Preventing Bed-rest Induced Muscle Loss in the Elderly
Condition: Muscle Loss; Disuse Atrophy; Protein Metabolism; Prehabilitation; Sarcopenia
MeSH terms: Muscular Disorders, Atrophic; Sarcopenia; Atrophy
Study type: Interventional

Summary: 
      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: 
      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:

        1. 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.

        2. Lower-limb function: The short physical performance battery (SPPB) test will be used.

        3. Body composition: bioelectrical impedance analysis will be used to determine
           fat/fat-free mass on a whole-body and anatomical regional basis (CRF nurse).

        4. Muscle size/architecture: The thickness of the thigh muscles will be determined via
           non-invasive ultrasound imaging.

        5. Leg strength and muscle activation: Estimated maximal leg strength will be measured
           firstly on a standard knee extension exercise machine.

        6. 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.

        7. Participants will be fitted with an accelerometer and pedometer to asses daily activity
           levels.

        8. 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.
    

Intervention name(s): Resistance exercise
Intervention type(s): Other
Intervention description(s): Single-legged resistance exercise
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention 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)
Primary purpose: Basic Science