Studies of glutamine metabolism in skeletal muscle and other tissues

Cells of the immune system, both resting and stimulated, utilize glutamine at a high rate (see Ardawi 1983 and Newsholme et al 1985). Skeletal muscle is considered to be an important source of glutamine for cells of the immune system (see Newsholme and Parry-Billings 1990). It is proposed that the process of glutamine release from skeletal muscle is the flux-generating step for the pathway of glutamine utilization by cells of the immune system, and that, control of glutamine release from skeletal muscle influences the rate of glutamine utilization by cells of the immune sytem, and hence the function of these cells.
Studies using an in vitro skeletal muscle (soleus) preparation, identifying factors/conditions (e.g. branched chain amino acids, dexamethasone and hyperthyroidism) that modify both the rate of glutamine release from muscle and muscle glutamine concentration, illustrated that glutamine release from muscle is independent of the intracellular glutamine concentration (Parry-Billings 1989). However, the rate of glutamine release from muscle over time was non-linear, which may have lead to misinterpretation of the results reported by Parry- Billings (1989). Investigation of the linearity of the rate of glutamine release from soleus muscle over time, in the present study, using the in vitro muscle preparation, has shown that non-linearity of the rate of glutamine release is due to the presence of an artefact in the muscle incubation medium, rather than the process of muscle glutamine release.
With the "correction" of the linearity for muscle glutamine release, a reinvestigation of the effect(s) of factors (e.g. branched chain amino acids) on the rate of glutamine release from muscle (soleus and extensor digitorum longus) and muscle glutamine concentration verified that the process of glutamine release from muscle is independent of the intracellular glutamine concentration. The changes in the concentration of glutamine in muscle caused by these factors suggests that they may affect the process of muscle glutamine synthesis. Quantitative analysis of muscle glutamine release and concentration data plus a study of the effects of factors on the maximal activity of muscle glutamine synthetase confirmed this.
Results of the study on the effect(s) of factors on muscle glutamine synthesis, release, and concentration are discussed in relation to a systematic approach used for a study of the control of metabolic pathways (see Newsholme and Crabtree 1979) and are found to be consistent with the predictions made using this systematic approach.
The possibility that other tissues, namely rat adipose tissue and immune cells of the rat, are able to provide glutamine, was investigated by determining whether these tissues possess glutamine synthetase activity and thus synthesize glutamine. The present study indicates that, although rat adipose tissue possesses a maximal glutamine synthetase activity that is approximately 6-7 times greater than that of muscle, on a whole body (200g rat) basis, rat adipose tissue may not be a significant contributor of glutamine. In contrast, a study by Frayn et al (1991) suggests that human adipose tissue may be a significant contributor of glutamine. For cells of the immune system, the present study indicates that immune cells possess glutamine synthetase activity and thus can synthesize glutamine. This ability to synthesize glutamine may be of physiological significance since it is suggested that glutamine synthetase in cells of the immune system may provide enough glutamine to maintain some immune cell function during conditions, for example following surgery, injury and during sepsis, in which the plasma glutamine concentration is decreased.