Nutritional, pharmacological and hormonal manipulation of muscle metabolism

Abstract

Sarcopenia and cachexia occur when there is a deficit between the rates of muscle protein synthesis and breakdown, such that a negative balance exists. In this thesis, the current literature regarding prevalence, pathophysiology and implications of muscle wasting is reviewed, and the following hypotheses are tested and discussed: 1) thalidomide, taken for 6 weeks, is superior to placebo in terms of weight gain in patients with oesophageal cancer and cachexia; 2) administration of high doses of insulin overcomes anabolic blunting in older human beings; and 3) the effect of a modest increase in blood insulin concentration upon suppression of leg protein breakdown is diminished in with ageing. The data generated from three separate studies reveals that only the last of these hypotheses is likely to be true; nevertheless data obtained from the other two studies also adds to the existing literature. Specifically, patients with end-stage oesophageal cancer do not tolerate 200 mg per day of thalidomide nor does it carry any benefit in terms of acquisition of lean tissue or other control of disease-related symptoms, whereas aggressive medical and dietary support results in weight gain, including lean body mass, in the same patient group. Healthy volunteer studies using high dose insulin to overcome anabolic blunting in ageing were hampered by insufficient plasma AA concentrations; however blunted signalling responses remained despite equivocal rates of muscle protein turnover. Finally, the last study demonstrates a difference between young and older healthy volunteers in proteolytic responses to administration of modest doses of insulin. This thesis reveals that deficits in protein turnover which occur with ageing are two-fold: both blunted anabolism and accelerated insulin-driven catabolism. Whether these defects are due to “insulin resistance” of muscle metabolism or other age related phenomena is unclear, although attempts to overcome anabolic blunting with supraphysiological insulin availability were unsuccessful.