Sleep-disordered breathing is characterized primarily by partial or total upper airway obstruction during sleep. The most common form of sleep-disordered breathing is obstructive sleep apnea due to recurrent collapse of the upper airway with the onset of sleep state. The major risk factors associated with the development of sleep apnea are obesity, male sex, and post menopausal status. Currently, our overall hypothesis is that sex and fat distribution predict sleep apnea susceptibility due to alterations in upper airway mechanical load compensatory neuromuscular control. Based on our most recent findings, we demonstrate that obesity is associated with elevations in the upper airway load (passive Pcrit) that are counterbalanced by compensatory upper airway neural responses. Moreover, we show that female sex, peripheral adiposity, and younger age are associated with increased compensatory neuromuscular responses, while male sex, central adiposity, and older age are associated with blunted compensatory responses. The loss of the compensatory neuromuscular responses leads to obstructive sleep apnea and testosterone replacement may reverse both the mechanical and neurocompensatory alterations in aging men. In Specific Aim 1, we will define the effects of sex and age status on upper airway compensatory responses normal individuals. We hypothesize that: women will demonstrate greater compensatory neuromuscular responses than men, and that age-related declines in these compensatory responses will occur in both sexes. In Specific Aim 2, we will determine the effects of body composition on upper airway neuromuscular responses. We hypothesize that visceral adiposity is the major determinate of decrement in neuromuscular responses in older men compared to women The proposed studies are designed to elucidate the pathophysiologic basis for the development of obstructive sleep apnea. Novel physiologic techniques have been developed to allow partitioning of the mechanical and neural regulation of upper airway control during sleep. The studies also provide insights into the neurohumoral regulation of upper airway function.

It is now appreciated that obesity and male sex are the major risk factors for the development of sleep apnea. The current proposal focuses on the sex differences in body fat distribution and why women are protected against developing sleep apnea, but men are predisposed.