzed throughout the intervention using an isokinetic dynamometer. Isometric muscle torque (i.e., strength [N*m]) of the knee extensor will be measured. | Baseline, Day 5 and Day 14 (Post) | 
| Change in Muscle Cross-Sectional Area using Ultrasonography | The investigators will measure changes in vastus lateralis muscle cross sectional area (cm^2) throughout the intervention using ultrasonography. | Baseline, Day 5 and Day 14 (Post) |