Effects of phytoestrogens on genioglossus contractile properties in ovariectomized rats exposed to chronic intermittent hypoxia may be independent of their estrogenicity

Abstract

Chronic intermittent hypoxia (CIH) is a frequent feature of obstructive sleep apnea/hypopnea syndrome (OSAHS), and it may alter upper airway muscle endurance. We have previously reported the positive effects of estrogen on genioglossus fatigue resistance in rats. Our present study was designed to evaluate the effects of two phytoestrogens - genistein and coumestrol - on genioglossus contractile function and estrogen receptor (ER) expression in female rats exposed to CIH. Eight-wk-old female rats were ovariectomized and exposed to CIH for 5 wk. Genistein and coumestrol, respectively, were administered by intraperitoneal injection, at a dose of 2.5 mg kg(-1) d(-1), during the last 4 d of exposure to CIH. The contractile properties of the genioglossus were measured. Real-time RT-PCR and western blotting were performed to determine the expression of ERs in the genioglossus. Phytoestrogens were found to significantly increase genioglossus fatigue resistance, the effect of genistein being more powerful than that of coumestrol. However, higher levels of ER mRNA and protein were detected in the coumestrol group than in the genistein group. We conclude that phytoestrogens, especially genistein, could improve the endurance of the genioglossus muscle in ovariectomized rats exposed to CIH, and this effect is, in part, not related to its estrogenic action.

Respiratory muscle dysfunction in animal models of hypoxic disease: antioxidant therapy goes from strength to strength

“…That sex hormones may influence respiratory muscle responses to intermittent hypoxic stress is evinced by studies involving male vs. female comparison,40,46,59,60 ovariectomized females,40,59 estrogen replacement therapy,40,41 and phytoestrogens 42,44,59,61. Female skeletal muscle is usually less fatigable than male, but differences are task specific and dependent upon contraction velocity and specific muscle groups,62,63 though of interest, sex differences can persist with aging 64.…”

Sex, stress and sleep apnoea: Decreased susceptibility to upper airway muscle dysfunction following intermittent hypoxia in females

“…Longer-lasting exposures to CIH (35 days compared with 9 days in Skelly et al, 2012a) cause genioglossus dysfunction in female rats Huang & Liu, 2011;Lu et al, 2014;Li & Liu, 2009), but interestingly, CIH-induced upper airway muscle dysfunction is exacerbated in ovariectomized females Huang & Liu, 2011), and partially ameliorated by oestrogen replacement therapy , which is also effective in restoring CIH-induced HIF-1 levels and decreased SERCA activity . Phytoestrogens, particularly genistein, improves upper airway muscle function in ovariectomized females exposed to CIH (Huang & Liu, 2011), associated with muscle upregulation of oestrogen receptor  (Li & Liu, 2009), though the effects may be unrelated to oestrogenic actions (Huang & Liu, 2011).…”

“…Phytoestrogens, particularly genistein, improves upper airway muscle function in ovariectomized females exposed to CIH (Huang & Liu, 2011), associated with muscle upregulation of oestrogen receptor  (Li & Liu, 2009), though the effects may be unrelated to oestrogenic actions (Huang & Liu, 2011). Genestein also attenuates upper airway muscle fatigue in male rats (Ding & Liu, 2011;Zhou & Liu, 2013), which may be HIF-1-dependent (Zhou & Liu, 2013).…”

“…When extended for several weeks of exposure, CIH can also increase upper airway muscle fatigue and delay recovery from fatigue (McGuire et al, 2002a,b). CIH increases genioglossus fatigue Huang & Liu, 2011;Ding & Liu, 2011;Wang et al, 2013;Lu et al, 2014;Li & Liu, 2009), which may be HIF-1-dependent Ding & Liu, 2011), and related to mitochondrial dysfunction (Zhang et al, 2010;Huang et al, 2012Huang et al, , 2014. CIH increases endoplasmic reticulum stress and apoptotic signalling , with evidence of aberrant sub-cellular structural remodelling (Huang et al, 2012;Zhang et al, 2010), although only modest cellular oxidative stress has been noted in some models .…”

“…However, surprisingly, an absence of sex differences is consistently reported for contractile and endurance properties of upper airway muscles in humans and animal models (Cantillon & Bradford 1998Skelly et al, 2012a;McDonald et al, 2015;Lewis et al, 2016). Considering the beneficial effects of oestrogen, and the clear detrimental effects of its withdrawal in female upper airway muscle Huang & Liu, 2011), it is interesting to consider that male upper airway muscle is capable of matching female performance under control conditions, perhaps related to basal oestrogen-mediated mitochondrial maintenance amongst other factors. Female advantage intrinsic to upper airway muscle is revealed however in response to stress.…”