Cytokine Hypothesis of Overtraining

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Cytokine Hypothesis of Overtraining (OTS)

OTS occurs when excessive training leads to performance decline, mood changes, and physiological alterations.
No global hypothesis currently explains OTS.
High training volume/intensity with insufficient rest causes muscle/skeletal/joint trauma.
Injury-related cytokines activate circulating monocytes, producing pro-inflammatory cytokines (IL-1β, IL-6, TNF-α), leading to systemic inflammation.

Systemic Inflammation Effects

CNS communication induces "sickness" behavior (mood changes) to resolve inflammation.
Altered liver function supports gluconeogenesis and acute phase protein synthesis, causing a hypercatabolic state.
Impacts immune function.
OTS is viewed as a protective third stage of Selye’s general adaptation syndrome, focused on recovery.
Potential markers of OTS are based on systemic inflammatory conditions.

Overtraining Syndrome (OTS) Details

Athletes train hard to optimize performance, but there is a fine line between improvement and deterioration.
Overtraining leads to performance decline, fatigue, depression, muscle/joint pain, and appetite loss.
Symptoms are categorized by physiological, psychological, immunological, and biochemical parameters.
No universal symptom cluster exists for OTS.

Overtraining vs. Overreaching

Overreaching is a temporary performance deterioration with rapid recovery and adaptation.
OTS involves a continued performance decrement despite rest.
OTS is common due to imbalance between training, competition, and recovery.
Treatment involves reduced training volume or complete rest (6-12 weeks).
OTS is also prevalent among recreational athletes, but attention is lacking.

Existing Theories of OTS

Hypothalamus role: activation of autonomic nervous system, HPA axis, and HPG axis, altering catecholamine, glucocorticoid, and testosterone levels.
Glutamine theory: Reduced blood glutamine impairs immune response due to lymphocyte fuel reduction.
Tryptophan theory: Reduced blood tryptophan leads to increased brain serotonin, causing mood and behavioral changes.
Glycogen hypothesis: Insufficient calorie/carbohydrate intake leads to reduced muscle glycogen, causing fatigue.
Monotony theory: Lack of training variation induces OTS; monotonous intense training stresses the musculoskeletal-joint system which increases injury risk.
No all-encompassing hypothesis for OTS exists.

Muscle Trauma and Systemic Inflammation

Muscle, skeletal, and/or joint system trauma frequently initiates OTS.
Training and competition result in micro-trauma to tissues, referred to as adaptive micro-trauma (AMT).
AMT requires rest, hard/easy work days, or cross-training for recovery.
Eccentric movements induce tissue trauma.
High-intensity exercise may induce ischemia/reperfusion injury.
High volume repetitions induce AMT in joint structures.
AMT results in mild inflammation for healing and adaptation.

Musculoskeletal Injury and OTS

Musculoskeletal-joint trauma/injury, is proposed as the underlying cause of OTS, may progress from AMT-stage to subclinical injury with excessive training.
Continued training before recovery from acute injury may exacerbate the initial injury.
Injuries range from obvious to subclinical, decreasing performance.
Injury compromises performance by affecting strength and range of motion.
Athletes may modify participation, causing injury in distant parts of the kinetic chain.
OTS may cause musculoskeletal overuse injuries or vice versa.
Elevated serum creatine kinase, Muscle and joint soreness and tenderness are indicative of possible injury in an overtrained athlete.
Repetitive trauma to the musculoskeletal system, due to high intensity/volume training with insufficient rest/recovery time, is the predominant cause of overtraining.

Injury, Inflammation, and Cytokines

Subacute exercise-induced musculoskeletal trauma results in release of local inflammatory factors, cytokines.
Continued high-volume/intensity training with limited rest leads to chronic inflammation, activating circulating monocytes.
Activated monocytes produce large quantities of pro-inflammatory cytokines, which leads to systemic inflammation.
Inflammation is the body's generalized response to tissue injury, with the primary focus of acute inflammation being healing.
Overt signs and symptoms of inflammation include swelling, redness, heat, pain, and reduction in function; variations depend upon injury extent, tissue type, and nutritional status.

Inflammatory Response

In response to tissue injury, the body mounts an elaborate, synchronized response, characterized by movement of fluid, plasma protein, and leukocytes into injured tissue.
Neutrophils are the first wave of infiltrating cells, followed by monocytes that transform into macrophages.
Activated monocytes/macrophages secrete over 100 different chemicals, central to the local and systemic inflammatory process.
Coordination and amplification of inflammation are accomplished by cytokines, soluble hormone-like proteins.
Cytokines are produced by immune cells, endothelial cells, and fat-storing cells, activated by stimuli like free radicals and tissue injury.

Cytokine Function

Cytokines integrate systemic inflammatory events.
Cells and organs respond to various cytokines.
Cytokines stimulate surrounding cells (paracrine) or themselves (autocrine), amplifying responses.
Cytokines are grouped into interleukins (IL), interferons (INF), tumor necrosis factor (TNF), growth factors, and chemokines.
Cytokines are broadly classified as pro- or anti-inflammatory.
Proinflammatory cytokines include IL-1β, IL-6, IL-8, and TNF-α.
Anti-inflammatory cytokines include IL-4, IL-10, IL-13, and IL-1 receptor antagonist (IL-1ra).

