Sex and APOE Genotype Influence Respiratory Function Under Hypoxic and Hypoxic-Hypercapnic Conditions

Abstract

ABSTRACTVentilation is regulated across many systems, with respiratory rhythm formation occurring in the brainstem but modulated in response to: chemoreception, respiratory muscle afferents, and volitional control. Alterations within any of these systems may result in disruptions of appropriate respiratory control and ultimately, disease. The apolipoprotein (APOE) gene has been studied due to its influence on Alzheimer’s disease (AD) development and work in an APOE mouse model recently demonstrated impaired respiratory motor plasticity following spinal cord injury (SCI). Additionally, individuals with AD may co-present with obstructive sleep apnea (OSA). Despite the prominence of APOE genotype and sex as factors in differing AD and OSA severity, little is known about the impact of these on respiratory control. Using mice expressing two different humanized APOE alleles, we characterized how sex and the presence of E3 or E4 alleles influenced ventilation during baseline (normoxia) and during respiratory challenge. We show that sex and genotype influence breathing under hypoxia, which may have clinical implications in the context of AD and OSA. Additionally, female mice, while responding robustly to hypoxia, were unable to recover to baseline respiratory levels, emphasizing sex differences in disordered breathing and potentially indicative of high metabolic cost.