Sex-specific metabolic and oxidative stress profiles associated to myocardial infarct size in mice after exposure to intermittent hypoxia.

Abstract

Sleep apnea (SA) is a highly prevalent disorder that worsens the response to myocardial infarction (MI). Intermittent hypoxia (IH), the hallmark of SA alters insulin signalling and pro/anti-oxidant balance, two key mechanisms that may underlie the increased susceptibility to MI. Although sleep apnea affects both sexes, experimental studies have focused only on males, and whether IH distinct oxidative and insulin-related metabolic stress across metabolically active tissues differ between males and females remains unknown. Male and female 8-week-old C57BL/6J mice were exposed to 21 days of IH (60 cycles/h, 5 % nadir, 8h/day) or normoxia. In a first cohort (n = 20/group),in-vivo myocardial ischemia-reperfusion was induced on day 21 to measure infarct size. In a second, independent cohort, an insulin tolerance test (n = 21/group) was performed on day 14. On day 21, heart, adipose tissue, liver, gastrocnemius muscle, and blood were collected to measure the homeostatic model assesment of insulin resistance (HOMA-IR), oxidative stress (enzymatic assays and histology) and insulin signaling (Western blots). IH significantly increased infarct size in both sexes. However, only males developed whole-body and signaling insulin resistance across tissues associated with oxidative stress in the adipose tissue. Contrastingly, females mainly exhibited pro/anti-oxidant balance disturbance with enhanced oxidative stress in the myocardium and gastrocnemius. In conclusion, IH induces tissue- and sex-specific metabolic and oxidative disturbances that may underlie sex-dependent vulnerability to myocardial infarction, emphasizing the need to consider sex as a biological variable in sleep apnea research in order to ensure equal health outcomes.