Key Cytokines in Overtraining

IL-1β and TNF-α are secreted at the onset of inflammation, acting locally to activate endothelial cells and systemically to regulate acute phase protein synthesis and body temperature.
IL-6 is synthesized after IL-1β and TNF-α, modulating local and systemic inflammation and immunity.
IL-6 stimulates glucocorticoid synthesis and inhibits IL-1β and TNF-α expression.
IL-6 elevations are reported after intense exercise or muscle injury, with muscle cells producing IL-6 in response to injury.

Cytokine Levels and Overtraining Data

Limited data is available concerning blood cytokine levels in OTS.
Cytokine levels were found to be several-fold greater than age-matched controls in an individual suffering from chronic plantar fasciatus, possibly indicating a relationship between chronic injury and cytokine levels.
Higher levels of IL-1 and TNF were found in a participant self-reporting as performing below anticipated levels.
Local production of cytokines in injured muscle assists with local inflammatory response, healing, and termination of inflammation.
Increased levels of circulating cytokines coordinate systemic inflammation, engaging the liver and central nervous system, leading to signs and symptoms associated with OTS.

Mood, Behavior, and Cognitive Changes

Overtrained athletes experience changes in mood, behavior, and cognition.
Anaerobic athletes experience anxiety/agitation, while endurance athletes experience depression.
Changes include a fatigued athlete, discouraged and disinterested in training and life.
Changes are associated with intense training or precipitate it.
Symptoms are similar to clinical depression.
Reduced circulating tryptophan (TRY) levels may represent part of OTS (needed for serotonin production, inducing sleep and reducing appetite).

Psychoneuroimmunological (PNI) Model

Explains body-mind interaction in high volume training impact.
CNS outflow pathways (sympathetic nervous system and HPA axis) are activated within the hypothalamus.
Brain and peripheral immune/inflammatory cells form a bidirectional communication network.
Cytokines (IL-1β, IL-6, and TNF-α) are major messenger molecules.
Activation of the CNS results in "sickness," including reduced appetite, weight loss, reduced thirst, reduced libido, depression, loss of interest, fear, and sleep disturbances.
Behaviors are an adaptation to infection/injury, reducing energy cost and directing resources to survival.

Cytokines and Psychological Depression

Systemic cytokines are related to psychological depression.
Depressed patients have elevated IL-1β and IL-6 levels.
Exogenous cytokine administration induces a distressed mood state.
A dose-dependent relationship exists between cytokine levels and depression severity.
Injured/infected individuals exhibit sickness/depressive-like behavior.
Cytokines access the CNS directly or via afferent neurons.
Interleukin receptors, specifically IL-1 receptors, are abundant in the hippocampal area of the brain, related to learning, memory, and cognition, but systemic inflammation may lead to cognitive alterations.

Commonalities

Similarities exist between clinical depression, sickness behavior, and overtraining, with physiological, biochemical, cognitive, and psychological/behavioral signs and symptoms.
Elevated levels of IL-1, IL-6, and/or TNF-α may exist in OTS.
Organic, physical causes may underlie mood, behavioral, and cognitive changes in OTS.

Glutamine, Hypercatabolism, and OTS

Intense training may cause a decrease in blood levels of glutamine.
Reduced glutamine levels may indicate metabolic fault and be an indicator of OTS.
Glutamine is a primary fuel utilized by lymphocyte cells.
Glutamine is the most abundant amino acid in human plasma and muscle.

Catabolic State and Glutamine

Systemic inflammation is associated with a catabolic state.
Gluconeogenesis is up-regulated to maintain blood glucose levels, with glutamine and alanine being primary precursors.
Systemic inflammation increases amino acid demands for protein synthesis by the liver.
Glutamine is a primary precursor for many protein molecules.
Amino acid flow is redirected to the liver, stimulated by IL-6 and TNF-α with the help of glucocorticoids.
Muscle proteolysis is augmented to support biosynthetic pathways, contributing to negative nitrogen balance and loss of lean body mass.
Increased urine output is also necessary for urinary nitrogen excretion which could result from augmented muscle proteolysis.

Hypercatabolism Symptoms

Elevated basal metabolic rate.
Negative nitrogen balance.
Decreased lean body mass and fat mass.
Increased uric acid production.
Increased urination and thirst.
Shift in fuel usage from glucose-fat to fats.

Tryptophan and OTS

Increased uptake of tryptophan (TRY) by the brain, resulting in increased brain serotonin levels.
Decreased levels of branched chain amino acids (BCAA) lead to increased serotonin.
In specific areas of the brain, serotonin induces sleep, depresses motor neuron excitability and appetite, and alters autonomic and endocrine function.
Inconclusive evidence of increased serotonin uptake is present in human research.

