The Mitochondrial Phenotype of Peripheral Muscle in Chronic Obstructive Pulmonary Disease

Picard, Martin; Godin, Richard; Sinnreich, Michael; Baril, Jacinthe; Bourbeau, Jean; Perrault, Hélène; Taivassalo, Tanja; Burelle, Yan

doi:10.1164/rccm.200807-1005oc

Cited by 85 publications

(127 citation statements)

References 62 publications

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“…In electron microscopic examination of lung tissues, we demonstrated that mitochondria in bronchial epithelial cells tended to be fragmented in COPD but not in smokers without COPD, suggesting the fission process dominancy of mitochondrial dynamics in COPD pathogenesis. These results are in accordance with previous reports demonstrating that mitochondria in skeletal muscles from COPD patients tended to be smaller in size accompanied by increased ROS production (16,37,39).…”

Section: Discussionsupporting

confidence: 93%

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Hara

Araya

Ito

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

176

166

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Mitochondria are dynamic organelles that continuously change their shape through fission and fusion. Disruption of mitochondrial dynamics is involved in disease pathology through excessive reactive oxygen species (ROS) production. Accelerated cellular senescence resulting from cigarette smoke exposure with excessive ROS production has been implicated in the pathogenesis of chronic obstructive pulmonary disease (COPD). Hence, we investigated the involvement of mitochondrial dynamics and ROS production in terms of cigarette smoke extract (CSE)-induced cellular senescence in human bronchial epithelial cells (HBEC). Mitochondrial morphology was examined by electron microscopy and fluorescence microscopy. Senescence-associated β-galactosidase staining and p21 Western blotting of primary HBEC were performed to evaluate cellular senescence. Mitochondrial-specific superoxide production was measured by MitoSOX staining. Mitochondrial fragmentation was induced by knockdown of mitochondrial fusion proteins (OPA1 or Mitofusins) by small-interfering RNA transfection. N-acetylcysteine and Mito-TEMPO were used as antioxidants. Mitochondria in bronchial epithelial cells were prone to be more fragmented in COPD lung tissues. CSE induced mitochondrial fragmentation and mitochondrial ROS production, which were responsible for acceleration of cellular senescence in HBEC. Mitochondrial fragmentation induced by knockdown of fusion proteins also increased mitochondrial ROS production and percentages of senescent cells. HBEC senescence and mitochondria fragmentation in response to CSE treatment were inhibited in the presence of antioxidants. CSE-induced mitochondrial fragmentation is involved in cellular senescence through the mechanism of mitochondrial ROS production. Hence, disruption of mitochondrial dynamics may be a part of the pathogenic sequence of COPD development.

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Section: Discussionsupporting

confidence: 93%

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Hara

Araya

Ito

et al. 2013

American Journal of Physiology-Lung Cellular and Molecular Phys

176

166

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“…Given the tendency for a greater acidosis in patients with COPD (7.06 Ϯ 0.10 in control and 6.95 Ϯ 0.22 in COPD), lower end exercise pH may have slowed the PCr recovery time constant, confounding our interpretation of this parameter. However, despite this difference in pH in this group, the PCr recovery time constant was not significantly different between controls and COPD, which further illustrates that muscle oxidative capacity was preserved in patients with COPD as previously suggested in vivo (20) and in permeabilized muscle fibers (24).…”

Section: Discussionsupporting

confidence: 80%

Evidence that a higher ATP cost of muscular contraction contributes to the lower mechanical efficiency associated with COPD: preliminary findings

