HIF-P4H-2 deficiency protects against skeletal muscle ischemia-reperfusion injury

We show here that mice hypomorphic for hypoxia-inducible factor prolyl 4-hydroxylase-2 (hif-p4h-2) (hif-p4h-2 gt/gt ), the main regulator of the stability of the hifα subunits, have normoxic stabilization of hif-1α and hif-2α in their skeletal muscles. the size of the capillaries, but not their number, was increased in the skeletal muscles of the hif-p4h-2 gt/gt mice, whereas the amount of glycogen was reduced. the expression levels of genes for glycolytic enzymes, glycogen branching enzyme 1 and monocarboxylate transporter 4, were increased in the hif-p4h-2 gt/gt skeletal muscles, whereas no significant increases were detected in the levels of any vasculature-influencing factor studied. serum lactate levels of the hif-p4h-2 gt/gt mice recovered faster than those of the wild type following exercise. the hif-p4h-2 gt/gt mice had elevated hepatic phosphoenolpyruvate carboxykinase activity, which have contributed to the faster clearance of lactate. the hif-p4h-2 gt/gt mice had smaller infarct size following limb ischemia-reperfusion injury. the increased capillary size correlated with the reduced infarct size. following ischemia-reperfusion, glycogen content and atp/adp and crp/cr levels of the skeletal muscle of the hif-p4h-2 gt/gt mice were higher than in the wild type. the higher glycogen content correlated with increased expression of phosphofructokinase messenger rna (mrna) and the increased atp/adp and crp/cr levels with reduced apoptosis, suggesting that hif-p4h-2 deficiency supported energy metabolism during ischemia-reperfusion and protection against injury.