Effect of Lipopolysaccharide on Skeletal Muscle Functions

Study Overview
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Brief Summary
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The investigators aim to examine how the skeletal muscles of the human volunteers respond to experimental septic conditions to aid understanding of muscle wasting and its biology.. Six healthy men aged 18-30 will be randomly assigned to two metabolic study visits. On the first visit, while resting on a bed, they will have four cannulae inserted including one in the upper thigh, for blood sampling and the infusion of insulin, glucose and normal and tracer amino acids (which allow us to measure muscle protein metabolism). Subjects will receive either injection of purified bacterial product called lipopolysaccharide (LPS) to induce flu-like symptoms or normal saline according to randomization followed by a metabolic test to stimulate muscle synthesis and glucose transport. Three small samples of muscle will be obtained under local anaesthetic from the thigh to measure molecular events in muscle. By performing these measurements, the investigators will determine the consequences of LPS on muscle production and carbohydrate metabolism.

Detailed Description
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During sepsis, the ability of the body to prevent muscle wasting is impaired resulting in loss of skeletal muscle. In addition, skeletal muscle handling of carbohydrate becomes less efficient. These changes could result in delayed recovery, prolonged rehabilitation and in severe cases mortality of patients. It is still unclear how these changes occur in the human skeletal muscles but animal experiments suggest that protein molecules that are released during sepsis are responsible for these changes. Due to the biological differences between animals and humans in metabolic rate and stability, disease susceptibility and response to infection, simple translation of knowledge from animals to patients could be highly misleading. Therefore, we aim to examine how the skeletal muscles of the human volunteers respond to experimental septic conditions. Following medical screening, six healthy men aged 18-30 will have two metabolic study visits in a random manner. On the first visit, while resting on a bed, they will have four cannulae inserted including one in the upper thigh, for blood sampling and the infusion of insulin, glucose and normal and tracer amino acids (which allow us to measure muscle protein metabolism). Subjects will receive either injection of purified bacterial product called lipopolysaccharide (LPS) to induce flu-like symptoms or normal saline according to randomization followed by a metabolic test to stimulate muscle synthesis and glucose transport. Three small samples of muscle will be obtained under local anaesthetic from the thigh to measure molecular events in muscle. By performing these measurements, we will determine the consequences of LPS on muscle production and carbohydrate metabolism.

Official Title
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Impact & Time-Course of Effect of Intravenous Lipopolysaccharide Infusion on Skeletal Muscle Protein Turnover and Insulin Sensitivity in Healthy Human Volunteers

Conditions
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Sepsis

Intervention / Treatment
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* Biological: Lipopolysaccharide infusion
* Other: saline


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male 18-30yrs Exclusion Criteria: Clotting disorders Metabolic disease e.g. diabetes, thyroid dysfunction Inflammatory conditions e.g. Crohn's Disease Tobacco smoker Cardiac or Renal pathology Respiratory problems including Asthma Active infectious conditions

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: Basic Science
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Lipopolysaccharide infusion<br>Lipopolysaccharide infusion; dosage 4ng/kg body weight | Biological: Lipopolysaccharide infusion<br>* Lipopolysaccharide 4 nanogram/kg body weight<br>* Other names: Endotoxin;|
| Placebo Comparator: saline<br>0.9% saline infusion | Other: saline<br> <br> * Other names: 0.9% saline infusion;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Skeletal Muscle Protein Turnover (muscle tracer incorporation) | incorporation of 1,2 13C-leucine into muscle tissue | 4 hr following LPS infusion | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Whole body glucose disposal | Glucose uptake calculated from glucose infused to maintain euglycemia during a constant insulin infusion. | 4 h Glucose insulin clamp | 
| Expression of genes that regulate muscle protein balance and insulin signalling | Changes in mRNA levels of several transcripts associated with metabolism or muscle growth in skeletal muscle | 4 h following LPS infusion | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Sepsis, Inflammation, Lipopolysaccharide, Muscle protein turnover, Insulin resistance