Mechanisms and meaning of activation of Hypoxia-Inducible-Factor-1 (HIF-1) in muscle after mechanical trauma

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During the course of mechanical muscle trauma hypoxic regions develop due to the rupture of blood vessels or their compression by oedema. Gene expression in hypoxic tissue areas is coordinated through activation of hypoxia-inducible factor 1 (HIF-1). In particular leukocytes that extravasate from the vessels into the hypoxic tissue depend on HIF-1 activated gene expression for their proper function. Mice with targeted deletion of HIF-1α, the oxygen regulated subunit of HIF-1, either in myeloid or muscle cells were used in a model of closed muscle trauma. Knockout of HIF-1α in myeloid cells revealed a major delay in the extravasation of leukocytes and the onset of regeneration. Muscle cells without HIF-1α tended to be damaged more rapidly but to also started regeneration earlier. Immuno-histochemistry for HIF-1α and its homolog HIF-2α revealed a pronounce increase in HIF-2α positive cells up to 7 days after a trauma. We will now study a myeloid specific knockout of HIF-2α. In addition, mice that lack myeloid von-Hippel-Lindau protein that is responsible for HIF-α degradation will be tested for the effect of high HIF-1/2α levels in leukocytes in muscle trauma. Since drugs that increase HIF-1/2α are already in clinical testing, our studies may provide the basis for such kind of treatment in mechanical muscle trauma.