Melatonin supplementation ameliorates oxidative stress and inflammatory signaling induced by strenuous exercise in adult human males

Abstract:  Strenuous exercise induces inflammatory reactions together with high production of free radicals and subsequent muscle damage. This study was designed to investigate for the first time and simultaneously whether over‐expression of inflammatory mediators, oxidative stress, and alterations in biochemical parameters induced by acute exercise could be prevented by melatonin. This indoleamine is a potent, endogenously produced free radical scavenger and a broad‐spectrum antioxidant; consequently, it might have positive effects on the recovery following an exercise session. The participants were classified into two groups: melatonin‐treated men (MG) and placebo‐treated individuals (controls group, CG). The physical test consisted in a constant run that combined several degrees of high effort (mountain run and ultra‐endurance). The total distance of the run was 50 km with almost 2800 m of ramp in permanent climbing and very changeable climatic conditions. Exercise was associated with a significant increase in TNF‐α, IL‐6, IL‐1ra (in blood), and also an increase in 8‐hydroxy‐2′‐deoxyguanosine (8‐OHdG) and isoprostane levels (in urine), and indicated the degree of oxidative stress and inflammation induced. Oral supplementation of melatonin during high‐intensity exercise proved efficient in reducing the degree of oxidative stress (lower levels of lipid peroxidation, with a significant increase in antioxidative enzyme activities); this would lead to the maintenance of the cellular integrity and reduce secondary tissue damage. Data obtained also indicate that melatonin has potent protective effects, by preventing over‐expression of pro‐inflammatory mediators and inhibiting the effects of several pro‐inflammatory cytokines. In summary, melatonin supplementation before strenuous exercise reduced muscle damage through modulation of oxidative stress and inflammation signaling associated with this physical challenge.

[1]  D. Hanahan,et al.  The preparation of red cell ghosts (membranes). , 1974, Methods in enzymology.

[2]  R. Armstrong,et al.  Eccentric exercise-induced injury to rat skeletal muscle. , 1983, Journal of applied physiology: respiratory, environmental and exercise physiology.

[3]  L. Flohé,et al.  Assays of glutathione peroxidase. , 1984, Methods in enzymology.

[4]  H. Aebi,et al.  Catalase in vitro. , 1984, Methods in enzymology.

[5]  L. Moldawer,et al.  Tumor necrosis factor soluble receptors circulate during experimental and clinical inflammation and can protect against excessive tumor necrosis factor alpha in vitro and in vivo. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[6]  B. Föger,et al.  Kinetics of lipids, apolipoproteins, and cholesteryl ester transfer protein in plasma after a bicycle marathon. , 1994, Metabolism: clinical and experimental.

[7]  M. Meltz,et al.  The neurohormone melatonin inhibits cytokine, mitogen and ionizing radiation induced NF-kappa B. , 1995, Biochemistry and molecular biology international.

[8]  R. Reiter,et al.  Melatonin in edible plants identified by radioimmunoassay and by high performance liquid chromatography‐mass spectrometry , 1995, Journal of pineal research.

[9]  M. Meltz,et al.  EFFECT OF MELATONIN ON NF‐κB DNA‐BINDING ACTIVITY IN THE RAT SPLEEN , 1996 .

[10]  M. Meltz,et al.  Effect of melatonin on NF-kappa-B DNA-binding activity in the rat spleen. , 1996, Cell biology international.

[11]  R. Reiter,et al.  Oxidative damage in the liver induced by ischemia-reperfusion: protection by melatonin. , 1996, Hepato-gastroenterology.

[12]  Takuro Suzuki,et al.  Tissue changes in glutathione metabolism and lipid peroxidation induced by swimming are partially prevented by melatonin. , 1996, Pharmacology & toxicology.

[13]  H. Tilg,et al.  IL-6 and APPs: anti-inflammatory and immunosuppressive mediators. , 1997, Immunology today.

[14]  D. Cardinali,et al.  Effect of melatonin on serum cholesterol and phospholipid levels, and on prolactin, thyroid-stimulating hormone and thyroid hormone levels, in hyperprolactinemic rats. , 1997, Life sciences.

