Abstract
Exposure to acute intermittent hypoxia (AIH) elicits a form of respiratory plasticity known as long-term facilitation (LTF). Interest has grown in developing AIH interventions to treat ventilatory insufficiency, with promising results in spinal cord injury and amyotrophic lateral sclerosis. Therapeutic AIH may have application in neuromuscular disorders including muscular dystrophies. We sought to establish hypoxic ventilatory responsiveness and the expression of ventilatory LTF in X-linked muscular dystrophy (mdx) mice.
Experiments were performed in 15 male wild-type (BL10) and 15 male mdx mice at 4 months of age. Ventilation was assessed using whole-body plethysmography. Baseline measures of ventilation and metabolism were established. Mice were exposed to 10 successive bouts of hypoxia, each lasting 5 min, interspersed with 5-min bouts of normoxia. Measurements were taken for 60 min following termination of AIH.
In mdx mice, ventilation was significantly increased 60 min post-AIH compared to baseline. However, metabolic CO2 production was also increased. Therefore, ventilatory equivalent was unaffected by AIH exposure, i.e., no ventilatory LTF manifestation. In wild-type mice, ventilation and metabolism were not affected by AIH.
Eliciting ventilatory LTF is dependent on many factors and may require concomitant isocapnia or hypercapnia during AIH exposures and/or repeated daily AIH exposures, which is worthy of further pursuit.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Similar content being viewed by others
References
Burns DP, Roy A, Lucking EF, McDonald FB, Gray S, Wilson RJ et al (2017) Sensorimotor control of breathing in the mdx mouse model of Duchenne muscular dystrophy. J Physiol 595(21):6653–6672. [Internet] [cited 2022 Nov 15]. Available from: https://pubmed.ncbi.nlm.nih.gov/28952155/
Burns DP, Canavan L, Rowland J, O’Flaherty R, Brannock M, Drummond SE et al (2018) Recovery of respiratory function in mdx mice co-treated with neutralizing interleukin-6 receptor antibodies and urocortin-2. J Physiol 596(21):5175–5197. [Internet] [cited 2022 Nov 15]. Available from: https://pubmed.ncbi.nlm.nih.gov/30160301/
Burns DP, Murphy KH, Lucking EF, O’Halloran KD (2019a) Inspiratory pressure-generating capacity is preserved during ventilatory and non-ventilatory behaviours in young dystrophic mdx mice despite profound diaphragm muscle weakness. J Physiol 597(3):831. [Internet] [cited 2022 Nov 15]. Available from: https://physoc.onlinelibrary.wiley.com/doi/10.1113/JP277443
Burns DP, Drummond SE, Bolger D, Coiscaud A, Murphy KH, Edge D et al (2019b) N-acetylcysteine decreases fibrosis and increases force-generating capacity of mdx diaphragm. Antioxidants 8(12). [Internet] [cited 2022 Nov 15]. Available from: https://www.mdpi.com/2076-3921/8/12/581
Drummond SE, Burns DP, O’Connor KM, Clarke G, O’Halloran KD (2021) The role of NADPH oxidase in chronic intermittent hypoxia-induced respiratory plasticity in adult male mice. Respir Physiol Neurobiol 292:103713. [Internet] [cited 2022 Nov 15]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1569904821000987
Drummond SE, Burns DP, El Maghrani S, Ziegler O, Healy V, O’Halloran KD (2022) NADPH oxidase 2 is necessary for chronic intermittent hypoxia-induced sternohyoid muscle weakness in adult male mice. Exp Physiol 107(8):946–964. [Internet] [cited 2022 Nov 15]. Available from: https://pubmed.ncbi.nlm.nih.gov/35728802/
Golder FJ, Mitchell GS (2005) Spinal synaptic enhancement with acute intermittent hypoxia improves respiratory function after chronic cervical spinal cord injury. J Neurosci 25(11):2925. [Internet] [cited 2022 Nov 15]. Available from: https://www.jneurosci.org/content/25/11/2925.long
Gumerson JD, Michele DE (2011) The dystrophin-glycoprotein complex in the prevention of muscle damage. J Biomed Biotechnol 2011:210797 [Internet] [cited 2021 Sep 21]. Available from: https://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22007139/?tool=EBI
Hickner S, Hussain N, Angoa-Perez M, Francescutti DM, Kuhn DM, Mateika JH (2014) Ventilatory long-term facilitation is evident after initial and repeated exposure to intermittent hypoxia in mice genetically depleted of brain serotonin. J Appl Physiol 116(3):240. [Internet] [cited 2022 Nov 14]. Available from: https://journals.physiology.org/doi/full/10.1152/japplphysiol.01197.2013
Hoffman MS, Mitchell GS (2013) Spinal 5-HT7 receptors and protein kinase A constrain intermittent hypoxia-induced phrenic long-term facilitation. Neuroscience 250:632–643. [Internet] [cited 2022 Nov 15]. Available from: https://www.sciencedirect.com/science/article/pii/S0306452213005745?via%3Dihub
Hoffman MS, Golder FJ, Mahamed S, Mitchell GS (2010) Spinal adenosine A2A receptor inhibition enhances phrenic long term facilitation following acute intermittent hypoxia. J Physiol 588(Pt 1):255. [Internet] [cited 2022 Nov 15]. Available from: https://physoc.onlinelibrary.wiley.com/doi/full/10.1113/jphysiol.2009.180075
