Reduced mitochondrial density in the vastus lateralis muscle of patients with COPD

Gosker, Harry R.; Hesselink, Matthijs K. C.; Duimel, Hans; Ward, Katie; Schols, A.M.W.J.

doi:10.1183/09031936.00146906

Cited by 134 publications

(119 citation statements)

References 31 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: 83%

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

180

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: 83%

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

180

166

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“…Mechanical unloading due to physical inactivity contributes to peripheral muscle abnormalities and dysfunction. Muscle weakness in COPD has been reported primarily in thigh musculature (quadriceps, in both men and women [41]), and more recently documented in the ankle dorsiflexors and plantarflexors [42,43]. Taken together, these abnormalities indicate an overall decline in both the contractile and oxidative capacity of lower limbs muscles in patients with COPD [11].…”

Section: Source Of Gait Abnormalities In Copdmentioning

confidence: 80%

Gait analysis in patients with chronic obstructive pulmonary disease: a systematic review

et al. 2018

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Background: Gait instability is a major fall-risk factor in patients with chronic obstructive pulmonary disease (COPD). Clinical gait analysis is a reliable tool to predict fall onsets. However, controversy still exists on gait impairments associated with COPD. Research question: Thus, the aims of this review were to evaluate the current understanding of spatiotemporal, kinematic and kinetic gait features in patients with COPD. Methods: In line with PRISMA guidelines, a systematic literature search was performed throughout Web of Science, PubMed Medline, Scopus, PEDro and Scielo databases. We considered observational cross-sectional studies evaluating gait features in patients with COPD as their primary outcome. Risk of bias and applicability of these papers were assessed according to the QUADAS-2 tool. Results: Seven articles, cross-sectional studies published from 2011 to 2017, met the inclusion criteria. Sample size of patients with COPD ranged 14-196 (mean age range: 64-75 years). The main reported gait abnormalities were reduced step length and cadence, and altered variability of spatiotemporal parameters. Only subtle biomechanical changes were reported at the ankle level. Significance: A convincing mechanistic link between such gait impairments and falls in patients with COPD is still lacking. The paucity of studies, small sample sizes, gender and disease status pooling were the main risk of biases affecting the results uncertainty. Two research directions emerged: stricter cohorts characterization in terms of COPD phenotype and longitudinal studies. Quantitative assessment of gait would identify abnormalities and sensorimotor postural deficiencies that in turn may lead to better falling prevention strategies in COPD.

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“…In the context of earlier 31 P-MRS measurements of CK reaction kinetics in human calf muscle (7) and estimates of mitochondrial spacing in mammalian myocytes (17,42,44), knowledge about D PCr provides important insights into the role that PCr diffusion could play in energy transfer via the putative PCr shuttle mechanism in human muscle.…”

mentioning

confidence: 99%

High-energy phosphate transfer in human muscle: diffusion of phosphocreatine

Gabr¹,

El-Sharkawy²,

Schär

et al. 2011

American Journal of Physiology-Cell Physiology

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The creatine kinase (CK) reaction is central to muscle energetics, buffering ATP levels during periods of intense activity via consumption of phosphocreatine (PCr). PCr is believed to serve as a spatial shuttle of high-energy phosphate between sites of energy production in the mitochondria and sites of energy utilization in the myofibrils via diffusion. Knowledge of the diffusion coefficient of PCr (D PCr) is thus critical for modeling and understanding energy transport in the myocyte, but DPCr has not been measured in humans. Using localized phosphorus magnetic resonance spectroscopy, we measured D PCr in the calf muscle of 11 adults as a function of direction and diffusion time. The results show that the diffusion of PCr is anisotropic, with significantly higher diffusion along the muscle fibers, and that the diffusion of PCr is restricted to a ϳ28-m pathlength assuming a cylindrical model, with an unbounded diffusion coefficient of ϳ0.69 ϫ 10 Ϫ3 mm 2 /s. This distance is comparable in size to the myofiber radius. On the basis of prior measures of CK reaction kinetics in human muscle, the expected diffusion distance of PCr during its half-life in the CK reaction is ϳ66 m. This distance is much greater than the average distances between mitochondria and myofibrils. Thus these first measurements of PCr diffusion in human muscle in vivo support the view that PCr diffusion is not a factor limiting high-energy phosphate transport between the mitochondria and the myofibrils in healthy resting myocytes. myocyte; energy metabolism; creatine kinase shuttle; human studies PHOSPHOCREATINE (PCr) serves as the main short-term energy reserve in muscle, heart, and brain. PCr generates ATP to fuel cellular processes, including ion transport and muscular contraction, via the creatine kinase (CK) reaction. The CK reaction reversibly transfers a phosphoryl group between PCr and ATP, with unphosphorylated Cr and ADP as the other reactants and k as the forward pseudo-first-order rate constant of the reaction: PCr ϩ ADP ϩ H ϩ ↔ k ATP ϩ Cr . It was long ago hypothesized that the CK reaction serves as an intracellular energy shuttle, facilitating the transfer of high-energy phosphate from sites of de novo ATP creation in the mitochondria to sites of energy utilization, such as the myofibrils (4, 29, 45). The energy transfer mechanism in this PCr shuttle hypothesis involves 1) the creation of PCr at the mitochondria from the reverse CK reaction, 2) the diffusion of PCr to the point of use (including possible recycling through CK in the cytosol), and 3) the regeneration of ATP from ADP and PCr via the forward CK reaction to supply the needed energy (Fig. 1). Provided that the rate of ATP production via CK is manyfold higher than that generated by oxidative phosphorylation, the CK reaction could serve as a temporal-spatial energy buffer, supplying ATP when and where it is needed during periods of acute demand and/or stress.Since PCr diffusion is central to the PCr shuttle hypothesis, knowledge of its diffusion coefficient (D PCr ) is ...

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Reduced mitochondrial density in the vastus lateralis muscle of patients with COPD

Cited by 134 publications

References 31 publications

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Mitochondrial fragmentation in cigarette smoke-induced bronchial epithelial cell senescence

Gait analysis in patients with chronic obstructive pulmonary disease: a systematic review

High-energy phosphate transfer in human muscle: diffusion of phosphocreatine

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