Proceedings of The Physiological Society
University of Oxford (2011) Proc Physiol Soc 23, PC280
Chronic intermittent hypoxia induces respiratory muscle weakness in neonatal rats which persists into early adult life.
R. A. O'Connell1, K. D. O'Halloran1
1. UCD, Dublin, Ireland.
The respiratory system is subject to considerable developmental plasticity and perturbations during vulnerable periods of early life can induce persistent maladaptive changes. Exposure to intermittent bouts of hypoxia (IH) is a common consequence of several neonatal respiratory disorders - such as apnoea of prematurity. Oxidative stress is implicated in hypoxia-induced muscle dysfunction in disease states. In this study we sought to investigate the effects of chronic IH (CIH) during early development on respiratory muscle structure and function, and to determine if CIH exposure during early neonatal life has long-lasting effects on respiratory muscle function. Litters of Wistar rats, together with their dams, were placed from birth in hypoxia chambers. The CIH litters received alternating cycles of 90 sec hypoxia (reaching 5% O2 at the nadir) and 210 sec normoxia for 8hr/day for 7 days. Sham litters were exposed to circulating normoxic gas for 7 days. After gas treatments, Sham (n=8) and CIH (n=8) sternohyoid (pharyngeal dilator) muscle functional properties were examined in vitro. Littermates from sham and CIH groups were returned to normoxia for 7 or 21 days, after which functional studies were performed (n=8 all groups). Adult sham (n=8) and CIH (n=8) Wistar rats were also studied. Sternohyoid muscle fibre type and size was evaluated by myosin heavy chain (MHC) immunofluorescence. Lipid peroxidation in muscle was evaluated by TBARS assay. CIH caused a significant depression of sternohyoid force at post-natal day (PD) 7; peak force was 4.3±0.8 N/cm2 vs. 1.6±0.3 N/cm2; control vs. CIH, Student’s t test, P<0.01. There was no major structural reorganization in CIH-treated PD7 muscle, though the areal density of MHC developmental fibres was significantly decreased, whereas MHC I (slow) fibres was significantly increased compared to sham muscles. In comparison CIH had no effect on adult sternohyoid muscle force. The negative inotropic effect of CIH on sternohyoid force persisted 7 (8.6±1.0 N/cm2 vs. 6.0± 1.1 N/cm2) and 21 (12.9±0.7 N/cm2 vs. 11.0±0.6 N/cm2) days after CIH treatment (P<0.001, two-way ANOVA). Contrary to expectation, there was no evidence of increased lipid peroxidation in CIH treated muscles. CIH causes upper airway dilator muscle impairment in neonatal but not adult rats. Respiratory muscle weakness in CIH-treated neonates persists into early adult life despite a return to normoxia. Impaired pharyngeal dilator muscle function could have deleterious consequences for the maintenance of upper airway patency in vivo. We speculate that CIH-induced respiratory muscle remodelling could exacerbate and perpetuate neonatal respiratory disorders characterized by recurrent hypoxia.
Where applicable, experiments conform with Society ethical requirements