Early Life Exposure to Chronic Intermittent Hypoxia Primes Increased Susceptibility to Hypoxia-Induced Weakness in Rat Sternohyoid Muscle during Adulthood

Abstract

Intermittent hypoxia is a feature of apnea of prematurity (AOP), chronic lung disease, and sleep apnea. Despite the clinical relevance, the long-term effects of hypoxic exposure in early life on respiratory control are not well defined. We recently reported that exposure to chronic intermittent hypoxia (CIH) during postnatal development (pCIH) causes upper airway muscle weakness in both sexes, which persists for several weeks. We sought to examine if there are persistent sex-dependent effects of pCIH on respiratory muscle function into adulthood and/or increased susceptibility to re-exposure to CIH in adulthood in animals previously exposed to CIH during postnatal development. We hypothesized that pCIH would cause long-lasting muscle impairment and increased susceptibility to subsequent hypoxia. Within 24 h of delivery, pups and their respective dams were exposed to CIH: 90 s of hypoxia reaching 5% O2 at nadir; once every 5 min, 8 h per day for 3 weeks. Sham groups were exposed to normoxia in parallel. Three groups were studied: sham; pCIH; and pCIH combined with adult CIH (p+aCIH), where a subset of the pCIH-exposed pups were re-exposed to the same CIH paradigm beginning at 13 weeks. Following gas exposures, sternohyoid and diaphragm muscle isometric contractile and endurance properties were examined ex vivo. There was no apparent lasting effect of pCIH on respiratory muscle function in adults. However, in both males and females, re-exposure to CIH in adulthood in pCIH-exposed animals caused sternohyoid (but not diaphragm) weakness. Exposure to this paradigm of CIH in adulthood alone had no effect on muscle function. Persistent susceptibility in pCIH-exposed airway dilator muscle to subsequent hypoxic insult may have implications for the control of airway patency in adult humans exposed to intermittent hypoxic stress during early life.

Effects of Gestational and Postnatal Exposure to Chronic Intermittent Hypoxia on Diaphragm Muscle Contractile Function in the Rat

“…Animals were exposed to either gestational CIH (gCIH) or postnatal CIH (pCIH) using commercial chambers in which the environmental oxygen concentration was carefully controlled to achieve desired profiles (Oxycyler™; Biospherix, Lacona, NY, USA). The CIH protocol adopted in the study has been described previously (McDonald et al, 2014 , 2015b , 2016 ). Animals were placed in environmental chambers every morning in their conventional cages with free access to food and water for the duration of the treatment; they were housed in room air overnight.…”

“…The aim of this study was to investigate the effects of exposure to gestational CIH and postnatal CIH on diaphragm muscle function in male and female rats. Both male and female animals were studied given the evidence of male susceptibility to early life stressors (Zeitlin et al, 2002 ; Mage and Donner, 2006 ; Johnston and Hagberg, 2007 ), notwithstanding our previous observation that there are no sex differences in the effects of pCIH on sternohyoid muscle force (McDonald et al, 2015b , 2016 ).…”

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

“…In contrast, increased susceptibility to upper airway muscle weakness following CIH (FiO 2 =5% at nadir; 12 cycles per hour; 8 hours per day) is observed during early life compared with adult animals 17,58. Moreover, upper airway muscle dysfunction following neonatal exposure to CIH extends into young adulthood suggesting lasting effects of antecedent exposure to CIH during critical windows of development 15,17. Indeed, neonatal exposure to CIH primes increased susceptibility to subsequent hypoxic stress in later life 15.…”

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

“…Concerning the issue of sex-related susceptibility to airway collapsibility, CIH-induced pharyngeal dilator muscle weakness was observed in male but not female rats in a model of moderate sleep-disordered breathing (Skelly et al, 2012a). The putative role of sex hormones is inferred from observation that whilst female upper airway muscle shows an apparent resilience to CIH-related stress when exposed during adulthood, CIH exposure during neonatal development causes upper airway muscle weakness, which is equivalent in young males and females studied at 3 and 6 weeks of age (McDonald et al, 2016).…”

“…However, there is increased susceptibility to CIH in early life. A modest CIH paradigm producing no discernible effect on upper airway muscle contractile properties in adult animals resulted in persistent upper airway muscle weakness when exposure to CIH occurred during neonatal development , an effect also associated with increased susceptibility to a subsequent bout of exposure to CIH in adulthood (McDonald et al, 2016). Surprisingly, in the light of sex-related differences in the prevalence and manifestation of OSAS (Young et al, 1993;Seneratna et al, 2016), and the wealth of evidence indicative of sex differences in the response of various homeostatic systems to stressors, there is a dearth of information comparing homeostatic system responses to CIH challenge between the sexes.…”