[15]  T. Nyokong,et al.  The interaction of melatonin and its precursors with aluminium, cadmium, copper, iron, lead, and zinc: An adsorptive voltammetric study , 1998, Journal of pineal research.

[16]  D. S. St. Clair,et al.  An intronic NF-kappaB element is essential for induction of the human manganese superoxide dismutase gene by tumor necrosis factor-alpha and interleukin-1beta. , 1999, DNA and cell biology.

[17]  Sato Honma,et al.  Melatonin induces γ-glutamylcysteine synthetase mediated by activator protein-1 in human vascular endothelial cells , 1999 .

[18]  D. Acuña-Castroviejo,et al.  Melatonin but not vitamins C and E maintains glutathione homeostasis in t‐butyl hydroperoxide‐induced mitochondrial oxidative stress , 2000, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[19]  R. Reiter,et al.  Melatonin and Its Relation to the Immune System and Inflammation , 2000, Annals of the New York Academy of Sciences.

[20]  Josep M. Guerrero,et al.  Serum cholesterol and lipid peroxidation are decreased by melatonin in diet‐induced hypercholesterolemic rats , 2000, Journal of pineal research.

[21]  J. Sastre,et al.  Free Radicals in Exhaustive Physical Exercise: Mechanism of Production, and Protection by Antioxidants , 2000, IUBMB life.

[22]  Katsuhiko Suzuki,et al.  Circulating cytokines and hormones with immunosuppressive but neutrophil-priming potentials rise after endurance exercise in humans , 2000, European Journal of Applied Physiology.

[23]  S. Blair,et al.  Sedentary Habits, Health, and Function in Older Women and Men , 2000, American journal of health promotion : AJHP.

[24]  J. Calvo,et al.  Characterization of the protective effects of melatonin and related indoles against α‐naphthylisothiocyanate‐induced liver injury in rats , 2001, Journal of cellular biochemistry.

[25]  Yi-Ping Li,et al.  Cytokines and oxidative signalling in skeletal muscle. , 2001, Acta physiologica Scandinavica.

[26]  M. Febbraio,et al.  Muscle‐derived interleukin‐6: mechanisms for activation and possible biological roles , 2002, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[27]  F. Cuttitta,et al.  Adrenomedullin expression is up-regulated by ischemia–reperfusion in the cerebral cortex of the adult rat , 2002, Neuroscience.

[28]  P. Sacco,et al.  Muscle Damage in Resistance Training , 2003 .

[29]  M. Febbraio,et al.  The metabolic role of IL-6 produced during exercise: is IL-6 an exercise factor? , 2004, The Proceedings of the Nutrition Society.

[30]  B. Saltin,et al.  Searching for the exercise factor: is IL-6 a candidate? , 2004, Journal of Muscle Research & Cell Motility.

[31]  Vanesa Martín,et al.  Regulation of antioxidant enzymes: a significant role for melatonin , 2004, Journal of pineal research.

[32]  J. Keul,et al.  Influence of acute maximal exercise on lecithin: cholesterol acyltransferase activity in healthy adults of differing aerobic performance , 2004, European Journal of Applied Physiology and Occupational Physiology.

[33]  B. Østerud,et al.  The in vivo effect of melatonin on cellular activation processes in human blood during strenuous physical exercise , 2005, Journal of pineal research.

[34]  A. Coto-Montes,et al.  A proposed mechanism to explain the stimulatory effect of melatonin on antioxidative enzymes , 2005, Journal of pineal research.

[35]  P. Thompson,et al.  The effects of physical activity on serum C-reactive protein and inflammatory markers: a systematic review. , 2005, Journal of the American College of Cardiology.

[36]  N. Secher,et al.  Cerebrospinal fluid IL-6, HSP72, and TNF-alpha in exercising humans. , 2006, Brain, behavior, and immunity.

[37]  J. González‐Gallego,et al.  Melatonin inhibits the expression of the inducible isoform of nitric oxide synthase and nuclear factor kappa B activation in rat skeletal muscle , 2006, Journal of pineal research.

