Specific motor cortex hypoexcitability and hypoactivation in COPD patients with peripheral muscle weakness.

BACKGROUND: Peripheral muscle weakness can be caused by both peripheral muscle and neural alterations. Although peripheral alterations cannot totally explain peripheral muscle weakness in COPD, the existence of an activation deficit remains controversial. The heterogeneity of muscle weakness (between 32 and 57% of COPD patients) is generally not controlled in studies and could explain this discrepancy. This study aimed to specifically compare voluntary and stimulated activation levels in COPD patients with and without muscle weakness. METHODS: Twenty-two patients with quadriceps weakness (COPDMW), 18 patients with preserved quadriceps strength (COPDNoMW) and 20 controls were recruited. Voluntary activation was measured through peripheral nerve (VAperipheral) and transcranial magnetic (VAcortical) stimulation. Corticospinal and spinal excitability (MEP/Mmax and Hmax/Mmax) and corticospinal inhibition (silent period duration) were assessed during maximal voluntary quadriceps contractions. RESULTS: COPDMW exhibited lower VAcortical and lower MEP/Mmax compared with COPDNoMW (p < 0.05). Hmax/Mmax was not significantly different between groups (p = 0.25). Silent period duration was longer in the two groups of COPD patients compared with controls (p < 0.01). Interestingly, there were no significant differences between all COPD patients taken together and controls regarding VAcortical and MEP/Mmax. CONCLUSIONS: COPD patients with muscle weakness have reduced voluntary activation without altered spinal excitability. Corticospinal inhibition is higher in COPD regardless of muscle weakness. Therefore, reduced cortical excitability and a voluntary activation deficit from the motor cortex are the most likely cortical mechanisms implicated in COPD muscle weakness. The mechanisms responsible for cortical impairment and possible therapeutic interventions need to be addressed.

Impact of Chronic Obstructive Pulmonary Disease on Cognitive and Motor Performances in Dual-Task Walking.

When two tasks are performed simultaneously, they compete for attentional resources, resulting in a performance decrement in one or both tasks. Patients with attention disorders have a reduced ability to perform several tasks simultaneously (e.g., talking while walking), which increases the fall risk and frailty. This study assessed the cognitive and motor performances of patients with COPD and healthy controls within a dual-task walking paradigm. A subobjective was to assess the impact of a pulmonary rehabilitation program on the dual-task performances in COPD. Twenty-five patients with COPD and 20 controls performed a cognitive task (subtraction) and a 15-m walking test separately (single-task; ST) and jointly (dual-task; DT). In addition, a subsample of 10 patients performed the same evaluations 5 weeks later after a pulmonary rehabilitation program following current recommendations. Cognitive and gait performances in ST showed no differences between patients with COPD and controls (all p > 0.05). However, COPD patients exhibited a greater increase in gait variability than controls in DT (4.07 ± 1.46% vs. 2.17 ± 0.7%, p < 0.001). The pulmonary rehabilitation program had no effect on the dual-task impairment for the subsample of patients (p = 0.87). This study provides evidence of insufficient attentional resources to successfully deal with DT in patients with COPD, and this was expressed through an exaggerated increase in gait variability in DT walking. Given the high risk of falls and disability associated with altered gait variability, dual-task training interventions should be considered in pulmonary rehabilitation programs.

The self-perception of dyspnoea threshold during the 6-min walk test: a good alternative to estimate the ventilatory threshold in chronic obstructive pulmonary disease.

To determine and/or adjust exercise training intensity for patients when the cardiopulmonary exercise test is not accessible, the determination of dyspnoea threshold (defined as the onset of self-perceived breathing discomfort) during the 6-min walk test (6MWT) could be a good alternative. The aim of this study was to evaluate the feasibility and reproducibility of self-perceived dyspnoea threshold and to determine whether a useful equation to estimate ventilatory threshold from self-perceived dyspnoea threshold could be derived. A total of 82 patients were included and performed two 6MWTs, during which they raised a hand to signal self-perceived dyspnoea threshold. The reproducibility in terms of heart rate (HR) was analysed. On a subsample of patients (n=27), a stepwise regression analysis was carried out to obtain a predictive equation of HR at ventilatory threshold measured during a cardiopulmonary exercise test estimated from HR at self-perceived dyspnoea threshold, age and forced expiratory volume in 1 s. Overall, 80% of patients could identify self-perceived dyspnoea threshold during the 6MWT. Self-perceived dyspnoea threshold was reproducibly expressed in HR (coefficient of variation=2.8%). A stepwise regression analysis enabled estimation of HR at ventilatory threshold from HR at self-perceived dyspnoea threshold, age and forced expiratory volume in 1 s (adjusted r=0.79, r=0.63, and relative standard deviation=9.8 bpm). This study shows that a majority of patients with chronic obstructive pulmonary disease can identify a self-perceived dyspnoea threshold during the 6MWT. This HR at the dyspnoea threshold is highly reproducible and enable estimation of the HR at the ventilatory threshold.

