Obstructive sleep apnea is associated with neural injury and dysfunction.
Hypoxia/reoxygenation exposures, modeling
sleep apnea, injure select populations of neurons, including hypoglossal motoneurons. The mechanisms underlying this motoneuron injury are not understood. We hypothesize that endoplasmic reticulum injury contributes to motoneuron demise.
Hypoxia/reoxygenation exposures across 8 weeks in adult mice upregulated the unfolded protein response as evidenced by increased phosphorylation of PERK [PKR-like endoplasmic reticulum (ER)
kinase] in facial and hypoglossal motoneurons and persistent upregulation of
CCAAT/enhancer-binding protein-homologous
protein (CHOP)/growth arrest and DNA damage-inducible
protein (GADD153) with nuclear translocation. Long-term
hypoxia/reoxygenation also resulted in cleavage and nuclear translocation of
caspase-7 and
caspase-3 in hypoglossal and facial motoneurons. In contrast, occulomotor and trigeminal motoneurons showed persistent phosphorylation of eIF-2a across
hypoxia/reoxygenation, without activations of CHOP/GADD153 or either
caspase. Ultrastructural analysis of rough ER in hypoglossal motoneurons revealed
hypoxia/reoxygenation-induced
luminal swelling and ribosomal detachment. Protection of
eIF-2alpha phosphorylation with systemically administered
salubrinal throughout
hypoxia/reoxygenation exposure prevented CHOP/GADD153 activation in susceptible motoneurons. Collectively, this work provides evidence that long-term exposure to
hypoxia/reoxygenation events, modeling
sleep apnea, results in significant endoplasmic reticulum injury in select upper airway motoneurons. Augmentation of eIF-2a phosphorylation minimizes motoneuronal injury in this model. It is anticipated that
obstructive sleep apnea results in endoplasmic reticulum injury involving motoneurons, whereas a critical balance of phosphorylated eIF-2a should minimize motoneuronal injury in
obstructive sleep apnea.