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Exposure to cigarette smoke induces overexpression of von Hippel-Lindau tumor suppressor in mouse skeletal muscle
Department of Clinical Medicine, Örebro University, Örebro, Sweden.
Department of Clinical Medicine, Örebro University, Örebro, Sweden.
Department of Clinical Medicine, Örebro University, Örebro, Sweden.
Department of Environmental Medicine, Lung Biology and Disease Program, University of Rochester Medical Center, Rochester NY, USA.
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2012 (English)In: American Journal of Physiology - Lung cellular and Molecular Physiology, ISSN 1040-0605, E-ISSN 1522-1504, Vol. 303, no 6, p. L519-L527Article in journal (Refereed) Published
Abstract [en]

Cigarette smoke (CS) is a well established risk factor in the development of chronic obstructive pulmonary disease (COPD). In contrast, the extent to which CS exposure contributes to the development of the systemic manifestations of COPD, such as skeletal muscle dysfunction and wasting remains largely unknown. Decreased skeletal muscle capillarization has been previously reported in early stages of COPD and might play an important role in the development of COPD-associated skeletal muscle abnormalities. To investigate the effects of chronic CS exposure on skeletal muscle capillarization and exercise tolerance a mouse model of CS exposure was used. The129/SvJ mice were exposed to CS for 6 months, and the expression of putative elements of the hypoxia-angiogenic signaling cascade as well as muscle capillarization were studied. Additionally, functional tests assessing exercise tolerance/endurance were performed in mice. Compared to controls, skeletal muscles from CS-exposed mice exhibited significantly enhanced expression of von Hippel-Lindau tumor suppressor (VHL), ubiquitin-conjugating enzyme E2D1 (UBE2D1) and prolyl hydroxylase-2 (PHD2). In contrast, hypoxia-inducible factor-1 (HIF1-α) and vascular endothelial growth factor (VEGF) expression was reduced. Furthermore, reduced muscle fiber cross-sectional area, decreased skeletal muscle capillarization, and reduced exercise tolerance were also observed in CS-exposed animals. Taken together, the current results provide evidence linking chronic CS exposure and induction of VHL expression in skeletal muscles leading towards impaired hypoxia-angiogenesis signal transduction, reduced muscle fiber cross-sectional area and decreased exercise tolerance.

Place, publisher, year, edition, pages
Bethesda, USA: American Physiological Society , 2012. Vol. 303, no 6, p. L519-L527
Keywords [en]
Capillaries, chronic obstructive pulmonary disease, hypoxia inducible factor-1 alpha, pulmonary cachexia syndrome, vascular endothelial growth factor
National Category
Medical and Health Sciences Physiotherapy
Research subject
Biomedicine
Identifiers
URN: urn:nbn:se:oru:diva-24177DOI: 10.1152/ajplung.00007.2012ISI: 000309109300005PubMedID: 22842216Scopus ID: 2-s2.0-84866418091OAI: oai:DiVA.org:oru-24177DiVA, id: diva2:542405
Funder
NIH (National Institute of Health)
Note

Funding Agencies:

Olle Engkvist Byggmastare Fund, Sweden

NIEHS Environmental Health Science Center grant 

Available from: 2012-07-31 Created: 2012-07-31 Last updated: 2018-05-09Bibliographically approved
In thesis
1. Molecular mechanisms mediating development of pulmonary cachexia in COPD
Open this publication in new window or tab >>Molecular mechanisms mediating development of pulmonary cachexia in COPD
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Cigarette smoking (CS) represents the main causative agent underlying development and progress of COPD. Recently, involvement of CS in the pathogenesis of COPDassociated muscle abnormalities is becoming increasingly evident. Nevertheless, involved triggers and underlying mechanisms remain largely unknown. This study was conceived in order to examine effects of cigarette smoke exposure on skeletal muscle morphology, vascular supply and function. For this purpose, we have specifically designed murine COPD/emphysema model and gastrocnemius muscle was examined, while in vitro experiments were conducted using murine C2C12 skeletal muscle myocytes.

In addition to the mild emphysematous changes present in the lungs of CS-exposed mice, our results demonstrated evident signs of muscle atrophy reflected by decreased fiber cross-sectional area, profound fiber size variation and reduced body mass. Furthermore, we have observed impairment in terminal myogenesis and lower number of myonuclei in skeletal muscles of CS-exposed animals despite evident activation of muscle repair process. Additionally, our results demonstrate capillary rarefaction in skeletal muscles of CS-exposed animals which was associated with deregulation of hypoxia-angiogenesis signaling, reduced levels of angiogenic factors such as HIF1-α and VEGF and enhanced expression of VHL and its partner proteins PHD2 and Ube2D1. The results of our in-vitro experiments demonstrated that VHL and its ubiquitination machinery can be synergistically regulated by TNF and hypoxia consequentially impairing angiogenic potential of skeletal muscle myocytes. Finally, we have shown that CS elicits chronic ER stress in murine skeletal muscles which is associated with activation of ERAD and apoptotic pathways as mirrored by elevated expression of Usp19, caspase 12 and caspase 3 in skeletal muscles of CSexposed animals. Moreover, molecular and morphological alterations in CS-exposed mice resulted in impairment of muscle function as reflected by their impaired exercise capacity.

Taken together, from our results it is evident that cigarette smoke exposure elicits set of morphological, vascular and functional changes highly resembling those observed in COPD. Additionally, CS induces wide range of molecular alterations and signaling pathway deregulations suggesting profound effects of cigarette smoke exposure on skeletal muscle cell homeostasis.

Place, publisher, year, edition, pages
Örebro: Örebro university, 2014. p. 76
Series
Örebro Studies in Medicine, ISSN 1652-4063 ; 107
Keywords
COPD, cachexia, atrophy, cigarette smoke, myogenesis, angiogenesis
National Category
Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Biomedicine; Biochemistry
Identifiers
urn:nbn:se:oru:diva-36104 (URN)978-91-7529-031-7 (ISBN)
Public defence
2014-09-16, Universitetssjukhuset, hörsal C2, Södra Grev Rosengatan, Örebro, 09:15 (English)
Opponent
Available from: 2014-08-25 Created: 2014-08-25 Last updated: 2018-01-11Bibliographically approved

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Elmabsout, Ali AteiaSirsjö, AllanAbdel-Halim, Samy M.

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Basic, Vladimir TomislavElmabsout, Ali AteiaSirsjö, AllanAbdel-Halim, Samy M.
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