Brain Damage and Motor Cortex Impairment in Chronic Obstructive Pulmonary Disease: Implication of Nonrapid Eye Movement Sleep Desaturation.

STUDY OBJECTIVES: Nonrapid eye movement (NREM) sleep desaturation may cause neuronal damage due to the withdrawal of cerebrovascular reactivity. The current study (1) assessed the prevalence of NREM sleep desaturation in nonhypoxemic patients with chronic obstructive pulmonary disease (COPD) and (2) compared a biological marker of cerebral lesion and neuromuscular function in patients with and without NREM sleep desaturation. METHODS: One hundred fifteen patients with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] grades 2 and 3), resting PaO2 of 60-80 mmHg, aged between 40 and 80 y, and without sleep apnea (apnea-hypopnea index < 15) had polysomnographic sleep recordings. In addition, twenty-nine patients (substudy) were assessed i) for brain impairment by serum S100B (biological marker of cerebral lesion), and ii) for neuromuscular function via motor cortex activation and excitability and maximal voluntary quadriceps strength measurement. RESULTS: A total of 51.3% patients (n = 59) had NREM sleep desaturation (NREMDes). Serum S100B was higher in the NREMDes patients of the substudy (n = 14): 45.1 [Q1: 37.7, Q3: 62.8] versus 32.9 [Q1: 25.7, Q3: 39.5] pg.ml(-1) (P = 0.028). Motor cortex activation and excitability were lower in NREMDes patients (both P = 0.03), but muscle strength was comparable between groups (P = 0.58). CONCLUSIONS: Over half the nonhypoxemic COPD patients exhibited NREM sleep desaturation associated with higher values of the cerebral lesion biomarker and lower neural drive reaching the quadriceps during maximal voluntary contraction. The lack of muscle strength differences between groups suggests a compensatory mechanism(s). Altogether, the results are consistent with an involvement of NREM sleep desaturation in COPD brain impairment. CLINICAL TRIAL REGISTRATION: The study was registered at www.clinicaltrials.gov as NCT01679782.

Switching an O2 sensitive glucose oxidase bioelectrode into an almost insensitive one by cofactor redesign.

In the 5-8 mM glucose concentration range, of particular interest for diabetes management, glucose oxidase bioelectrodes are O2 dependent, which decrease their efficiencies. By replacing the natural cofactor of glucose oxidase, we succeeded in turning an O2 sensitive bioelectrode into an almost insensitive one.

Formation of high-valent iron-oxo species in superoxide reductase: characterization by resonance Raman spectroscopy.

Superoxide reductase (SOR), a non-heme mononuclear iron protein that is involved in superoxide detoxification in microorganisms, can be used as an unprecedented model to study the mechanisms of O2 activation and of the formation of high-valent iron-oxo species in metalloenzymes. By using resonance Raman spectroscopy, it was shown that the mutation of two residues in the second coordination sphere of the SOR iron active site, K48 and I118, led to the formation of a high-valent iron-oxo species when the mutant proteins were reacted with H2O2. These data demonstrate that these residues in the second coordination sphere tightly control the evolution and the cleavage of the O-O bond of the ferric iron hydroperoxide intermediate that is formed in the SOR active site.

Hydrogen bonding to the cysteine ligand of superoxide reductase: acid-base control of the reaction intermediates.

