Physical exercise, inflammatory process and adaptive condition: an overview <s> PRO-INflAmmATORy CyTOKINes <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> PRO-INflAmmATORy CyTOKINes <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> PRO-INflAmmATORy CyTOKINes <s> An athlete who trains intensely, yet consistently underperforms, ::: is considered to be suffering from overtraining syndrome ::: (OTS). OTS is a complex state that involves a large variety ::: of signs and symptoms. Symptoms include changes in mood ::: or behaviour, decreases or increases in concentration of different ::: blood molecules, and alterations in immune function. Although ::: several hypotheses have been proposed, each only explains a selective ::: aspect of OTS. Presently, the sole agreement is that OTS ::: is associated with excessive training and insufficient rest and ::: recovery. The hypothesis proposed in this paper suggests that ::: excessive training/competing causes repetitive tissue trauma, either ::: to muscle and/or connective tissue and/or to bony structures, ::: and that this results in chronic inflammation. It is further ::: proposed that traumatized tissue synthesizes a group of inflammatory ::: molecules, cytokines. Cytokines have been shown to coordinate ::: the different systems of the body to promote recovery. ::: Suggestions are made to detect, prevent, and rehabilitate the ::: overtrained athlete. <s> BIB003 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> PRO-INflAmmATORy CyTOKINes <s> Modified muscle use or injury can produce a stereotypic inflammatory response in which neutrophils rapidly invade, followed by macrophages. This inflammatory response coincides with muscle repair, regeneration, and growth, which involve activation and proliferation of satellite cells, followed by their terminal differentiation. Recent investigations have begun to explore the relationship between inflammatory cell functions and skeletal muscle injury and repair by using genetically modified animal models, antibody depletions of specific inflammatory cell populations, or expression profiling of inflamed muscle after injury. These studies have contributed to a complex picture in which inflammatory cells promote both injury and repair, through the combined actions of free radicals, growth factors, and chemokines. In this review, recent discoveries concerning the interactions between skeletal muscle and inflammatory cells are presented. New findings clearly show a role for neutrophils in promoting muscle damage soon after muscle injury or modified use. No direct evidence is yet available to show that neutrophils play a beneficial role in muscle repair or regeneration. Macrophages have also been shown capable of promoting muscle damage in vivo and in vitro through the release of free radicals, although other findings indicate that they may also play a role in muscle repair and regeneration through growth factors and cytokine-mediated signaling. However, this role for macrophages in muscle regeneration is still not definitive; other cells present in muscle can also produce the potentially regenerative factors, and it remains to be proven whether macrophage-derived factors are essential for muscle repair or regeneration in vivo. New evidence also shows that muscle cells can release positive and negative regulators of inflammatory cell invasion, and thereby play an active role in modulating the inflammatory process. In particular, muscle-derived nitric oxide can inhibit inflammatory cell invasion of healthy muscle and protect muscle from lysis by inflammatory cells in vivo and in vitro. On the other hand, muscle-derived cytokines can signal for inflammatory cell invasion, at least in vitro. The immediate challenge for advancing our current understanding of the relationships between muscle and inflammatory cells during muscle injury and repair is to place what has been learned in vitro into the complex and dynamic in vivo environment. <s> BIB004 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> PRO-INflAmmATORy CyTOKINes <s> Insulin and TNF-α exert opposing effects on skeletal muscle protein synthesis that are mediated in part by the rapamycin-sensitive mammalian target of rapamycin (mTOR) pathway and the PD-98059-sensitive, extracellular signal-regulated kinase (ERK)1/2 pathway. The present study examined the separate and combined effects of insulin (INS), TNF, PD-98059, or dnMEK1 adenovirus on the translational control of protein synthesis in C2C12 myotubes. Cultures were treated with INS, TNF, PD-98059, dnMEK1, or a combination of INS + TNF with PD-98059 or dnMEK1. INS stimulated protein synthesis, enhanced eIF4E·eIF4G association, and eIF4G phosphorylation and repressed eIF4E·4E-BP1 association vs. control. INS also promoted phosphorylation of ERK1/2, S6K1, and 4E-BP1 and dephosphorylation of eIF4E. TNF alone did not have an effect on protein synthesis (vs. control), eIF4E·eIF4G association, or the phosphorylation of eIF4G, S6K1, or 4E-BP1, although it transiently increased ERK1/2 and eIF4E phosphorylation. When myotubes ... <s> BIB005 </s> Physical exercise, inflammatory process and adaptive condition: an overview <s> PRO-INflAmmATORy CyTOKINes <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> BIB006
The main pro-inflammatory cytokines are Interleukin-1b (IL-1β) and Tumor Necrosis Factor-a (TNF-a). They are considered "alarm cytokines", since they are stimulated by events directly related to tissue injury, e.g., some intramuscular chemical mediators such as histamine, bradykinin, prostaglandins, leukotrienes and ROS BIB001 BIB006 . IL-1β and TNF-a are produced by monocytes, macrophages, neutrophils, endothelial cells and smooth and skeletal muscle cells. They play the role of enhancing the migration of monocytes and neutrophils into the inflammation site BIB002 . This signaling is further reinforced both by inducing the secretion of other chemotactic cytokines, particularly interleukin 8 (IL-8), and by inducing the synthesis of cell adhesion molecules (selectins, integrins) BIB004 , which promote the adhesion and subsequent infiltration of inflammatory cells into the injured tissue 3,20, which is a phenomenon characterized by chemotaxis, followed by diapedesis. IL-1β and TNF-a also have receptors in the hypothalamus. This interaction causes an increase in the synthesis of prostaglandins, which cause fever. They may also induce behavioral changes such as reduced appetite and thirst, decreased libido, depression and mood changes BIB003 . IL-1β and TNF-a induce the activation of hypothalamic-pituitaryadrenal axis and sympathetic nucleus, resulting in high plasma concentrations of stress hormones cortisol and catecholamines BIB001 . This physiological condition triggered by these cytokines is known as Sickness Behavior BIB002 . IL-1β and TNF-a also have receptors in liver, which binding indicates the synthesis of some acute phase proteins 3 (Picture 3). These cytokines also signal the increase in the production of Interleukin 6 (IL-6) by monocytes, macrophages, endothelial cells, epithelial cells, fibroblasts and skeletal muscle cells BIB002 , which may also signal, when produced in high amounts, proteolysis of the skeletal muscle tissue and inhibition of anabolism pathways BIB005 .