Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is a major determinant in the enhanced function of muscle-derived progenitors from MRL/MpJ mice

摘要

Although the mouse strain Murphy Roths Large (MRL/MpJ) possesses high regenerative potential, the mechanism of tissue regeneration, including skeletal muscle, in MRL/MpJ mice after injury is still unclear. Our previous studies have shown that muscle-derived stem/progenitor cell (MDSPC) function is significantly enhanced in MRL/MpJ mice when compared with MDSPCs isolated from age-matched wild-type (WT) mice. Using mass spectrometry-based proteomic analysis, we identified increased expression of hypoxia-inducible factor (HIF) 1 alpha target genes (expression of glycolytic factors and antioxidants) in sera from MRL/MpJ mice compared with WT mice. Therefore, we hypothesized that HIF-1 alpha promotes the high muscle healing capacity of MRL/MpJ mice by increasing the potency of MDSPCs. We demonstrated that treating MRL/MpJ MDSPCs with dimethyloxalylglycine and CoCl2 increased the expression of HIF-1 alpha and target genes, including angiogenic and cell survival genes. We also observed that HIF-1 alpha activated the expression of paired box (Pax)7 through direct interaction with the Pax7 promoter. Furthermore, we also observed a higher myogenic potential of MDSPCs derived from prolyl hydroxylase (Phd) 3-knockout (Phd3(-/-)) mice, which displayed higher stability of HIF-1 alpha. Taken together, our findings suggest that HIF-1 alpha is a major determinant in the increased MDSPC function of MRL/MpJ mice through enhancement of cell survival, proliferation, and myogenic differentiation.-Sinha, K. M., Tseng, C., Guo, P., Lu, A., Pan, H., Gao, X., Andrews, R., Eltzschig, H., Huard, J. Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is a major determinant in the enhanced function of muscle-derived progenitors from MRL/MpJ mice.