Life expectancy – Muscular dystrophy news [Internet] [cited 2021 Sep 21]. Available from: https://musculardystrophynews.com/life-expectancy/
Lovering RM, Iyer SR, Edwards B, Davies KE (2020) Alterations of neuromuscular junctions in Duchenne muscular dystrophy. Neurosci Lett 737:135304. [Internet] [cited 2022 Nov 15]. Available from: https://www.sciencedirect.com/science/article/pii/S0304394020305747?via%3Dihub
Manning J, O’Malley D (2015) What has the mdx mouse model of duchenne muscular dystrophy contributed to our understanding of this disease? J Muscle Res Cell Motil 36:155–167 [Internet] [cited 2021 Sep 15]. Available from: http://link.springer.com/10.1007/s10974-015-9406-4
Mendonça-Junior BA, Fernandes M, Zoccal DB (2021) Acute intermittent hypoxia evokes ventilatory long-term facilitation and active expiration in unanesthetized rats. Respir Physiol Neurobiol 294:103768. [Internet] [cited 2022 Nov 15]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1569904821001531
Mhandire DZ, Burns DP, Roger AL, O’Halloran KD, ElMallah MK (2022) Breathing in Duchenne muscular dystrophy: translation to therapy. J Physiol 600(15):3465–3482. [Internet] [cited 2022 Nov 15]. Available from: https://pubmed.ncbi.nlm.nih.gov/35620971/
Nichols NL, Satriotomo I, Allen LL, Grebe AM, Mitchell GS (2017) Mechanisms of Enhanced Phrenic Long-Term Facilitation in SOD1G93A Rats. J Neurosci 37(24):5834. [Internet] [cited 2022 Nov 15]. Available from: https://www.jneurosci.org/content/37/24/5834
O’Halloran KD (2016) Chronic intermittent hypoxia creates the perfect storm with calamitous consequences for respiratory control. Respir Physiol Neurobiol 226:63–67. [Internet] [cited 2022 Nov 15]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1569904815300677
O’Halloran KD, Lewis P, McDonald F (2017) Sex, stress and sleep apnoea: decreased susceptibility to upper airway muscle dysfunction following intermittent hypoxia in females. Respir Physiol Neurobiol 245:76–82. [Internet] [cited 2022 Nov 15]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S1569904816302154
Sajjadi E, Seven YB, Ehrbar JG, Wymer JP, Mitchell GS, Smith BK (2022) Acute intermittent hypoxia and respiratory muscle recruitment in people with amyotrophic lateral sclerosis: a preliminary study. Exp Neurol 347. [Internet] [cited 2022 May 6] . Available from: https://pubmed.ncbi.nlm.nih.gov/34624328/
Sawnani H, Thampratankul L, Szczesniak RD, Fenchel MC, Simakajornboon N (2015) Sleep disordered breathing in young boys with Duchenne muscular dystrophy. J Pediatr 166(3):640–645.e1. [Internet] [cited 2022 Nov 15]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S002234761401155X
Skelly JR, Edge D, Shortt CM, Jones JFX, Bradford A, O’Halloran KD (2012) Tempol ameliorates pharyngeal dilator muscle dysfunction in a rodent model of chronic intermittent hypoxia. Am J Respir Cell Mol Biol 46(2):139–48. [Internet] [cited 2022 Nov 15]. Available from: https://pubmed.ncbi.nlm.nih.gov/21868712/
Sutor T, Cavka K, Vose AK, Welch JF, Davenport P, Fuller DD et al (2021) Single-session effects of acute intermittent hypoxia on breathing function after human spinal cord injury. Exp Neurol 342:113735. [Internet] [cited 2022 Nov 15]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S0014488621001412
Wakai J, Takamura D, Morinaga R, Nakamuta N, Yamamoto Y (2015) Differences in respiratory changes and Fos expression in the ventrolateral medulla of rats exposed to hypoxia, hypercapnia, and hypercapnic hypoxia. Respir Physiol Neurobiol 215:64–72. [Internet] [cited 2022 Nov 14]. Available from: https://linkinghub.elsevier.com/retrieve/pii/S156990481500110X
Welch JF, Sutor TW, Vose AK, Perim RR, Fox EJ, Mitchell GS (2020). Synergy between acute intermittent hypoxia and task-specific training. Exerc Sport Sci Rev [Internet] [cited 2022 Nov 15];48(3):125. Available from: https://journals.lww.com/acsm-essr/Fulltext/2020/07000/Synergy_between_Acute_Intermittent_Hypoxia_and.4.aspx
Author information
Authors and Affiliations
Corresponding author
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 2023 The Author(s), under exclusive license to Springer Nature Switzerland AG
About this paper
Cite this paper
Maxwell, M.N., Marullo, A.L., Slyne, A.D., Lucking, E.F., O’Halloran, K.D. (2023). Ventilatory Effects of Acute Intermittent Hypoxia in Conscious Dystrophic Mice. In: Conde, S.V., Iturriaga, R., del Rio, R., Gauda, E., Monteiro, E.C. (eds) Arterial Chemoreceptors. ISAC XXI 2022. Advances in Experimental Medicine and Biology, vol 1427. Springer, Cham. https://doi.org/10.1007/978-3-031-32371-3_9
Download citation
DOI: https://doi.org/10.1007/978-3-031-32371-3_9
Published:
Publisher Name: Springer, Cham
Print ISBN: 978-3-031-32370-6
Online ISBN: 978-3-031-32371-3
eBook Packages: Biomedical and Life SciencesBiomedical and Life Sciences (R0)