Author/Editor		Pirkmajer, Sergej; Filipovič, Dragana; Marš, Tomaž; Miš, Katarina; Grubič, Zoran
Title		HIF-1alpha response to hypoxia is functionally separated from the glucocorticoid stress response in the in vitro regenerating human skeletal muscle
Type		članek
Source		Am J Physiol Regul Integr Comp Physiol
Vol. and No.		Letnik 299, št. 6
Publication year		2010
Volume		str. R1693-700
Language		eng
Abstract		Injury of skeletal muscle is followed by muscle regeneration in which new muscle tissue is formed from the proliferating mononuclear myoblasts, and by systemic response to stress which exposes proliferating myoblasts to increased glucocorticoid (GC) concentration. Due to its various causes hypoxia is a frequent condition affecting skeletal muscle and therefore both processes, which importantly determine the outcome of the injury, often proceed under hypoxic conditions. It is therefore important to identify and characterize in proliferating human myoblasts: 1) response to hypoxia which is generally organized by hypoxia inducible factor-1alpha (HIF-1alpha); 2) response to GCs which is mediated through the isoforms of glucocorticoid receptors (GRs) and 11beta-Hydroxysteroid Dehydrogenases (11beta-HSDs) and 3) the response to GCs under the hypoxic conditions and the influence of this combination on the factors controlling myoblast proliferation. Using real-time PCR, Western blotting and HIF-1alpha siRNA silencing we demonstrated that cultured human myoblasts possess both, the HIF-1alpha based response to hypoxia as well as the GC response system composed of GRalpha and types 1 and 2 11beta-HSDs. However, using combined dexamethasone and hypoxia treatments we demonstrated that these two systems operate practically without mutual interactions. A seemingly surprising separation of the two systems which both organize response to hypoxic stress can be explained on the evolutionary basis: phylogenetically older HIF-1alpha response is a protection at the cellular level, while GC stress response protects the organism as a whole. This necessitates actions, like downregulation of IL-6 secretion and VEGF, which might not be of direct benefit for the affected myoblasts.
Descriptors		MUSCLE, SKELETAL ANOXIA GLUCOCORTICOIDS STRESS RECEPTORS, GLUCOCORTICOID REGENERATION HYDROXYSTEROID DEHYDROGENASES ENDOTHELIAL GROWTH FACTORS ENDOTHELIUM, VASCULAR POLYMERASE CHAIN REACTION CELLS, CULTURED