BASIC SCIENCES Reviews Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress? LUCILLE LAKIER SMITH Department of Health, Leisure, and Exercise Science, Appalachian State University, Boone, NC 28608 ABSTRACT SMITH, L. L. Cytokine hypothesis of overtraining: a physiological adaptation to excessive stress? Med. Sci. Sports Exerc., Vol. 32, No. 2, pp. 317���331, 2000. 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-1b, and/or IL-6, and/or TNF-a, 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. Key Words: INTERLEUKIN-1b, INTERLEUKIN-6, TUMOR NECROSIS FACTOR-a, ACUTE PHASE PROTEINS, TISSUE TRAUMA The purpose of this paper is to integrate available information pertaining to the overtraining syndrome (OTS) into one paradigm, which will be referred to as the cytokine hypothesis of overtraining. The following hy- pothesis is not presented as complete but is advanced in an attempt to focus future research efforts. For brevity, refer- ences are generally limited to review articles. The predom- inant focus of this paper will be on the systemic immune/ inflammatory response. These terms are frequently used interchangeably due to their extensive overlap for concise- ness, the term systemic inflammation will be used. Athletes train hard to optimize performance. Inherent in all training programs is the application of the progressive overload principle, which implies working beyond a com- fortable level in order to maximize athletic ability (26,27,45,91). Unfortunately, there is a fine line between improved performance and deterioration. When deteriora- tion in performance occurs in association with an arduous training schedule, it is referred to as overtraining, staleness, or burnout (66). The universal criterion associated with overtraining is a decrease in performance. However, not all aspects of per- formance are affected simultaneously nor are they impacted to the same degree, making prediction and/or interpretation confusing (66). It is also probable that other signs/symptoms typically associated with overtraining are evident before a deterioration in performance. These might include general- ized fatigue, depression, muscle and joint pain, and loss of appetite. However, it is the decline in performance fre- quently associated with an increased volume or load of training, that captures the attention of the athlete and coach. A large number of symptoms associated with overtraining, have been reported in the literature. Fry et. al. (27) have categorized these according to physiological performance, psychological/information processing, immunological, and biochemical parameters (see Table 1). However, there is no 0195-9131/00/3202-0317/0 MEDICINE & SCIENCE IN SPORTS & EXERCISE�� Copyright �� 2000 by the American College of Sports Medicine Submitted for publication January 1999. Accepted for publication November 1999. 317

universally agreed upon cluster of symptoms, and no cluster that would conveniently describe overtraining associated with a particular sport, or a particular type of training (such as aerobic versus anaerobic). For the most part, multiple symptoms may be present in a variety of combinations, and it is this cluster that is referred to as OTS. In contrast to overtraining, overreaching is a term used to imply a temporary deterioration in performance, reflecting the time period between the application of a exacting stimulus, and subsequent recovery and adaptation (26,27,45,48,91). In many training cycles, athletes experience this short-term overreach- ing as they increase intensity and/or volume but recover rapidly and improve or maintain performance. However, if the athlete continues to show a decrement in performance, even with an appropriate rest/regeneration period, this is most likely OTS. Since there is a continual risk of imbalance between training, competition, and recovery, OTS is a common prob- lem (48). Sixty percent of distance runners, 21% Australian swimmers, and more than 50% of soccer players, have been classified as overtrained. Presently the only known treat- ment is a decrease in training volume or in some instances complete rest. ���Once the athlete has developed the full- blown overtraining syndrome, he or she must rest com- pletely for anything between 6 to 12 weeks. . .