Preventing Bed-rest Induced Muscle Loss in the Elderly

Study Overview
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Brief Summary
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Episodes of inactivity due to hospitalisation, as short as 5 days, are associated with rapid muscle and strength loss in the elderly. The observed muscle loss with inactivity is likely due to muscle anabolic resistance and increased breakdown rates of muscle tissue. This is of great concern as the average hospital stay in the elderly is 5-6 days. Moreover, minor illnesses not requiring hospitalisation generally require short-term periods of inactive home-based recovery. The accumulation of repeated disuse events in older individuals manifests in a chronic muscle anabolic resistance (i.e. the inability of muscle to respond to anabolic stimuli such as exercise and nutrition) that may underpin the slow but devastating process of age-related muscle loss. It is our belief that strategies to promote muscle health in ageing and reduce healthcare expenditure, should focus on alleviating muscle deterioration and anabolic resistance during short-term disuse. In this regard, we propose that resistance exercise (i.e. weight lifting) performed prior to a disuse event (termed 'prehabilitation') may be sufficient to offset muscle loss in older individuals. Thus, we suggest the potent effect of resistance exercise in older muscles may prevent muscle loss during short-term disuse.

Detailed Description
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Participants will be assigned to either single-bout (SINGLE; n=10) or multiple-bouts (MULTI; n=10) of resistance exercise prehabilitation prior to 5 consecutive days of bed rest. Groups will be matched for age, anthropometric characteristics and activity levels. Only males will be studied due to potential gender differences in muscle protein turnover. A single-leg resistance exercise prehabilitation model will allow for a direct within-subject comparison against the non-exercised control leg. Preliminary Assessments Following an induction meeting and obtainment of informed consent, participants will report to The National Institute of Health/Wellcome Trust Clinical Research Facility (CRF) at University Hospital Birmingham (UHB) at 0800h having fasted from 2100h the previous night. After measuring height and weight, the following parameters will be determined in the order outlined: Muscle biopsy, blood and saliva sampling: a muscle biopsy sample will be obtained from a specific thigh muscle under local anaesthetic. A blood sample will then be obtained from a forearm vein. Participants will also provide a saliva sample. This will be obtained prior to the following measurements. Lower-limb function: The short physical performance battery (SPPB) test will be used. Body composition: bioelectrical impedance analysis will be used to determine fat/fat-free mass on a whole-body and anatomical regional basis (CRF nurse). Muscle size/architecture: The thickness of the thigh muscles will be determined via non-invasive ultrasound imaging. Leg strength and muscle activation: Estimated maximal leg strength will be measured firstly on a standard knee extension exercise machine. Stable isotope procedure: Immediately following muscle biopsy, blood and saliva sampling, participants will orally consume a small bolus of 'heavy water' tracer to label the body water pool with a small amount of this isotope. Participants will provide a daily saliva sample to monitor body water tracer enrichment. This technique will allow us to quantify muscle protein synthesis over the course of prehabilitation and bed-rest. Participants will be fitted with an accelerometer and pedometer to asses daily activity levels. Participants are given a food diary to record daily nutritional intake over a 3-day period. Exercise Prehabilitation (Days 0-7) Participants will be randomly assigned to undergo 4 resistance exercise bouts the week before (Day 1, 2, 5 and 7), or 1 resistance exercise bout on the evening prior to bed rest (i.e. Day 7). Exercise bouts will consist of 8 sets of single-leg knee extension exercise and 8 sets of single-leg leg curls. The non-exercised control leg will remain passive throughout training. Resistance exercise will be performed at 70% of previously determined maximal strength (10-15 repetitions). Intervention - 5-days of bed-rest (Days 8-13) Participants will report to the CRF at 0700h the morning immediately after exercise prehabilitation phase. At 0800h, muscle biopsies will be obtained from both legs to assess changes in muscle metabolism over the 7 days of prehabilitation. Participants will then be transported for dual energy x-ray absorptiometry (DXA), Magnetic Resonance Imaging (MRI) and ultrasound assessment of body/muscle composition, after which the 5 consecutive days of strict bed rest will begin. The bed rest model will mimic a traditional inpatient hospital stay and reflect the level of muscle unloading that occurs in older individuals following acute illness. Participants will spend the majority of time in bed and will be allowed to adjust the hospital bed head height for reading, eating and watching television, but will otherwise be instructed to lie flat in bed. Bathing/hygiene will be performed in a wheelchair at a sink. The bathroom accessed using a wheelchair. Adherence to bed rest will be monitored by nursing staff and through daily analysis of accelerometry data. Post Intervention Assessments (Day 13) On the morning after completion of the 5-day bed rest phase (i.e. Day 13) participants will awake at 0700h in the CRF and remain in bed for assessment of muscle protein synthesis in trained and untrained control legs. A cannula will be inserted into a vein of both forearms for frequent blood sampling and a stable isotope tracer infusion. During the tracer infusion, muscle biopsies will be obtained from both trained and untrained legs before and after consumption of a milk protein drink, to assess muscle metabolism. Participants will then be transported by wheelchair for repeat bioelectrical impedance analysis, MRI and ultrasound scans to assess body/muscle composition. Leg strength will be reassessed in trained and untrained legs. A physiotherapist will perform a functional assessment of participants before they are discharged. Rehabilitation Training Participants will be given the opportunity to complete a 6-week rehabilitation programme, consisting of a progressive 3 x weekly leg resistance training with protein supplementation, designed to fully restore any loss in muscle mass and strength from short-term bed rest. Resistance training rehabilitation will not form a specific study objective, but muscle size and strength will be assessed to ensure restoration of any muscle decline from bed rest.

