Post-operative Electrical Muscle Stimulation to Stimulate Muscle Protein Synthesis in Humans

Study Overview
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Brief Summary
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Skeletal muscle accounts for approximately 45-55% of total body mass in healthy adults and plays a pivotal role in whole-body metabolic health, locomotion and physical independence. Undesirable loss of skeletal muscle mass (atrophy) is, however, a common feature of many communicable and non-communicable diseases including ageing, bed-rest/immobilisation, cancer and physical inactivity. As such, the design of optimal strategies (e.g., different types of exercise) to offset these detrimental losses of muscle is a focus for both researchers and clinicians. One situation where losses of muscle mass occur very quickly (i.e., within a few days) is after surgery. However, at this time, most people (especially if they have had major abdominal or lower-limb surgery) are not able to perform exercise and as such a different strategy to maintain muscle mass needs to be found. It has been shown that electrical stimulation of the leg muscles can maintain muscle mass and function in patients after surgery. It is not however yet known, what the optimal electrical stimulation regime is to preserve muscle mass during situations of disuse. This study aims to examine the impact of three different electrical stimulation protocols on muscle building processes in individuals age-matched to those most commonly presenting for major abdominal surgery. This information will then be used in a clinical trial of surgical patients to see if it can preserve their muscle mass and function in the post-operative period.

Detailed Description
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The contraction of skeletal muscles depends on the regulation of the nervous system and the coordination of neuromuscular function. The smallest motor nervous system associated with muscle contraction is the motor unit (MU), which consists of an efferent motor neuron and all of the muscle fibres it innervates. Muscle tissue also undergoes adaptive alternations in response to external stimuli, such as the gradual decline in muscle mass and strength during ageing, and atrophy following muscle disuse. A number of studies have demonstrated that different types of voluntary movements, such as resistance exercise training (RET), can prevent or attenuate such alternations to a certain extent via increases in muscle protein synthesis (MPS). However, certain situations such as post-operative bed rest render RET interventions an unachievable option. Neuromuscular electrical stimulation (NMES) can be applied as a surrogate; acting to evoke involuntary contraction of the target muscles via electrical current applied to the muscle belly. Although NMES stimulation has been widely tested in the intensive care environment, results have shown variable efficacy- perhaps due to the multi-organ failure and associated catabolic systemic environment encountered by the majority of these patients. It has recently shown that in post-operative abdominal surgery patients, 5-days of NMES, performed at frequency of 30 Hz in a 1 second on, 1 second off contraction pattern, can mitigate losses in muscle mass and function. However, this study 'borrowed' a protocol from previous intensive care literature, and as such may not be optimal with regards to frequency or contraction pattern. Given that this protocol was highly tolerated by patients in a previous study (i.e., based on 30 min of daily NMES, patients in this study said they would tolerate it for 45 to 240 (mean 90) min), it is plausible that higher frequency NMES ( 100 Hz), enabling greater force production may be both viable and result in further mitigation of muscle mass and function losses. It has also been demonstrated that the time muscle is under loaded tension during RET may be an important modulator of MPS and subsequent gains in muscle mass. Therefore, increasing the contraction relative to relaxation time during NMES (e.g., 3 seconds on, 1 second off) may be another feasible and perhaps more beneficial strategy to reduce muscle mass losses in populations where an increase in frequency may not be possible or tolerable. Knowing that muscle maintenance is based on a dynamic equilibrium between MPS and muscle protein breakdown, the impact of different NMES protocols on MPS, associated cell signalling, and nutrient delivery pathways needs to be explored so that an optimal intervention can be tested in clinical settings associated with disuse atrophy. To date, no previous studies have compared differing frequencies of NMES on the muscle metabolic responses in older adults, nor the effect of differing NMES-induced contraction patterns.

