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TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes
Örebro universitet, Institutionen för hälsovetenskap och medicin.
Charles Sturt University, Sydney NSW, Australien.
Örebro universitet, Institutionen för hälsovetenskap och medicin.
Danderyd Hospital, Stockholm, Sweden.
2014 (engelsk)Inngår i: International Journal of Molecular Medicine, ISSN 1107-3756, E-ISSN 1791-244X, Vol. 34, nr 1, s. 228-236Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Decreased skeletal muscle capillarization is considered to significantly contribute to the development of pulmonary cachexia syndrome (PCS) and progressive muscle wasting in several chronic inflammatory diseases, including chronic obstructive pulmonary disease (COPD). It is unclear to which extent the concurrent presence of systemic inflammation contributes to decreased skeletal muscle capillarization under these conditions. The present study was designed to examine in vitro the effects of the pro-inflammatory cytokine, tumor necrosis factor (TNF), on the regulation of hypoxia-angiogenesis signal transduction and capillarization in skeletal muscles. For this purpose, fully differentiated C2C12 skeletal muscle myocytes were stimulated with TNF and maintained under normoxic or hypoxic conditions. The expression levels of the putative elements of the hypoxia-angiogenesis signaling cascade were examined using qPCR, western blot analysis and immunofluorescence. Under normoxic conditinos, TNF stimulation increased the protein expression of anti-angiogenic von-Hippel Lindau (VHL), prolyl hydroxylase (PHD)2 and ubiquitin conjugating enzyme 2D1 (Ube2D1), as well as the total ubiquitin content in the skeletal muscle myocytes. By contrast, the expression levels of hypoxia-inducible factor 1‑α (HIF1-α) and those of its transcriptional targets, vascular endothelial growth factor (VEGF)A and glucose transporter 1 (Glut1), were markedly reduced. In addition, hypoxia increased the expression of the VHL transcript and further elevated the VHL protein expression levels in C2C12 myocytes following TNF stimulation. Consequently, an impaired angiogenic potential was observed in the TNF-stimulated myocytes during hypoxia. In conclusion, TNF increases VHL expression and disturbs hypoxia-angiogenesis signal transduction in skeletal muscle myocytes. The current findings provide a mechanism linking systemic inflammation and impaired angiogenesis in skeletal muscle. This is particularly relevant to further understanding the mechanisms mediating muscle wasting and cachexia in patients with chronic inflammatory diseases, such as COPD.

sted, utgiver, år, opplag, sider
Spandidos Publications , 2014. Vol. 34, nr 1, s. 228-236
HSV kategori
Forskningsprogram
Medicinsk handikappvetenskap
Identifikatorer
URN: urn:nbn:se:oru:diva-35141DOI: 10.3892/ijmm.2014.1776ISI: 000338178000027PubMedID: 24820910Scopus ID: 2-s2.0-84902649801OAI: oai:DiVA.org:oru-35141DiVA, id: diva2:719451
Tilgjengelig fra: 2014-05-25 Laget: 2014-05-25 Sist oppdatert: 2018-06-07bibliografisk kontrollert
Inngår i avhandling
1. Molecular mechanisms mediating development of pulmonary cachexia in COPD
Åpne denne publikasjonen i ny fane eller vindu >>Molecular mechanisms mediating development of pulmonary cachexia in COPD
2014 (engelsk)Doktoravhandling, med artikler (Annet vitenskapelig)
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.

sted, utgiver, år, opplag, sider
Örebro: Örebro university, 2014. s. 76
Serie
Örebro Studies in Medicine, ISSN 1652-4063 ; 107
Emneord
COPD, cachexia, atrophy, cigarette smoke, myogenesis, angiogenesis
HSV kategori
Forskningsprogram
Biomedicin; Biokemi
Identifikatorer
urn:nbn:se:oru:diva-36104 (URN)978-91-7529-031-7 (ISBN)
Disputas
2014-09-16, Universitetssjukhuset, hörsal C2, Södra Grev Rosengatan, Örebro, 09:15 (engelsk)
Opponent
Tilgjengelig fra: 2014-08-25 Laget: 2014-08-25 Sist oppdatert: 2018-01-11bibliografisk kontrollert

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