[38]  N. Secher,et al.  Cerebrospinal fluid IL-6, HSP72, and TNF-α in exercising humans , 2006, Brain, Behavior, and Immunity.

[39]  É. Hajduch,et al.  IL‐1 receptor antagonist in metabolic diseases: Dr Jekyll or Mr Hyde? , 2006, FEBS letters.

[40]  R. Reiter,et al.  Chronic melatonin treatment prevents age-dependent cardiac mitochondrial dysfunction in senescence-accelerated mice , 2007, Free radical research.

[41]  D. Bandyopadhyay,et al.  Melatonin protects against oxidative damage and restores expression of GLUT4 gene in the hyperthyroid rat heart , 2007, Journal of pineal research.

[42]  T. Huizinga,et al.  Cutting Edge: TNFR-Shedding by CD4+CD25+ Regulatory T Cells Inhibits the Induction of Inflammatory Mediators1 , 2008, The Journal of Immunology.

[43]  I. Vega-Naredo,et al.  Favorable effects of a prolonged treatment with melatonin on the level of oxidative damage and neurodegeneration in senescence‐accelerated mice , 2008, Journal of pineal research.

[44]  B. Dawson,et al.  Athletic induced iron deficiency: new insights into the role of inflammation, cytokines and hormones , 2008, European Journal of Applied Physiology.

[45]  E. Vara,et al.  Melatonin is able to prevent the liver of old castrated female rats from oxidative and pro‐inflammatory damage , 2008, Journal of pineal research.

[46]  A. Kriska,et al.  Role of physical activity in diabetes management and prevention. , 2008, Journal of the American Dietetic Association.

[47]  S. Powers,et al.  Exercise-induced oxidative stress: cellular mechanisms and impact on muscle force production. , 2008, Physiological reviews.

[48]  R. Reiter,et al.  Reducing oxidative/nitrosative stress: a newly-discovered genre for melatonin , 2009, Critical reviews in biochemistry and molecular biology.

[49]  A. Jamurtas,et al.  Blood as a reactive species generator and redox status regulator during exercise. , 2009, Archives of biochemistry and biophysics.

[50]  Giuseppe Lippi,et al.  Serum Creatinine Concentration and Creatinine-Based Estimation of Glomerular Filtration Rate in Athletes , 2009, Sports medicine.

[51]  W. Kraus,et al.  Exercise Training, Lipid Regulation, and Insulin Action: A Tangled Web of Cause and Effect , 2009, Obesity.

[52]  R. Reiter,et al.  Kynuramines, metabolites of melatonin and other indoles: the resurrection of an almost forgotten class of biogenic amines , 2009, Journal of pineal research.

[53]  L. Acarín,et al.  Interleukin-10 and Interleukin-10 Receptor-I Are Upregulated in Glial Cells After an Excitotoxic Injury to the Postnatal Rat Brain , 2009, Journal of neuropathology and experimental neurology.

[54]  J. González‐Gallego,et al.  Melatonin reduces cardiac inflammatory injury induced by acute exercise , 2009, Journal of pineal research.

[55]  R. Reiter,et al.  Melatonin, cardiolipin and mitochondrial bioenergetics in health and disease , 2010, Journal of pineal research.

[56]  T. Peng,et al.  Visualization of Melatonin's Multiple Mitochondrial Levels of Protection Against Mitochondrial Ca2+-Mediated Permeability Transition and Beyond in Rat Brain Astrocytes , 2010 .

[57]  M. Muñoz,et al.  Effect of melatonin on hyperlipidemic nephropathy under constant light exposure , 2002, Journal of Physiology and Biochemistry.

[58]  C. Chiao,et al.  Visualization of melatonin’s multiple mitochondrial levels of protection against mitochondrial Ca2+‐mediated permeability transition and beyond in rat brain astrocytes , 2010, Journal of pineal research.

[59]  M. Iriti,et al.  Melatonin in traditional Mediterranean diets , 2010, Journal of pineal research.

[60]  José A. García,et al.  Melatonin-mitochondria interplay in health and disease. , 2011, Current topics in medicinal chemistry.