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Cited by 46Mitochondrial Function and PathologyMuscle Physiology and DisordersChronic Obstructive Pulmonary Disease (COPD) Research

Failed Upregulation of TFAM Protein and Mitochondrial DNA in Oxidatively Deficient Fibers of Chronic Obstructive Pulmonary Disease Locomotor Muscle

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Konokhova, Yana, Spendiff, Sally, Jagoe, R. Thomas, Aare, Sudhakar, Kapchinsky, Sophia, MacMillan, Norah J., Rozakis, Paul, Picard, Martin +5 more·2016·Skeletal Muscle
DOI 10.1186/s13395-016-0083-9PMC PMC4758107
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Abstract

BACKGROUND: Low mitochondrial content and oxidative capacity are well-established features of locomotor muscle dysfunction, a prevalent and debilitating systemic occurrence in patients with chronic obstructive pulmonary disease (COPD). Although the exact cause is not firmly established, physical inactivity and oxidative stress are among the proposed underlying mechanisms. Here, we assess the impact of COPD pathophysiology on mitochondrial DNA (mtDNA) integrity, biogenesis, and cellular oxidative capacity in locomotor muscle of COPD patients and healthy controls. We hypothesized that the high oxidative stress environment of COPD muscle would yield a higher presence of deletion-containing mtDNA and oxidative-deficient fibers and impaired capacity for mitochondrial biogenesis. METHODS: Vastus lateralis biopsies were analyzed from 29 COPD patients and 19 healthy age-matched controls for the presence of mtDNA deletions, levels of oxidatively damaged DNA, mtDNA copy number, and regulators of mitochondrial biogenesis as well the proportion of oxidative-deficient fibers (detected histologically as cytochrome c oxidase-deficient, succinate dehydrogenase positive (COX(-)/SDH(+) )). Additionally, mtDNA copy number and mitochondrial transcription factor A (TFAM) content were measured in laser captured COX(-)SDH(+) and normal single fibers of both COPD and controls. RESULTS: Compared to controls, COPD muscle exhibited significantly higher levels of oxidatively damaged DNA (8-hydroxy-2-deoxyguanosine (8-OHdG) levels = 387 ± 41 vs. 258 ± 21 pg/mL) and higher prevalence of mtDNA deletions (74 vs. 15 % of subjects in each group), which was accompanied by a higher abundance of oxidative-deficient fibers (8.0 ± 2.1 vs. 1.5 ± 0.4 %). Interestingly, COPD patients with mtDNA deletions had higher levels of 8-OHdG (457 ± 46 pg/mL) and longer smoking history (66.3 ± 7.5 years) than patients without deletions (197 ± 29 pg/mL; 38.0 ± 7.3 years). Transcript levels of regulators of mitochondrial biogenesis and oxidative metabolism were upregulated in COPD compared to controls. However, single fiber analyses of COX(-)/SDH(+) and normal fibers exposed an impairment in mitochondrial biogenesis in COPD; in healthy controls, we detected a marked upregulation of mtDNA copy number and TFAM protein in COX(-)/SDH(+) compared to normal fibers, reflecting the expected compensatory attempt by the oxidative-deficient cells to increase energy levels; in contrast, they were similar between COX(-)/SDH(+) and normal fibers in COPD patients. Taken together, these findings suggest that although the signaling factors regulating mitochondrial biogenesis are increased in COPD muscle, impairment in the translation of these signals prevents the restoration of normal oxidative capacity. CONCLUSIONS: Single fiber analyses provide the first substantive evidence that low muscle oxidative capacity in COPD cannot be explained by physical inactivity alone and is likely driven by the disease pathophysiology.

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  • Data consistently show a decreased mitochondrial density in COPD muscle tissue, usually reflected by a decrease in citrate synthase expression or activity.

    “data consistently show a decreased mitochondrial density in COPD muscle tissue, usually reflected by a decrease in citrate synthase expression or activity, as a mitochondrial mass marker [87].”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [87]

  • Evidence for DNA damage in COPD muscle is scarce but includes higher 8-OHdG levels in COPD quadriceps compared to controls.

    “The evidence for DNA damage is scarce but includes higher (8-OHdG) levels in COPD quadriceps compared to controls [87].”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [87]

  • Several studies have found increased lipofuscin accumulation in COPD quadriceps and higher levels of 4-HNE in quadriceps tissue, as well as in cultured myotubes from COPD patients.

    “For example, several studies have found an increased lipofuscin accumulation in COPD quadriceps [126] and higher levels of hydroxy-2-nonenal (4-HNE) in quadriceps tissue [87,127], as well as in cultured myotubes from COPD patients [128].”

    From Main Pathogenic Mechanisms and Recent Advances in COPD Peripheral Skeletal Muscle Wasting (2023) · cites this paper as [87]

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Authors
Konokhova, Y., Spendiff, S., Jagoe, R. T., Aare, S., Kapchinsky, S., MacMillan, N. J., Rozakis, P., Picard, M., Aubertin-Leheudre, M., Pion, C. H., Bourbeau, J., Hepple, R. T., & Taivassalo, T.
Affiliations
  • McGill University Health Centre (CA)
  • McGill University (CA)
  • Columbia University Irving Medical Center (US)
  • Université du Québec à Montréal (CA)
Corresponding author
Taivassalo, Tanja
ORCID
Venue
Skeletal Muscle
Publisher
Springer Science and Business Media LLC
Published
2016-02-18
Volume
6
Issue
1
Pages
10-10
ISSN
2044-5040 (ISSN-L)
DOI
10.1186/s13395-016-0083-9
PMC
PMC4758107
OpenAlex
W2283053705
Cited by
46
References
63
Citations by year
2026: 3 · 2025: 2 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 6 · 2020: 7 · 2019: 2 · 2018: 4 · 2017: 7 · 2016: 3 · 2015: 1
FWCI
2.77
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • Skeletal Muscle (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
Funders
  • Canadian Institutes of Health Research (162111)
  • Natural Sciences and Engineering Research Council of Canada (303606)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Mitochondrial Function and Pathology
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Chronic Obstructive Pulmonary Disease (COPD) Research
Keywords
chronic obstructive pulmonary disease, locomotor muscles, mitochondrial DNA deletions, oxidative stress, mitochondrial biogenesis, TFAM, mitochondrial DNA copy number, cytochrome c oxidase deficiency, succinate dehydrogenase, 8-hydroxy-2'-deoxyguanosine, vastus lateralis, smoking history, skeletal muscle dysfunction, oxidative metabolism
MeSH terms
Aged, Organelle Biogenesis, Electron Transport Complex IV, DNA Damage, DNA-Binding Proteins, DNA, Mitochondrial, Female, Humans, Male, Middle Aged, Mitochondria, Muscle, Succinate Dehydrogenase, Transcription Factors, Transcription, Genetic, Up-Regulation, Case-Control Studies, Oxidative Stress, Muscle Fibers, Skeletal, Mitochondrial Proteins, Pulmonary Disease, Chronic Obstructive, Quadriceps Muscle

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