||The conditions and mechanisms that produce decrements in exercise performance have been an important area of research for decades. However, the sensation of fatigue that may persist for hours or days after exercise has received less attention. This long-lasting fatigue sensation is common in clinical populations. In chronic fatigue syndrome (CFS), moderate physical activity can produce increased fatigue sensations that last for several days. A recent study of CFS patients demonstrated significant increases in fatigue and pain sensations that were closely related to gene expression changes in metabolite-detecting, adrenergic, and immune markers following 25 minutes of moderate, whole body exercise. This exercise stimulus did not produce long-lasting fatigue or changes in gene expression in healthy age and gender-matched controls. The graded exercise test (GXT) is commonly applied in CFS research. Although intense, the GXT rarely produces long-lasting fatigue in healthy individuals and its effect on CFS patients' postexertional fatigue is unclear. Thus, the goals of these studies were to examine gene expression and fatigue sensations in healthy, trained individuals during and after three different exercise stressors: a GXT, a 40k time trial in ambient conditions (AT), and the same time trial in adverse, hot conditions (HT). It was hypothesized that there would be larger changes in gene expression following both AT and HT, compared to GXT. The first study explored the differences in gene expression following GXT and AT. Following AT, there were larger decreases in metabolite-detecting mRNA, larger increases in adrenergic, immunologic, and serotonin mRNA as compared to GXT. Further, these gene expression changes were different from postexercise responses of CFS patients. The goal of the second study was to add an additional stressor to the 40k time trial - heat. Because TRPV receptors are sensitive to heat, it was thought that the heat stress would cause larger increases in TRPV mRNA. However, because exercise power was reduced during HT, there were no differences in gene expression between the two trials except that IL6 mRNA decreased significantly more following AT compared to HT. Collectively, these results show that gene expression in healthy individuals is affected by the intensity and length of the exercise. The decreases in metabolite-detecting mRNA are thought to be an attempt to restore homeostasis in the fatigue and pain detecting receptors. The fact that there was no difference between AT and HT suggests that heat is an additional metabolite that activates the metabolite-detecting receptors, helping to regulate the intensity of exercise and the amount of fatigue during exercise. Adrenergic receptors increased, possibly causing a decrease in blood flow following exercise and increasing the resting levels of metabolites and subsequently increasing the resting fatigue signal. The change in the ratio of serotonin/dopamine may also contribute to the increased fatigue sensation following exercise.