Official Title
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Exercise 'Prehabilitation': A Novel Intervention to Protect Against Disuse-induced Muscle Atrophy and Sarcopenia in the Old

Conditions
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Prehabilitation, Muscle Loss, Disuse Atrophy, Protein Metabolism, Sarcopenia

Intervention / Treatment
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* Other: Resistance exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males aged between 65-80 years No history of structured resistance training within 10 years prior to study participation. Generally good health as indicated by a thorough health questionnaire. A score of ≥9 points on the Short Physical Performance Battery to assess lower extremity function. Body Mass Index <30kg/m2 Exclusion Criteria: Coagulation disorders Myocardial infarction Artery/vein disease Hormone replacement therapy Other chronic/systemic illnesses (i.e. renal failure, chronic obstructive pulmonary disease, cancer). Undergone 2 or more muscle biopsies from each leg previously. Received a stable isotope infusion in the last 3 years prior to study enrollment.

Ages Eligible for Study
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Minimum Age: 65 Years
Maximum Age: 80 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: Basic Science
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Participants will be randomly allocated to one of two intervention groups. Due to the single-legged typed of resistance exercise, each subject will be its own control.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Single Exercise<br>Subjects allocated to this group will perform a single bout of one-legged resistance exercise. This bout will take place 1 day prior to the start of the bed rest. The resistance exercise will consist of 8 sets of leg extensions and 8 sets of leg curls. The non-exercising leg will serve as an internal control. The dominant leg will perform the exercise. | Other: Resistance exercise<br>* Single-legged resistance exercise<br>|
| Experimental: Multi Exercise<br>Subjects allocated to this group will perform 4 bouts of one-legged resistance exercise. These bouts will take place on alternate days the week leading up to the bed rest. Each resistance exercise bout will consist of 8 sets of leg extensions and 8 sets of leg curls. The non-exercising leg will serve as an internal control. The dominant leg will perform the exercise. | Other: Resistance exercise<br>* Single-legged resistance exercise<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Integrated myofibrillar protein synthesis rates | Myofibrillar protein synthesis rates will be measured during the prehabilitation and bed rest period in both the exercising and resting leg. | 2 years | 
| Muscle mass via MRI | Muscle volume in the quadriceps will be assessed before and after bed rest using magnetic resonance imaging techniques | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Muscle fibre properties | Via immunohistochemical staining procedures muscle fibre cross sectional area will be determined | 2 years | 
| Physical activity levels | Daily average time spent in sedentary, light, moderate or vigorous intensity activity using an accelerometer | 2 years | 
| Step-count | activity will be determined using accelerometry. Furthermore, step count will be Daily step-count assessed using a hip-worn pedometer | 2 years | 
| Plasma biomarkers of metabolic health | Blood markers - serum total cholesterol, serum high-density lipoprotein cholesterol, serum non-high-density lipoprotein cholesterol, total cholesterol, serum non-esterified fatty acids, serum triglycerides (units of measure for all - mmol/L) | 2 years | 
| Serum insulin | Via ELISA kits, resting insulin will be assessed using baseline plasma samples from before and after the bed rest period (pmol/l) | 2 years | 
| Intramuscular signaling via western blot | Western blots for phosphorylation of key anabolic and catabolic signaling proteins will be performed. | 2 years | 
| Gene expression | Search Results Web results Reverse transcription polymerase chain reaction (RT-PCR) will be performed to assess gene-expression of muscle anabolic and catabolic genes. | 2 years | 
| Dietary intake | Dietary intake will be assessed using 3-day weighed food diaries. | 2 years | 
| Body composition | Bioelectrical impedance analysis will be used to determine whole body fat and fat-free mass (units are % of total body mass for both fat and fat-free mass). | 2 years | 
| Leg strength | Estimated maximal leg strength will be determined for the leg extension and leg curl before and after the bed rest period | 2 years | 
| Height | measured using a stadiometer (cm) | 2 years | 
| Body weight | Measured using a digital weighing scale (kg) | 2 years | 
| Body Mass Index | Weight and height will be combined to report BMI in kg/m^2 | 2 years |