Superoxide reductase (SOR) is a non-heme iron metalloenzyme that detoxifies superoxide radical in microorganisms. Its active site consists of an unusual non-heme Fe(2+) center in a [His4Cys1] square pyramidal pentacoordination, with the axial cysteine ligand proposed to be an essential feature in catalysis. Two NH peptide groups from isoleucine 118 and histidine 119 establish hydrogen bonds involving the sulfur ligand (Desulfoarculus baarsii SOR numbering). To investigate the catalytic role of these hydrogen bonds, the isoleucine 118 residue of the SOR from Desulfoarculus baarsii was mutated into alanine, aspartate, or serine residues. Resonance Raman spectroscopy showed that the mutations specifically induced an increase of the strength of the Fe(3+)-S(Cys) and S-Cß(Cys) bonds as well as a change in conformation of the cysteinyl side chain, which was associated with the alteration of the NH hydrogen bonding involving the sulfur ligand. The effects of the isoleucine mutations on the reactivity of SOR with O2 (•-) were investigated by pulse radiolysis. These studies showed that the mutations induced a specific increase of the pK a of the first reaction intermediate, recently proposed to be an Fe(2+)-O2 (•-) species. These data were supported by density functional theory calculations conducted on three models of the Fe(2+)-O2 (•-) intermediate, with one, two, or no hydrogen bonds involving the sulfur ligand. Our results demonstrated that the hydrogen bonds between the NH (peptide) and the cysteine ligand tightly control the rate of protonation of the Fe(2+)-O2 (•-) reaction intermediate to form an Fe(3+)-OOH species.

Assessing the role of the active-site cysteine ligand in the superoxide reductase from Desulfoarculus baarsii.

Superoxide reductase is a novel class of non-heme iron proteins that catalyzes the one-electron reduction of O(2)(.) to H(2)O(2), providing an antioxidant defense in some bacteria. Its active site consists of an unusual non-heme Fe(2+) center in a [His(4) Cys(1)] square pyramidal pentacoordination. In this class of enzyme, the cysteine axial ligand has been hypothesized to be an essential feature in the reactivity of the enzyme. Previous Fourier transform infrared spectroscopy studies on the enzyme from Desulfoarculus baarsii revealed that a protonated carboxylate group, proposed to be the side chain of Glu(114), is in interaction with the cysteine ligand. In this work, using pulse radiolysis, Fourier transform infrared, and resonance Raman spectroscopies, we have investigated to what extent the presence of this Glu(114) carboxylic lateral chain affects the strength of the S-Fe bond and the reaction of the iron active site with superoxide. The E114A mutant shows significantly modified pulse radiolysis kinetics for the protonation process of the first reaction intermediate. Resonance Raman spectroscopy demonstrates that the E114A mutation results in both a strengthening of the S-Fe bond and an increase in the extent of freeze-trapping of a Fe-peroxo species after treatment with H(2)O(2) by a specific strengthening of the Fe-O bond. A fine tuning of the strength of the S-Fe bond by the presence of Glu(114) appears to be an essential factor for both the strength of the Fe-O bond and the pK(a) value of the Fe(3+)-peroxo intermediate species to form the reaction product H(2)O(2).

Detoxification of superoxide without production of H2O2: antioxidant activity of superoxide reductase complexed with ferrocyanide.

The superoxide radical O(2)(-.) is a toxic by-product of oxygen metabolism. Two O(2)(-.) detoxifying enzymes have been described so far, superoxide dismutase and superoxide reductase (SOR), both forming H2O2 as a reaction product. Recently, the SOR active site, a ferrous iron in a [Fe(2+) (N-His)(4) (S-Cys)] pentacoordination, was shown to have the ability to form a complex with the organometallic compound ferrocyanide. Here, we have investigated in detail the reactivity of the SOR-ferrocyanide complex with O(2)(-.) by pulse and gamma-ray radiolysis, infrared, and UV-visible spectroscopies. The complex reacts very efficiently with O(2)(-.). However, the presence of the ferrocyanide adduct markedly modifies the reaction mechanism of SOR, with the formation of transient intermediates different from those observed for SOR alone. A one-electron redox chemistry appears to be carried out by the ferrocyanide moiety of the complex, whereas the SOR iron site remains in the reduced state. Surprisingly, the toxic H2O2 species is no longer the reaction product. Accordingly, in vivo experiments showed that formation of the SOR-ferrocyanide complex increased the antioxidant capabilities of SOR expressed in an Escherichia coli sodA sodB recA mutant strain. Altogether, these data describe an unprecedented O(2)(-.) detoxification activity, catalyzed by the SOR-ferrocyanide complex, which does not conduct to the production of the toxic H2O2 species.