Down-regulation of hypoxia inducible factor-1alpha: a possible explanation for the protective effects of estrogen on genioglossus fatigue resistance.

ABSTRACT

Patients with obstructive sleep apnea/hypopnea syndrome (OSAHS) often exhibit fatigued or inefficient upper airway dilator muscle activity. It has been shown that estrogen may have some impact on upper airway contractility under normoxic conditions. Chronic intermittent hypoxia (CIH) is a frequent feature of OSAHS, and it may alter muscle susceptibility to oxidative stress, a characteristic of a fatigable nature. Hypoxia inducible factor-1 (HIF-1) is a transcription factor that is responsible for the regulation of oxygen homeostasis under hypoxic conditions. We examined the effects of estrogen on the contractility of the genioglossus by exposing rats to alternating cycles of 6-8% O(2) every 15 s for a total duration of 35 d. The results showed that muscle fatigue resistance was significantly decreased after CIH but was partially reversed after estrogen treatment. Compared with the control group, real-time reverse transcription-polymerase chain reaction and western blotting showed higher levels of HIF-1alpha messenger RNA and protein in the CIH group, but estrogen treatment reduced, in a dose-independent manner, the levels of HIF-1alpha messenger RNA and protein in rats exposed to CIH. We conclude that CIH induced the expression of HIF-1alpha in the genioglossus and altered the physical properties towards a more fatigable phenotype, whereas estrogen inhibited the over-expression of HIF-1alpha, and this may account for the improvement of upper airway muscle endurance in CIH rats.