��� (64). OTS is most likely also prevalent amongst recreational athletes, but has not received the same attention, for obvious reasons. Existing Theories of OTS A variety of hypotheses have been proposed to account for OTS. A number of these hypotheses remain viable, whereas others have gained minimal support. It will be suggested that many of these hypotheses represent pertinent aspects of the syndrome (45,47,89). For more extensive information, the reader is referred to excellent reviews (24,26,27,91). Several investigators have focused on the role of the hypothalamus, which results in activation of the autonomic nervous system (47), and the hypothalamic-pituitary-adre- nal axis (HPA), as well as involvement of the hypothalamic- pituitary-gonadal axis (HPG) this results in alterations of blood catecholamine, glucocorticoid, and testosterone levels TABLE 1. The major symptoms of overtraining as indicated by their prevalence in the literature (Reprinted from Fry, Morton, and Keast, 1991) Physiological performance Decreased performance Decreased serum ferritin Lowered TIBC Mineral depletion (Zn, Co, Al, Mn, Se, Cu, etc.) Increased urea concentrations Decreased serum ferritin Lowered TIBC Mineral depletion (Zn, Co, Al, Mn, Se, Cu, etc.) Increased urea concentrations Inability to meet previously attained performance standards or criteria Recovery prolonged Reduced toleration of loading Decreased muscular strength Decreased maximum work capacity Loss of coordination Decreased efficiency or decreased amplitude of movement Reappearance of mistakes already corrected Reduced capacity of differentiation and corrected Reduced capacity of differentiation and correcting technical faults Increased difference between lying and standing heart rate Abnormal T wave pattern in ECG Heart discomfort on slight exertion Changes in blood pressure Changes in heart rate at rest, exercise, and recovery Increased frequency of respiration Perfuse respiration Decreased body fat Increased oxygen consumption at submaximal workloads Increased ventilation and heart rate at submaximal workloads Shift of the lactate curve towards the X-axis Decreased evening postworkout weight Elevated basal metabolic rate Chronic fatigue Insomnia with and with night sweats Feels thirsty Anorexia nervosa Loss of appetite Bulimia Amenorrhea or oligomenorrhea Headaches Nausea Increased aches and pains Gastrointestinal disturbances Muscle soreness or tenderness Tendonostic complaints Periosteal complaints Muscle damage Elevated C-reactive Rhabdomyolysis Psychological/information processing Feelings of depression General apathy Decreased self-esteem or worsening feelings of self Emotional instability Difficulty in concentrating at work and training Sensitive to environmental and emotional stress Fear of competition Changes in personality Decreased ability to narrow concentration Increased internal and external distractibility Decreased capacity to deal with large amounts of information Gives up when going gets tough Immunological Increased susceptibility to and severity of illnesses, colds, and allergies Flu-like illness Unconfirmed glandular fever Minor scratches heal slowly Swelling of the lymph glands One-day colds Decreased functional activity of neutrophils Decreased total lymphocyte counts Reduced response to mitogens Increased blood eosinophil count Decreased proportion of null (non-T, non-B) lymphocytes Bacterial infection Reactivation of herpes viral infection Significant variations in CD4: CD8 lymphocytes TABLE 1.���Continued Biochemical Negative nitrogen balance Hypothalamic dysfunction Flat glucose tolerance curves Depressed muscle glycogen concentration Decreased bone mineral content Delayed menarche Decreased hemoglobin Decreased serum iron Decreased serum ferritin Lowered TIBC Mineral depletion (Zn, Co, Al, Mn, Se, Cu, etc.) Increased urea concentrations Elevated cortisol levels Elevated ketosteroids Low free testosterone Increased serum hormone binding globulin Decreased ratio to free testosterone to cortisol of more than 30% Increased uric acid production 318 Official Journal of the American College of Sports Medicine http://www.msse.org

(37). Undoubtedly, there is involvement of these systems in OTS, since heavy training represents an extreme stress, both physically and psychologically. However, it will be pro- posed that activation of these pathways may be a conse- quence, and not necessarily a primary initiator. There is substantial evidence demonstrating reductions in blood levels of the amino acid, glutamine, in OTS (36). Newsholme���s glutamine theory (62) proposes that reduced blood glutamine is responsible for the frequently observed impaired immune response and associated increased rate of infection seen in OTS, since glutamine is a primary fuel utilized by lymphocyte cells (69). Several investigators (44,62) have focused on the reduc- tion of circulating levels of the amino acid tryptophan (TRY). Reduced blood levels of TRY have been interpreted to reflect a greater uptake of this amino acid by the brain. Tryptophan is the precursor for synthesis of the brain neu- rotransmitter serotonin. Increased brain levels of serotonin are