TNF stimulation induces VHL overexpression and impairs angiogenic potential in skeletal muscle myocytes

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinsk bioteknologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Medical Biotechnology (hsv//eng)

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Medicinsk handikappvetenskap

Medical Disability Research

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