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The present study was undertaken to test whether endurance training in patients with COPD, along with enhancement of muscle bioenergetics, decreases muscle redox capacity as a result of recurrent episodes of cell hypoxia induced by high intensity exercise sessions. Seventeen patients with COPD (FEV(1), 38 +/- 4% pred; PaO2), 69 +/- 2.7 mm Hg; PaCO2, 42 +/- 1.7 mm Hg) and five age-matched control subjects (C) were studied pretraining and post-training. Reduced (GSH) and oxidized (GSSG) glutathione, lipid peroxidation, and gamma-glutamyl cysteine synthase heavy subunit chain mRNA expression (gammaGCS-HS mRNA) were measured in the vastus lateralis. Pretraining redox status at rest and after moderate (40% Wpeak) constant-work rate exercise were similar between groups. After training (DeltaWpeak, 27 +/- 7% and 37 +/- 18%, COPD and C, respectively) (p < 0.05 each), GSSG levels increased only in patients with COPD (from 0.7 +/- 0.08 to 1.0 +/- 0.15 nmol/ mg protein, p < 0.05) with maintenance of GSH levels, whereas GSH markedly increased in C (from 4.6 +/- 1.03 to 8.7 +/- 0.41 nmol/ mg protein, p < 0.01). Post-training gammaGCS-HS mRNA levels increased after submaximal exercise in patients with COPD. No evidence of lipid peroxidation was observed. We conclude that although endurance training increased muscle redox potential in healthy subjects, patients with COPD showed a reduced ability to adapt to endurance training reflected in lower capacity to synthesize GSH.

Post-training downregulation of muscle tumour necrosis factor (TNF)-a messenger ribonucleic acid (mRNA) expression and decrease in cellular TNF-a levels have been reported in the elderly. It is hypothesised that chronic obstructive pulmonary disease (COPD) patients may not show these adaptations due to their reduced ability to increase muscle antioxidant capacity with training.Eleven COPD patients (forced expiratory volume in one second 40¡4.4% of the predicted value) and six age-matched controls were studied. Pre-and post-training levels of TNF-a, soluble TNF receptors (sTNFRs: sTNFR55 and sTNFR75) and interleukin (IL)-6 in plasma at rest and during exercise and vastus lateralis TNF-a mRNA were examined.Moderate-intensity constant-work-rate exercise (11 min at 40% of pretraining peak work-rate) increased pretraining plasma TNF-a levels in COPD patients (from 17 ¡ 3.2 to 23¡2.7 pg?mL -1 ; pv0.005) but not in controls (from 19¡4.6 to 19¡3.2 pg?mL -1 ). No changes were observed in sTNFRs or IL-6 levels. After 8 weeks9 endurance training, moderate-intensity exercise increased plasma TNF-a levels similarly to pretraining (from 16¡3 to 21¡4 pg?mL -1 ; pv0.01). Pretraining muscle TNF-a mRNA expression was significantly higher in COPD patients than in controls (29.3¡13.9 versus 5.0¡1.5 TNF-a/18S ribonucleic acid, respectively), but no changes were observed after exercise or training.It is concluded that moderate-intensity exercise abnormally increases plasma tumour necrosis factor-a levels in chronic obstructive pulmonary disease patients without exercise-induced upregulation of the tumour necrosis factor-a gene in skeletal muscle. Eur Respir J 2003; 21: 789-794.

Cholesterol is a critical component of membrane bilayers where it plays key structural and functional roles by regulating the activity of diverse signaling platforms and pathways. Particularly enriched in brain, cholesterol homeostasis in this organ is singular with respect to other tissues and exhibits a heterogeneous regulation in distinct brain cell populations. Due to the key role of cholesterol in brain physiology and function, alterations in cholesterol homeostasis and levels have been linked to brain diseases and neurodegeneration. In the case of Alzheimer disease (AD), however, this association remains unclear with evidence indicating that either increased or decreased total brain cholesterol levels contribute to this major neurodegenerative disease. Here, rather than analyzing the role of total cholesterol levels in neurodegeneration, we focus on the contribution of intracellular cholesterol pools, particularly in endolysosomes and mitochondria through its trafficking via specialized membrane domains delineated by the contacts between endoplasmic reticulum and mitochondria, in the onset of prevalent neurodegenerative diseases such as AD, Parkinson disease, and Huntington disease as well as in lysosomal disorders like Niemann-Pick type C disease. We dissect molecular events associated with intracellular cholesterol accumulation, especially in mitochondria, an event that results in impaired mitochondrial antioxidant defense and function. A better understanding of the mechanisms involved in the distribution of cholesterol in intracellular compartments may shed light on the role of cholesterol homeostasis disruption in neurodegeneration and may pave the way for specific intervention opportunities.