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      Treadmill Slope Modulates Inflammation, Fiber Type Composition, Androgen, and Glucocorticoid Receptors in the Skeletal Muscle of Overtrained Mice

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          Abstract

          Overtraining (OT) may be defined as an imbalance between excessive training and adequate recovery period. Recently, a downhill running-based overtraining (OTR/down) protocol induced the nonfunctional overreaching state, which is defined as a performance decrement that may be associated with psychological and hormonal disruptions and promoted intramuscular and systemic inflammation. To discriminate the eccentric contraction effects on interleukin 1beta (IL-1β), IL-6, IL-10, IL-15, and SOCS-3, we compared the release of these cytokines in OTR/down with other two OT protocols with the same external load (i.e., the product between training intensity and volume), but performed in uphill (OTR/up) and without inclination (OTR). Also, we evaluated the effects of these OT models on the muscle morphology and fiber type composition, serum levels of fatigue markers and corticosterone, as well as androgen receptor (AR) and glucocorticoid receptor (GR) expressions. For extensor digitorum longus (EDL), OTR/down and OTR groups increased the cytokines and exhibited micro-injuries with polymorphonuclear infiltration. While OTR/down group increased the cytokines in soleus muscle, OTR/up group only increased IL-6. All OT groups presented micro-injuries with polymorphonuclear infiltration. In serum, while OTR/down and OTR/up protocols increased IL-1β, IL-6, and tumor necrosis factor alpha, OTR group increased IL-1β, IL-6, IL-15, and corticosterone. The type II fibers in EDL and soleus, total and phosphorylated AR levels in soleus, and total GR levels in EDL and soleus were differentially modulated by the OT protocols. In summary, the proinflammatory cytokines were more sensitive for OTR/down than for OTR/up and OTR. Also, the specific treadmill inclination of each OT model influenced most of the other evaluated parameters.

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          Most cited references52

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          Prevention, diagnosis, and treatment of the overtraining syndrome: joint consensus statement of the European College of Sport Science and the American College of Sports Medicine.

          Successful training not only must involve overload but also must avoid the combination of excessive overload plus inadequate recovery. Athletes can experience short-term performance decrement without severe psychological or lasting other negative symptoms. This functional overreaching will eventually lead to an improvement in performance after recovery. When athletes do not sufficiently respect the balance between training and recovery, nonfunctional overreaching (NFOR) can occur. The distinction between NFOR and overtraining syndrome (OTS) is very difficult and will depend on the clinical outcome and exclusion diagnosis. The athlete will often show the same clinical, hormonal, and other signs and symptoms. A keyword in the recognition of OTS might be "prolonged maladaptation" not only of the athlete but also of several biological, neurochemical, and hormonal regulation mechanisms. It is generally thought that symptoms of OTS, such as fatigue, performance decline, and mood disturbances, are more severe than those of NFOR. However, there is no scientific evidence to either confirm or refute this suggestion. One approach to understanding the etiology of OTS involves the exclusion of organic diseases or infections and factors such as dietary caloric restriction (negative energy balance) and insufficient carbohydrate and/or protein intake, iron deficiency, magnesium deficiency, allergies, and others together with identification of initiating events or triggers. In this article, we provide the recent status of possible markers for the detection of OTS. Currently, several markers (hormones, performance tests, psychological tests, and biochemical and immune markers) are used, but none of them meet all the criteria to make their use generally accepted.
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            Interleukin-6 in acute exercise and training: what is the biological relevance?

            It is now recognized that contracting skeletal muscle may synthesize and release interleukin-6 (IL-6) into the interstitium as well as into the systemic circulation in response to a bout of exercise. Although several sources of IL-6 have been demonstrated, contracting muscles contributes to most of the IL-6 present in the circulation in response to exercise. The magnitude of the exercise-induced IL-6 response is dependent on intensity and especially duration of the exercise, while the mode of exercise has little effect. Several mechanisms may link muscle contractions to IL-6 synthesis: Changes in calcium homeostasis, impaired glucose availability, and increased formation of reactive oxygen species (ROS) are all capable of activating transcription factors known to regulate IL-6 synthesis. Via its effects on liver, adipose tissue, hypothalamic-pituitary-adrenal (HPA) axis and leukocytes, IL-6 may modulate the immunological and metabolic response to exercise. However, prolonged exercise involving a significant muscle mass in the contractile activity is necessary in order to produce a marked systemic IL-6 response. Furthermore, exercise training may reduce basal IL-6 production as well as the magnitude of the acute exercise IL-6 response by counteracting several potential stimuli of IL-6. Accordingly, a decreased plasma IL-6 concentration at rest as well as in response to exercise appears to characterize normal training adaptation.
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              Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress?

              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.
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                Author and article information

                Contributors
                URI : http://frontiersin.org/people/u/478548
                URI : http://frontiersin.org/people/u/437372
                URI : http://frontiersin.org/people/u/480212
                URI : http://frontiersin.org/people/u/443358
                URI : http://frontiersin.org/people/u/392432
                URI : http://frontiersin.org/people/u/328056
                URI : http://frontiersin.org/people/u/129632
                URI : http://frontiersin.org/people/u/353850
                Journal
                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                1664-3224
                25 October 2017
                2017
                : 8
                : 1378
                Affiliations
                [1] 1Postgraduate Program in Rehabilitation and Functional Performance, Ribeirão Preto Medical School, University of São Paulo (USP) , Ribeirão Preto, Brazil
                [2] 2Department of Physical Education, State University of São Paulo (UNESP) , Presidente Prudente, Brazil
                [3] 3Department of Clinical, Toxicological, and Bromatological Analysis, Faculty of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo (USP) , Ribeirão Preto, Brazil
                [4] 4Department of Physiology, Ribeirao Preto Medical School, University of São Paulo (USP) , Ribeirão Preto, Brazil
                [5] 5Laboratory of Molecular Biology of Exercise (LaBMEx), School of Applied Sciences, University of Campinas (UNICAMP) , Campinas, Brazil
                [6] 6Department of Pharmaceutical Business and Administrative Sciences, MCPHS University , Boston, MA, United States
                [7] 7Department of Surgery, Brigham and Women’s Hospital, Harvard Medical School , Boston, MA, United States
                [8] 8School of Physical Education and Sport of Ribeirão Preto, University of São Paulo (USP) , Ribeirão Preto, Brazil
                Author notes

                Edited by: Fulvio D’Acquisto, Queen Mary University of London, United Kingdom

                Reviewed by: Giulia Maria Camerino, Università degli studi di Bari Aldo Moro, Italy; Donato A Rivas, Tufts University, United States

                *Correspondence: Adelino S. R. da Silva, adelinosanchez@ 123456usp.br

                Specialty section: This article was submitted to Inflammation, a section of the journal Frontiers in Immunology

                Article
                10.3389/fimmu.2017.01378
                5669301
                29163473
                425d2fd0-6d77-43c0-a5ed-86e9381d43a7
                Copyright © 2017 da Rocha, Pereira, Teixeira, Pinto, Frantz, Elias, Lira, Pauli, Cintra, Ropelle, de Moura, Mekary, de Freitas and da Silva.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 07 May 2017
                : 06 October 2017
                Page count
                Figures: 8, Tables: 1, Equations: 0, References: 64, Pages: 14, Words: 7794
                Funding
                Funded by: Fundação de Amparo à Pesquisa do Estado de São Paulo 10.13039/501100001807
                Award ID: 2013/19985-7, 2013/20591-3
                Categories
                Immunology
                Original Research

                Immunology
                overtraining,inflammatory signaling,skeletal muscle fiber type composition,androgen and glucocorticoid receptors

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