Skeletal Muscle Wasting and Insulin Resistance Following Surgical Stress

Does Surgical Stress Impair Skeletal Muscle Protein and Carbohydrate Metabolism?

Background: Skeletal muscle wasting or decrease in muscle mass occurs as a result of alteration in the body's mechanisms to make or break muscle protein. In animal models, the pathway termed as 'ubiquitin-proteasome pathway' (UPP) is primarily responsible for the regulation of skeletal muscle protein loss in wasting conditions and during infection(sepsis). Skeletal muscle wasting is noticed in patients having major surgery due to the inflammatory reaction triggered by special group of proteins called cytokines (inflammatory proteins), resulting in reduced muscle strength, impaired capacity to fight infections, change in bowel function, increased clinical complications and prolonged recovery. Major surgery also leads to decreased sensitivity to hormone known as insulin, resulting in 'diabeteslike'state.

We hypothesize that susceptibility of patients undergoing major abdominal surgery, to skeletal muscle wasting and insulin resistance, is determined by stress response to surgery over time, leading to changes in the pathways that make or break muscle protein, namely the Akt/Foxo signalling and UPP. Therefore, the aim of this study is to establish the underlying mechanisms of skeletal muscle wasting and insulin resistance in patients undergoing major abdominal surgery.

Experimental plan Fifteen adult patients undergoing major open elective abdominal surgery will be included in this nonrandomized study.

Objectives:

1. To study the expression proteins and metabolites involved in UPP mediated protein degradation, in blood and muscle biopsy samples.
2. To correlate the effects of surgery on the release of bacteria in blood from the bowel.

The analysis of the samples will include the following techniques, namely, RTPCR, ELISA, western blotting and metabolomics.

Establishing the association between these signaling mechanisms and expression of the individual proteins secondary to inflammation following surgery and infection would enable application of suitable therapeutic strategies that could reduce the inflammatory response to benefit all patients undergoing surgery.

Inclusion Criteria:

• All adult patients undergoing major open elective gastrointestinal surgery lasting 3 hours or more will be eligible for the study.

Exclusion Criteria:

• Patients who are:

  1. undergoing emergency surgery
  2. suffering from chronic illness, (e.g. diabetes) or other debilitating diseases
  3. on long term anti-inflammatory drugs, (e.g. NSAIDS, Steroids, immunosuppressant)
  4. on long term antibiotics
  5. on statins
  6. on full therapeutic dose of anticoagulants, or aspirin > 325 mg/day, clopidogrel > 75 mg/day
  7. suffering from bleeding diathesis
  8. unable to give consent
  9. pregnant or breastfeeding