Hypoxia-induced gene activity in disused oxidative muscle

Däpp, Christoph; Gassmann, Max; Hoppeler, Hans; Flück, Martin (2006). Hypoxia-induced gene activity in disused oxidative muscle. Advances in experimental medicine and biology, 588, pp. 171-188. Wien: Springer

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Hypoxia is an important modulator of the skeletal muscle's oxidative phenotype. However, little is known regarding the molecular circuitry underlying the muscular hypoxia response and the interaction of hypoxia with other stimuli of muscle oxidative capacity. We hypothesized that exposure of mice to severe hypoxia would promote the expression of genes involved in capillary morphogenesis and glucose over fatty acid metabolism in active or disused soleus muscle of mice. Specifically, we tested whether the hypoxic response depends on oxygen sensing via the alpha-subunit of hypoxia-inducible factor-1 (HIF-1 alpha). Spontaneously active wildtype and HIF-1 alpha heterozygous deficient adult female C57B1/6 mice were subjected to hypoxia (PiO2 70 mmHg). In addition, animals were subjected to hypoxia after 7 days of muscle disuse provoked by hindlimb suspension. Soleus muscles were rapidly isolated and analyzed for transcript level alterations with custom-designed AtlasTM cDNA expression arrays (BD Biosciences) and cluster analysis of differentially expressed mRNAs. Multiple mRNA elevations of factors involved in dissolution and stabilization of blood vessels, glycolysis, and mitochondrial respiration were evident after 24 hours of hypoxia in soleus muscle. In parallel transcripts of fat metabolism were reduced. A comparable hypoxia-induced expression pattern involving complex alterations of the IGF-I axis was observed in reloaded muscle after disuse. This hypoxia response in spontaneously active animals was blunted in the HIF-1 alpha heterozygous deficient mice demonstrating 35% lower HIF-1 alpha mRNA levels. Our molecular observations support the concept that severe hypoxia provides HIF-1-dependent signals for remodeling of existing blood vessels, a shift towards glycolytic metabolism and altered myogenic regulation in oxidative mouse muscle and which is amplified by enhanced muscle use. These findings further imply differential mitochondrial turnover and a negative role of HIF-1 alpha for control of fatty acid oxidation in skeletal muscle exposed to one day of severe hypoxia.

Item Type:	Journal Article (Original Article)
Division/Institute:	04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy > Functional Anatomy 04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
UniBE Contributor:	Däpp, Christoph, Hoppeler, Hans-Heinrich, Flück, Martin
ISSN:	0065-2598
ISBN:	17089889
Publisher:	Springer
Language:	English
Submitter:	Factscience Import
Date Deposited:	04 Oct 2013 14:46
Last Modified:	05 Dec 2022 14:14
PubMed ID:	17089889
Web of Science ID:	000241637100016
URI:	https://boris.unibe.ch/id/eprint/18931 (FactScience: 1202)