Effect of Lipopolysaccharide on Skeletal Muscle Functions

Overview

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.

Full Title of Study: “Impact & Time-Course of Effect of Intravenous Lipopolysaccharide Infusion on Skeletal Muscle Protein Turnover and Insulin Sensitivity in Healthy Human Volunteers”

Study Type

  • Study Type: Interventional
  • Study Design
    • Allocation: Randomized
    • Intervention Model: Crossover Assignment
    • Primary Purpose: Basic Science
    • Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
  • Study Primary Completion Date: December 2012

Detailed Description

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.

Interventions

  • Biological: Lipopolysaccharide infusion
    • Lipopolysaccharide 4 nanogram/kg body weight
  • Other: saline

Arms, Groups and Cohorts

  • Experimental: Lipopolysaccharide infusion
    • Lipopolysaccharide infusion; dosage 4ng/kg body weight
  • Placebo Comparator: saline
    • 0.9% saline infusion

Clinical Trial Outcome Measures

Primary Measures

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

Secondary Measures

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

Participating in This Clinical Trial

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

Gender Eligibility: Male

Minimum Age: 18 Years

Maximum Age: 30 Years

Are Healthy Volunteers Accepted: Accepts Healthy Volunteers

Investigator Details

  • Lead Sponsor
    • University of Nottingham
  • Provider of Information About this Clinical Study
    • Principal Investigator: Elizabeth Simpson, Senior Research Fellow – University of Nottingham
  • Overall Official(s)
    • Paul L Greenhaff, PhD, Principal Investigator, Professor of Muscle Metabolism, University of Nottingham

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