Systemic Inflammation and Tryptophan

Serum albumin concentrations are reduced during systemic inflammation which most likely reduces the availability of TRY to the CNS.
TRY is used for leukocyte activity and synthesis of inflammatory-related liver proteins.
Induction of indoleamine 2,3 dioxygenase (major TRP-catabolizing enzyme) (reduces availability of TRY).
A view in the psychology literature suggests that there is a correlation between circulating levels of TRY and brain levels, with low circulating levels reflecting low availability of TRY in the brain.
Reduced brain TRY levels are consistently associated with depressive symptoms.
Reduced albumin, uptake/usage for leukocyte acitivity increases uptake by liver, and degradation reduces TRY levels.

Acute Phase Proteins, Trace Metals, and OTS

Changes in blood proteins and trace metals are associated with OTS during the acute phase response (APR).
Tissue trauma induces local inflammation, dilation/leakage of blood vessels, platelet aggregation/clot formation, and WBC accumulation.
The systemic APR coordinates physiological systems to deal with inflammation.
Liver hepatocytes synthesize acute phase proteins (APP) in response to IL-1β, IL-6, and TNF-α.
Positive APP increase in concentration, while negative APP such as albumin decrease.

C-Reactive Protein and Trace Metals

C-reactive protein (CRP) is a primary APP that may increase 100–1000 fold with increase in positive APP, and a concomitant decrease in negative APP such as albumin.
Plasma iron and zinc concentrations fall, whereas plasma copper levels are elevated during infection with the inverse happening in OTS.

Muscle Glycogen, Blood Lactate, Insulin Resistance, and OTS

Reduced muscle glycogen levels are frequently reported in overtrained athletes.
Reduced muscle glycogen would cause fatigue and a decrement in performance. The glycogen theory has not been substantiated.
Excessive stress may result in systemic inflammation and “sickness” behavior, including anorexia which affects food intake, decreasing muscle glycogen levels.
Local muscle injury interferes with transport of glucose into the muscle cell, impairing glycogen synthesis and leads to a significant reduction in the glucose transporter protein GLUT-4.

Insulin Resistance

Whole-body insulin resistance is associated with muscle injury, mediated by TNF-α.
Insulin resistance does not appear to have been tested in the overtrained athlete.
Anorexia and reduced Glut-4 attenuate movement of glucose into cell inhibiting glycogen re-synthesis.
Muscle injury > systemic inflammation > cytokines > anorexia.

Hypothalamic-Related Hormones and OTS

The hypothalamus controls blood levels of stress hormones cortisol, epinephrine, and norepinephrine, and gonadal hormones, such as testosterone and estradiol.
Excessive physiological stress leads to altered hormonal balance.
Intense physical activity increases cortisol and decreases free testosterone.
Cytokines are potent activators of the hypothalamic-pituitary-adrenal axis (HPA), in particular IL-1 (35) and IL-6 (67).
Systemic inflammation may account for elevated cortisol levels and decreased reproductive function in OTS.
Corticotropin releasing hormone (CRH) stimulates release of pituitary adrenocorticotropin releasing hormone (ACTH), with subsequent release of cortisol from the adrenal cortex.
Systemic inflammation & elevated cytokines can account for elevated cortisol levels in overtrained athletes (26,27,91).
Controlling hormones in this instance are the luteinizing-hormone releasing hormone (LHRH) and pituitary gonadal hormones such as luteinizing hormone (LH), and follicle stimulating hormone (FSH).

Immune System and OTS

Anecdotal evidence suggests increased incidence of illness is associated with OTS.
High intensity training causes immune suppression.
Increased susceptibility to infection postsurgery/injury is similar to OTS, with up-regulated inflammation.
Anti-inflammatory factors counteract pro-inflammatory effects, resulting in immunosuppression.
Patients that suffer from early hyperinflammation ultimately suffer immunosuppression at a later stage.
Early hyperinflammation followed by late immunosuppression helps explain the immune response of the overtrained athlete.
Immunosuppression may reflect the body’s attempt to contain inflammation.

Theoretical Implications

Stress theory (Selye) proposes that a wide variety of diseases manifest similarly.
Disease progresses through the alarm, resistance and exhaustion stages.
OTS is a manifestation of the exhaustion stage of the general adaptation syndrome (GAS) due to excessive physical/physiological stress.
The GRES (generalize response to excessive stress) cycle consists of primary stimulus (muscle related trauma) leads to activation of monocytes & cytokines.
Termination of cycle requires stimulus withdrawal (rest (most potent healing agent)).
If OTS is a form of inflammation drug therapy maybe be an option.
Important to guard against overdiagnosing OTS.

Summary of Cytokine Hypothesis for OTS

OTS is a response to excessive musculoskeletal stress with insufficient rest, inducing local and chronic inflammation, leading to systemic inflammation.
Circulating monocytes are activated producing large quantities of pro-inflammatory cytokines (IL-1β, IL-6, and TNF-α).
Cytokines act on CNS inducing motivated behaviors (“sickness” behavior).
Pro-inflammatory cytokines up-regulate liver function to maintain blood glucose levels and synthesize inflammatory-related acute phase proteins.
Immune-related changes may be related to an immuno-suppression possibly due to counter regulation of inflammatory response.
OTS is viewed under the rubric of systemic inflammation reconcilling previous proposed mechanisms.