believed to result in mood and behavioral changes, such as inducing sleep and reducing appetite, both behaviors evident in OTS (44). The glycogen hypothesis of overtraining (14) has sug- gested that in response to dramatic increases in training load, certain athletes are unable to maintain sufficient intake of calories, in particular carbohydrate, and that this would result in reduced muscle glycogen, and could account in part, for feelings of fatigue and reduced performance. Al- though this phenomenon has been frequently observed in OTS, this theory has not been substantiated (89). Foster and Lehman (24) have suggested that the lack of day to day variation in training, could induce the OTS this is referred to as the monotony theory of overtraining. In- herent in this theory is the assumption that the psychological monotony can impact on physiological performance. An alternate interpretation for the involvement of monotony in OTS is that the daily ���sameness��� of intense training will impose excessive stress on the musculo-skeletal-joint sys- tem, thus making the athlete more prone to injury. At present, there is no all encompassing hypothesis for OTS. The view presented in this paper will attempt to integrate the above information into a unifying hypothesis. To be acceptable, it must account for the diverse physical, physiological, behavioral, and psychological changes asso- ciated with OTS. It must also explain how OTS, where similarities are more striking than differences, occurs in response to a wide array of training regimens and athletic events. Muscle Trauma and Systemic Inflammation The present hypothesis proposes that trauma to the mus- cular, skeletal, and/or joint system, is frequently the initiator of OTS. However, before presenting this argument, it seems appropriate to discuss the presence of ���naturally��� occurring, exercise-related, tissue trauma. It is now widely accepted that training and competing results in degrees of micro- trauma to muscle, connective tissue, and/or bones and joints (87). This type of ���injury��� will be referred to as adaptive microtrauma (AMT) and may be regarded as an initial phase along an ���injury continuum.��� Contending with this AMT may require nothing more than an appropriate training pro- gram that includes rest days, and/or hard and easy work days, and or cross-training, to allow for recovery. It is proposed that AMT may be induced via several mechanisms. It is well documented that the eccentric com- ponent of a movement will induce tissue trauma (86). Ad- ditionally, it is suggested that exercise requiring elevated local metabolic demands, such as high-intensity cycling, may induce ���pockets��� of ischemia, resulting in ischemic/ reperfusion injury (1,12). Finally, it is also proposed that joint structures involved in high volume repetitions, would induce AMT in these structures (see Fig. 1). The reason for referring to this microinjury as ���adaptive��� is that it is widely believed that AMT results in a mild inflammatory response, with the final purpose of ���healing��� (13,50,86). The healing process may result in an ���overshoot��� phenomenon and be associated with an adaptation (13) of muscle, bone, and/or connective tissue. Musculo-skeletal-joint trauma/injury, proposed as the un- derlying cause of OTS, may be induced by a variety of circumstances. Conceivably, this injury may be due to a progression from the initial benign AMT-stage, to a sub- clinical injury in the athlete who is training too hard and too frequently (2,71,82). Another possibility is a circumstance involving continued training, before recovery from an acute injury, which may exacerbate the initial injury (39,81,91). Kibler and Chandler (39) suggest that relative to overtrain- ing ���the types of injuries identified, range from the overt, that are obvious injuries and will usually prevent perfor- mance for some period of time, to the subclinical, that decrease performance but may be seldom recognized.��� As stated previously, the universally accepted sign of OTS is a decrease in performance (6,27,91). Injury would undoubtedly compromise performance. A large body of research demonstrates that even minor muscle trauma, as is seen after an unaccustomed bout of eccentrics, interferes with performance (13). Injury impacts locally on factors such as strength and range of motion, which affects overall performance. Due to injury ���the athlete may modify partic- ipation, and at times may cause an injury in a distant part of Figure 1���Schematic diagram of proposed manner by which various musculoskeletal actions may result in tissue trauma/injury. OVERTRAINING AND SYSTEMATIC INFLAMMATION Medicine & Science in Sports & ExerciseT 319