Combined therapeutic acute intermittent hypercapnic hypoxia and exercise-based respiratory training improve breathing after chronic cervical spinal cord injury
Authors: Long Mackenzie , Alvarez Victoria , Gomes Jefferson , Gonzalez-Rothi Elisa 
Published: May 2024

Therapeutic acute intermittent hypoxia (tAIH) is simple, safe, and effective means of inducing respiratory motor plasticity and improving breathing in rodent models of acute cervical spinal cord injury (SCI). Unfortunately, tAIH effects on breathing function are less effective with chronic injury. On the other hand, tAIH restores non-respiratory (limb) motor function with chronic SCI, but only when combined with task specific training (TST). The effcacy of combined tAIH and respiratory TST on breathing ability in rodent models (or humans) with chronic SCI has not been investigated. Here, we explore the potential for tAIH and respiratory TST to increase breathing ability; we further differentiate automatic vs. volitional TST, since the ability to sustain independent breathing is dependent on automatic (and not volitional) breathing function, which relies on distinct neural pathways. Physical exercise increases breathing automatically in direct proportion to metabolic rate, regulating arterial blood gases by a mechanism independent of chemoreceptor feedback (i.e. “exercise hyperpnea”). Thus, in ongoing studies, we are exploring treadmill training as a form of task-specific respiratory training in rats with chronic cervical SCI. We focus on a refined tAIH protocol that combines hypoxia with hypercapnia during each episode (therapeutic acute intermittent hypercapnic hypoxia; or tAIHH), since preliminary data suggests that tAIHH is a more potent stimulus to respiratory motor plasticity vs. tAIH alone. Adult Sprague-Dawley rats with chronic C2 spinal cord hemisection were treated with either 4 weeks of either tAIHH (10, 5-min episodes of 10.5% O2, 4% inspired CO2) combined with treadmill exercise (30 min total run time, 30 cm/sec) or tAIHH alone. Breathing function was assessed in awake, freely moving rats using whole-body plethysmography. In preliminary analyses, breathing capacity (i.e., minute ventilation in response to maximal chemoreflex activation) was increased in chronically injured rats treated with daily tAIHH paired with treadmill training relative to rats treated with tAIHH alone (120.7mL/min/100g vs. 98.7mL/min/100g; p=0.0018). Similar improvements in breathing function were not observed with tAIHH alone. These are the first studies to investigate the therapeutic effcacy of combined tAIH and exercise-based respiratory training targeting automatic breathing. These initial results indicate that, similar to non-respiratory motor systems, pairing tAIHH with respiratory TST improves breathing function in rodents with chronic cervical SCI. Supported by: Craig H. Neilsen Foundation (SCIRP891379), and the McKnight Brain Institute. This is the full abstract presented at the American Physiology Summit 2024 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.