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

Abstract

Alterations to the supply of oxygen during early life presents a profound stressor to physiological systems with aberrant remodeling that is often long-lasting. Chronic intermittent hypoxia (CIH) is a feature of apnea of prematurity, chronic lung disease, and sleep apnea. CIH affects respiratory control but there is a dearth of information concerning the effects of CIH on respiratory muscles, including the diaphragm—the major pump muscle of breathing. We investigated the effects of exposure to gestational CIH (gCIH) and postnatal CIH (pCIH) on diaphragm muscle function in male and female rats. CIH consisted of exposure in environmental chambers to 90 s of hypoxia reaching 5% O2 at nadir, once every 5 min, 8 h a day. Exposure to gCIH started within 24 h of identification of a copulation plug and continued until day 20 of gestation; animals were studied on postnatal day 22 or 42. For pCIH, pups were born in normoxia and within 24 h of delivery were exposed with dams to CIH for 3 weeks; animals were studied on postnatal day 22 or 42. Sham groups were exposed to normoxia in parallel. Following gas exposures, diaphragm muscle contractile, and endurance properties were examined ex vivo. Neither gCIH nor pCIH exposure had effects on diaphragm muscle force-generating capacity or endurance in either sex. Similarly, early life exposure to CIH did not affect muscle tolerance of severe hypoxic stress determined ex vivo. The findings contrast with our recent observation of upper airway dilator muscle weakness following exposure to pCIH. Thus, the present study suggests a relative resilience to hypoxic stress in diaphragm muscle. Co-ordinated activity of thoracic pump and upper airway dilator muscles is required for optimal control of upper airway caliber. A mismatch in the force-generating capacity of the complementary muscle groups could have adverse consequences for the control of airway patency and respiratory homeostasis.

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

“… 14 Sustained hypoxia did not affect muscle fiber-type distribution, or the activity of key representative oxidative or glycolytic enzyme activities. 14 Similar to observations following exposure to CIH during early life, 16 sustained hypoxia for 7 days had no deleterious effect on rat diaphragm functional properties 14 revealing muscle-specific effects of sustained hypoxic stress, with relative resilience in diaphragm muscle compared with airway dilator muscle to CSH during early development.…”

“… 15 , 17 Indeed, neonatal exposure to CIH primes increased susceptibility to subsequent hypoxic stress in later life. 15 Unlike airway dilator muscle responses, 15 , 17 exposure to CIH (FiO 2 =5% at nadir; 12 cycles per hour; 8 hours per day) has no discernible effect on diaphragm form or function, 16 an outcome that may relate to intrinsic differences in upper airway and diaphragm muscle fiber type and metabolic programming during development. 13 – 17 …”

Postnatal intermittent hypoxia enhances phrenic and reduces vagal upper airway motor activities in rats by epigenetic mechanisms

“…This observation indicates that the augmented ventilation induced by pCIH exposure may involve an amplification of inspiratory motor activity or muscle functioning. McDonald, Dempsey, and O'Halloran (), using a similar paradigm of pCIH, reported that intermittent hypoxia postnatally did not modify diaphragm muscle force‐generating capacity ex vivo . Interestingly, we found that in situ preparations of pCIH rats exhibited boosted phrenic burst amplitude under hyperoxic/normocapnic conditions, whilst the hypoglossal activity to tongue muscles that modifies pharyngeal calibre was not altered.…”

Diaphragm plasticity in aging and disease: therapies for muscle weakness go from strength to strength

“…Early life exposure to sustained hypoxic stress increases rat pharyngeal dilator muscle fatigue, whereas diaphragm fatigue tolerance is preserved (14). A similar outcome is noted in early life exposure to chronic intermittent hypoxia, with evidence of persistent pharyngeal dilator muscle weakness but maintenance of diaphragm forcegenerating capacity (70,71). The few studies that have explored this issue paint a portrait of an essential pump with properties that protect from the insidious effects of hypoxia.…”