Layec

Haseler

Hoff

et al. 2011

American Journal of Physiology-Regulatory, Integrative and Comp

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Layec G, Haseler LJ, Hoff J, Richardson RS. Evidence that a higher ATP cost of muscular contraction contributes to the lower mechanical efficiency associated with COPD: preliminary findings. Am J Physiol Regul Integr Comp Physiol 300: R1142-R1147, 2011. First published February 9, 2011 doi:10.1152/ajpregu.00835.2010.-Impaired metabolism in peripheral skeletal muscles potentially contributes to exercise intolerance in chronic obstructive pulmonary disease (COPD). We used 31 P-magnetic resonance spectroscopy ( 31 P-MRS) to examine the energy cost and skeletal muscle energetics in six patients with COPD during dynamic plantar flexion exercise compared with six well-matched healthy control subjects. Patients with COPD displayed a higher energy cost of muscle contraction compared with the controls (control: 6.1 Ϯ 3.1% of rest·min Ϫ1 ·W Ϫ1 , COPD: 13.6 Ϯ 8.3% of rest·min Ϫ1 ·W Ϫ1 , P ϭ 0.01). Although, the initial phosphocreatine resynthesis rate was also significantly attenuated in patients with COPD compared with controls (control: 74 Ϯ 17% of rest/min, COPD: 52 Ϯ 13% of rest/min, P ϭ 0.04), when scaled to power output, oxidative ATP synthesis was similar between groups (6.5 Ϯ 2.3% of rest·min Ϫ1 ·W Ϫ1 in control and 7.8 Ϯ 3.9% of rest·min Ϫ1 ·W Ϫ1 in COPD, P ϭ 0.52). Therefore, our results reveal, for the first time that in a small subset of patients with COPD a higher ATP cost of muscle contraction may substantially contribute to the lower mechanical efficiency previously reported in this population. In addition, it appears that some patients with COPD have preserved mitochondrial function and normal energy supply in lower limb skeletal muscle. 31 P-MRS; muscle metabolism; exercise; mitochondrial function LIMITED EXERCISE CAPACITY not only plays a central role in the life of patients with chronic obstructive pulmonary disease (COPD), but also acts both as a marker of well-being and a prognostic tool. Given that COPD is a disease of the lung, it has long been proposed that the inability to sustain a high level of ventilation was the main factor that limited exercise performance in these patients (3). However, as leg discomfort was a frequent exercise-limiting symptom invoked by patients with COPD during cycling exercise (15), peripheral muscle dysfunction has also been implicated (19). To date, the mechanistic basis for this exercise intolerance is still unresolved (6, 22), although a decrease in muscle strength and endurance along with reduced capillarization, percentage of oxidative fibers, and a reduced activity of different oxidative enzymes measured in vitro may play a role.These biochemical and histochemical changes observed in the peripheral skeletal muscle of patients with COPD (32) likely alter muscle energy production during exercise and recovery, which may, in turn, affect exercise capacity. Previously, a decreased mechanical efficiency (the chemical conversion of energy to mechanical work) has been reported in a small subset of patients with COPD (1, 25). In these studies, such a decrease in mechanical...

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“…Locomotor muscle oxidative capacity is reduced in COPD (44,45,(175)(176)(177)(178)(179)(185)(186)(187)(188)(189)(190)(191). This has been demonstrated by direct measures of mitochondrial density by electron microscopy (175); by spectrophotometric determination of mitochondrial enzyme activities including citrate synthase (CS), succinate dehydrogenase (SDH), 3-hydroxyacylcoenzyme A dehydrogenase (HAD), and cytochrome oxidase (COX) (176)(177)(178); and by measurements of respiration in permeabilized muscle fibers (179). In line with these observations, the mRNA and/or protein expression of key mitochondrial transcriptional factors and coactivators, including peroxisome proliferator-activated receptor g coactivator-1 (PGC1), peroxisome proliferator-activated receptors (PPAR), and mitochondrial transcription factor A (Tfam), are/is also reduced (180), suggesting a lower drive for mitochondrial biogenesis in COPD muscle.…”

Section: Mitochondrial Function Of Limb Muscle In Copd and Bioenergeticsmentioning

confidence: 99%

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

Maltais¹,

Decramer²,

Casaburi³

et al. 2014

Am J Respir Crit Care Med

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The Mitochondrial Phenotype of Peripheral Muscle in Chronic Obstructive Pulmonary Disease

Cited by 85 publications

References 62 publications

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Evidence that a higher ATP cost of muscular contraction contributes to the lower mechanical efficiency associated with COPD: preliminary findings

An Official American Thoracic Society/European Respiratory Society Statement: Update on Limb Muscle Dysfunction in Chronic Obstructive Pulmonary Disease

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