Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy ResPONse CONTROl <s> Overtraining syndrome (OTS) is a condition wherein an athlete is training excessively, yet performance deteriorates. This is usually accompanied by mood/behavior changes and a variety of biochemical and physiological alterations. Presently, there is no global hypothesis to account for OTS. The present paper will attempt to provide a unifying paradigm that will integrate previous research under the rubric of the cytokine hypothesis of overtraining. It is argued that high volume/intensity training, with insufficient rest, will produce muscle and/or skeletal and/or joint trauma. Circulating monocytes are then activated by injury-related cytokines, and in turn produce large quantities of proinflammatory IL-1beta, and/or IL-6, and/or TNF-alpha, producing systemic inflammation. Elevated circulating cytokines then co-ordinate the whole-body response by: a) communicating with the CNS and inducing a set of behaviors referred to as "sickness" behavior, which involves mood and behavior changes that support resolution of systemic inflammation: b) adjusting liver function, to support the up-regulation of gluconeogenesis, as well as de novo synthesis of acute phase proteins, and a concomitant hypercatabolic state; and c) impacting on immune function. Theoretically, OTS is viewed as the third stage of Selye's general adaptation syndrome, with the focus being on recovery/survival, and not adaptation, and is deemed to be "protective," occurring in response to excessive physical/physiological stress. Recommendations are made for potential markers of OTS, based on a systemic inflammatory condition. <s> BIB001 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy ResPONse CONTROl <s> AbstractCytokines are soluble glycoproteins that are produced by and mediate communication between and within immune and nonimmune cells, organs and organ systems throughout the body. Pro- and anti-inflammatory mediators constitute the inflammatory cytokines, which are modulated by various stimuli, including physical activity, trauma and infection. Physical activity affects local and systemic cytokine production at different levels, often exhibiting striking similarity to the cytokine response to trauma and infection.The present review examines the cytokine response to short term exercise stress, with an emphasis on the balance between pro- and anti-inflammatory mechanisms and modulation of both innate and specific immune parameters through cytokine regulation. The effects of long term exercise on cytokine responses and the possible impact on various facets of the immune system are also discussed, with reference to both cross-sectional and longitudinal studies of exercise training. Finally, the validity of using exercise as a model for trauma and sepsis is scrutinised in the light of physiological changes, symptomatology and outcome, and limitations of the model are addressed.Further studies, examining the effect of exercise, trauma and infection on novel cytokines and cytokine systems are needed to elucidate the significance of cytokine regulation by physical activity and, more importantly, to clarify the health implications of short and long term physical activity with respect to overall immune function and resistance to infection. <s> BIB002 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy ResPONse CONTROl <s> Regular exercise offers protection against all-cause mortality, primarily by protection against cardiovascular disease and Type 2 diabetes mellitus. The latter disorders have been associated with chronic low-grade systemic inflammation reflected by a two- to threefold elevated level of several cytokines. Adipose tissue contributes to the production of TNF-α, which is reflected by elevated levels of soluble TNF-α receptors, IL-6, IL-1 receptor antagonist, and C-reactive protein. We suggest that TNF-α rather than IL-6 is the driver behind insulin resistance and dyslipidemia and that IL-6 is a marker of the metabolic syndrome, rather than a cause. During exercise, IL-6 is produced by muscle fibers via a TNF-independent pathway. IL-6 stimulates the appearance in the circulation of other anti-inflammatory cytokines such as IL-1ra and IL-10 and inhibits the production of the proinflammatory cytokine TNF-α. In addition, IL-6 enhances lipid turnover, stimulating lipolysis as well as fat oxidation. We suggest that regular exercise induces suppression of TNF-α and thereby offers protection against TNF-α-induced insulin resistance. Recently, IL-6 was introduced as the first myokine, defined as a cytokine that is produced and released by contracting skeletal muscle fibers, exerting its effects in other organs of the body. Here we suggest that myokines may be involved in mediating the health-beneficial effects of exercise and that these in particular are involved in the protection against chronic diseases associated with low-grade inflammation such as diabetes and cardiovascular diseases. <s> BIB003 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> INflAmmATORy ResPONse CONTROl <s> Skeletal muscle is comprised of heterogeneous muscle fibers that differ in their physiological and metabolic parameters. It is this diversity that enables different muscle groups to provide a variety of functional properties. In response to environmental demands, skeletal muscle remodels by activating signaling pathways to reprogram gene expression to sustain muscle performance. Studies have been performed using exercise, electrical stimulation, transgenic animal models, disease states, and microgravity to show genetic alterations and transitions of muscle fibers in response to functional demands. Various components of calcium-dependent signaling pathways and multiple transcription factors, coactivators and corepressors have been shown to be involved in skeletal muscle remodeling. Understanding the mechanisms involved in modulating skeletal muscle phenotypes can potentiate the development of new therapeutic measures to ameliorate muscular diseases. <s> BIB004
A group of glycoproteins collectively called as cytokines are the responsible for coordination, amplification and regulation of the magnitude and duration of inflammatory events and, consequently, their effects BIB001 BIB002 . Cytokines are produced and released mainly by immune system cells, besides the active muscles and by a variety of tissues such as adipose tissue and endothelial cells BIB003 . Cytokines may have pro-inflammatory (IL-1β, TNF-a, IL-6), anti-inflammatory activity (IL-6, IL-10, IL-4, IL-5, IL-13 and IL-1ra) or even behave as inflammatory modulators (IL-6), regulating, besides inflammation, the activation of the energy pathways to support this process BIB003 . Cytokines are responsible for intercellular, inter-organ and intersystem communication BIB002 , allowing different systems to be informed about the injury in a specific tissue. They enable the influx of neutrophils, monocytes, lymphocytes and other cells that participate in tissue regeneration and cleaning, indirectly indicating the increased permeability of blood vessels and hence an increase in the transition of fluids and proteins between intra and extra-cellular spaces BIB002 . Tissue trauma in muscle tissue induced by exercise can signalize through the action of cytokines other tissues such as brain, liver, kidney, endothelium, immune cells and endocrine system, especially the hypothalamic-pituitary-adrenal and hypothalamic-pituitary-gonads axes to promote the combined action required to cure / repair the injury BIB001 . Thus, the balance between pro-and antiinflammatory actions of different cytokines contributes to the complete recovery of the injured tissue BIB001 BIB004 .