Official Title
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Optimisation of Post-operative Electrical Muscle Stimulation (PoEMS) to Stimulate Muscle Protein Synthesis in Humans

Conditions
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Skeletal Muscle Atrophy

Intervention / Treatment
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* Other: Neuromuscular electrical stimulation (NMES/0


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Aged 60-85 y Willing and able to give informed consent for participation in the study Exclusion Criteria: BMI <18.5 or >35kg/m2 Participation in any regular, structured RET within the past 6 months Musculoskeletal disorders Severe respiratory disease: COPD Pulmonary hypertension Neurological disorders: Cerebrovascular disease (cerebral haemorrhage; cerebral ischemic stroke) Intracranial space-occupying lesion Epilepsy Metabolic disease: Hyper and hypo parathyroidism Untreated hyper and hypothyroidism Cushing's disease Type 1 or 2 diabetes Active cardiovascular problems: Uncontrolled hypertension (BP>160/100mmHg) Recent cardiac event Heart failure (Class III/IV) Arrhythmia Angina Blood clotting disorders Active inflammatory bowel or renal disease Recent malignancy (in previous 3 years) Recent steroid treatment within 6 months or hormone replacement therapy Family history of early (<55yrs) death from cardiovascular disease Known sensitivity to Sonovue

Ages Eligible for Study
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Minimum Age: 60 Years
Maximum Age: 85 Years

Sexes Eligible for Study
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All

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: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: 30Hz (low-intensity)<br>Volunteers receive 30 mins of neuromuscular electrical stimulation at 30Hz with a contraction pattern of 1 second on and 1 second off | Other: Neuromuscular electrical stimulation (NMES/0<br>* NMES will be applied for 30 min and will be delivered using an approved, CE-marked device (Premier Combo Plus, Med-Fit Ltd, UK) using two large (7.5 × 13 cm) electrodes placed proximally and distally over the lateral quadriceps. The set protocols will be pre-programmed into to the device and the amplitude value will match the setting that was determined during a familiarisation visit<br>|
| Experimental: 100Hz (higher-intensity)<br>Volunteers receive 30 mins of neuromuscular electrical stimulation at 100Hz with a contraction pattern of 1 second on and 1 second off | Other: Neuromuscular electrical stimulation (NMES/0<br>* NMES will be applied for 30 min and will be delivered using an approved, CE-marked device (Premier Combo Plus, Med-Fit Ltd, UK) using two large (7.5 × 13 cm) electrodes placed proximally and distally over the lateral quadriceps. The set protocols will be pre-programmed into to the device and the amplitude value will match the setting that was determined during a familiarisation visit<br>|
| Experimental: 30Hz (low-intensity, 3:1)<br>Volunteers receive 30 mins of neuromuscular electrical stimulation at 30Hz with a contraction pattern of 3 seconds on and 1 second off | Other: Neuromuscular electrical stimulation (NMES/0<br>* NMES will be applied for 30 min and will be delivered using an approved, CE-marked device (Premier Combo Plus, Med-Fit Ltd, UK) using two large (7.5 × 13 cm) electrodes placed proximally and distally over the lateral quadriceps. The set protocols will be pre-programmed into to the device and the amplitude value will match the setting that was determined during a familiarisation visit<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skeletal Muscle Protein Synthesis | A primed continuous infusion of a stable isotope tracer (1,2 13C2] leucine) will be initiated (Prime: 0.7 mg/kg; Constant: 1.0 mg/kg/h) at time 0h. After 60 min of stable isotope infusion, a single muscle biopsy will be taken from one leg. Another biopsy from the same leg will be taken 120 min later, and a third 240 min after the second to provide rates of muscle protein synthesis in the rested condition and in response to NMES, respectively. The fractional synthetic rate (FSR) of the myofibrillar fraction was calculated from the incorporation of [1,2 13C2] leucine, using venous plasma labelling between muscle biopsies to represent the immediate precursor for protein synthesis. This will give a rate (%/hour) of muscle protein synthesis. | 4 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skeletal Muscle Anabolic Signalling | Total and phosphorylation of established anabolic proteins in human skeletal muscle will be quantified via Western Blotting. | 4 hours | 
| Skeletal Muscle Blood Flow | Contrast enhanced ultrasound (CEUS) measurements will be made 60 min before the NMES and 30 min after. To achieve this, a custom-made probe holder will be placed on the leg to be stimulated at the start of the study. For each measurement, Sonovue will be infused at 2ml/min for 1 minute and then 1ml/min for 30 sec to achieve systemic steady state, with a continued infusion at 1ml/min for the duration of the measurements. Each measurement will include three, 30-second capture-flash cycles which will form a Sonovue replenishment curve for the portion of vastus lateralis muscle (VL) under the probe. blood flow will be calculated by measuring the reperfusion rate of the microbubbles in the muscle microvasculature following destruction with a high mechanical index flash, given the infusion of contrast is continuous. | Baseline and 30 minutes post neuromuscular stimulation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Muscle, Protein Synthesis, Neuromuscular electrical stimulation, Muscle blood flow