Sex differences in spontaneous respiratory recovery following chronic c2 hemisection

Abstract

Respiratory deficits after cervical spinal cord injury (cSCI) have been well documented through single sex investigations. To our knowledge, only one report has evaluated sex in respiratory recovery after cSCI. This study showed that females have an enhanced tidal volume and phrenic burst amplitude 2 weeks post-injury. Despite this documented sex difference, it remains unknown if sex impacts spontaneous respiratory recovery at chronic time points. Thus, we conducted a longitudinal study to provide a comprehensive sex-based characterization of respiratory deficits and recovery after cSCI. We hypothesized that female rats would have a greater respiratory motor recovery compared to male rats at chronic time points post-injury. To test this hypothesis, we implanted custom electromyography (EMG) electrodes in the mid-costal region of the left and right hemidiaphragms and wires were connected to a headcap to enable chronic recordings. One-week after implantation, animals received a left C2 hemisection (C2Hx). We recorded whole-body plethysmography and bilateral diaphragm EMG activity before, 1 day, and weekly after C2Hx in awake, behaving male (n=5) and female (n=6) Sprague-Dawley rats for 8 weeks. At 9 weeks post-injury, we performed terminal phrenic nerve recordings in anesthetized and ventilated male (n=7) and female (n=6) rats. Consistent with published data, all rats showed a decrease in tidal volume (mL/breath/100g) that persisted for 8 weeks (male: P=0.0013; females: P=0.0036 vs. pre-injury), and a decrease in ipsilateral diaphragm EMG amplitude (% change pre-injury) at 1-week post-injury (males: P=0.0119; females: P=0.0004 vs. pre-injury). Female rats showed a greater improvement in tidal volume (mL/breath/100g) at 3 weeks post-cSCI which remained elevated for 8 weeks (all P≤0.0467 vs. male rats). Interestingly, males displayed an increased rate of weight gain (% baseline) compared to females, beginning 2 weeks post-cSCI (all P≤0.0418), which may have masked improvements in tidal volume in males. No sex differences in ipsilateral diaphragm EMG amplitude were observed at any time point post-injury (P≥0.8601). Similarly, no sex-based differences were observed in ipsilateral phrenic nerve amplitude during respiratory challenges (% change from baseline; all P≥0.2221). Despite using apneic threshold to set baseline CO2, arterial CO2 was higher in females (P=0.0003 vs. males), indicating a differential CO2 ventilatory threshold post-cSCI. Our data illustrate sex differences in tidal volume and CO2 ventilatory threshold at chronic time points after cSCI. These results highlight the need for sex to be included as a biological variable in the development of respiratory therapeutic strategies following cSCI. This work was supported by funding from the National Institute of Health, grant numbers: K99/R00 HL143207-01 (KAS). The authors declare no competing financial interests. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.