Deleterious effects of short-term, high-intensity exercise on immune function: evidence from leucocyte mitochondrial alterations and apoptosis.

BACKGROUND: Although moderate exercise can benefit health, acute and vigorous exercise may have the opposite effect. Strenuous exercise can induce alterations in the physiology and viability of circulating leucocytes, which have a causal relationship with exercise-induced immune distress. OBJECTIVES: To investigate the use of mitochondrial transmembrane potential (MTP), a functional marker of the energy and viability status of leucocytes, for monitoring the immunomodulating effects of short-term, high-intensity exercise. METHODS: 12 healthy volunteers with a mean Vo(2)max of 70.4 ml/kg/min carried out 3 consecutive days of high-intensity exercise (85% of Vo(2)max for 30 min every day). Blood samples were collected at multiple time points immediately before and after each exercise session and at 24 and 72 h after the completion of exercise. Leucocyte MTP, apoptosis and circulatory inflammation markers were measured by flow cytometry and enzyme-linked immunosorbent assays. RESULTS: MTP of peripheral blood leucocytes had declined immediately after the first exercise session and remained subnormal 24 h later. It did not normalise until 72 h after exercise. The sequential changes in MTP were consistent among the three leucocyte subpopulations (polymorphonuclear neutrophils, lymphocytes and monocytes) and were significant (p<0.05). Leucocytes displayed a gradual and incremental change in their propensity for apoptosis during and after exercise. Similarly, plasma concentrations of tumour necrosis factor-alpha and soluble Fas ligand were raised during the exercise sessions and had not normalised by 72 h after the completion of exercise. Correlation between changes in leucocyte MTP and plasma concentrations of tumour necrosis factor-alpha and soluble Fas ligand was variable, but significant for polymorphonuclear neutrophils and lymphocytes (p<0.05). CONCLUSIONS: Short-term, high-intensity exercise can lead to a significant and prolonged dysfunction of the mitochondrial energy status of peripheral blood leucocytes, which is accompanied by an increased propensity for apoptosis and raised pro-inflammatory mediators. These results support the immunosuppressive effects of excessive exercise and suggest that MTP is a useful marker of these effects.

Oxidative DNA damage in human peripheral leukocytes induced by massive aerobic exercise.

Reactive oxygen species produced during vigorous exercise may permeate into cell nuclei and induce oxidative DNA damage, but the supporting evidence is still lacking. By using a 42 km marathon race as a model of massive aerobic exercise, we demonstrated a significant degree of unrepaired DNA base oxidation in peripheral immunocompetent cells, despite a concurrent increase in the urinary excretion of 8-hydroxy-2'-deoxyguanosine. Single cell gel electrophoresis with the incorporation of lesion-specific endonucleases further revealed that oxidized pyrimidines (endonuclease III-sensitive sites) contributed to most of the postexercise nucleotide oxidation. The oxidative DNA damage correlated significantly with plasma levels of creatinine kinase and lipid peroxidation metabolites, and lasted for more than 1 week following the race. This phenomenon may be one of the mechanisms behind the immune dysfunctions after exhaustive exercise.

Age-related changes in the mitochondrial depolarization induced by oxidative injury in human peripheral blood leukocytes.

Aging is associated with impaired immunity and reduced host defenses. Mitochondrial bioenergetic dysfunctions and reduced antioxidative ability of immunocompetent cells may contribute to this phenomenon. In this study, 60 healthy volunteers of different age groups donated their blood after overnight fasting. Leukocytes were subjected to oxidative injuries by exposure to t-butylhydroperoxide, and were labeled with fluorochromes for measuring mitochondria transmembrane potential (delta psi m), membrane peroxidation and mitochondrial oxidant formation. delta psi m declined after t-butylhydroperoxide exposure, and the change was more prominent in leukocytes from older individuals. Cyclosporin A partly restored delta psi m, implying the contributing role of mitochondrial permeability transition pores. The mitochondrial depolarization was accompanied by increased oxidant formation and oxidation of pyridine nucleotides, which were more prominent in older subjects. The results support the view that the bioenergetic functions of mitochondria are more susceptible to oxidative injury in aged individuals. The decreased ability of leukocytes to resist oxidative stress may contribute to immunosenescence in humans.

Leukocyte mitochondria depolarization and apoptosis in advanced heart failure: clinical correlations and effect of therapy.

OBJECTIVES: The purpose of this study was to examine the changes in leukocyte mitochondrial transmembrane potential (MTP) and its association with apoptosis in congestive heart failure (CHF). BACKGROUND: Congestive heart failure is a heterogeneous syndrome with multiple hemodynamic, neuroendocrine and immune abnormalities. Although edematous CHF may be associated with endotoxemia and increased cytokine production, peripheral blood leukocyte functions in advanced CHF remain unclear. METHODS: Thirty patients with acute decompensated CHF (mean age [+/- SEM] 74.9 +/- 3.1 years) and 20 healthy controls underwent determination of MTP, intracellular oxidants and apoptosis in three subsets of peripheral blood leukocytes. The measurements were repeated after the time of recompensation. RESULTS: Patients with acute CHF showed marked MTP reduction and increased intracellular oxidant formation in three subsets of leukocytes upon entry into the study. These changes were more prominent in patients with peripheral edema. The decline in MTP was correlated with the severity of the peripheral edema and plasma concentration of cortisol, nitrogen metabolites and tumor necrosis factor-alpha (p < 0.01). After clinical stabilization, MTP gradually recovered. Leukocytes underwent increased propensity of apoptosis one week after the time of recompensation. CONCLUSIONS: The mitochondrial depolarization and apoptosis of leukocytes in decompensated heart failure suggest that CHF is associated with severity-dependent impairments in leukocyte function. Accentuated hormonal and cytokine abnormalities and increased circulating oxidants may contribute to these changes. Early and aggressive management of advanced heart failure is helpful in the recovery of these immune abnormalities.