Nair Jayakrishnan, Welch Joseph F, Marciante Alexandria B, Hou Tingting, Lu Qing, Fox Emily J, Mitchell Gordon S
Breathing Research and Therapeutics Center Department of Physical Therapy, University of Florida.
Current address: Department of Physical Therapy, Thomas Jefferson University, PA.
bioRxiv. 2023 Jan 7:2023.01.06.522840. doi: 10.1101/2023.01.06.522840.
Acute intermittent hypoxia (AIH) is a promising strategy to induce functional motor recovery following chronic spinal cord injuries and neurodegenerative diseases. Although significant results are obtained, human AIH trials report considerable inter-individual response variability.
Identify individual factors ( , genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH).
Associations of individual factors with the magnitude of AIHH (15, 1-min O =9.5%, CO =5% episodes) induced changes in diaphragm motor-evoked potential amplitude (MEP) and inspiratory mouth occlusion pressures (P ) were evaluated in 17 healthy individuals (age=27±5 years) compared to Sham. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity ( ) and neuronal plasticity (apolipoprotein E, ) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized ( ) knock-in rats were performed to test causality.
AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for ( ) allele other genotypes (p=0.048). No significant differences were observed between any other SNPs investigated, notably ( ). Males exhibited a greater diaphragm MEP enhancement females, regardless of age (p=0.004). Age was inversely related with change in P within the limited age range studied (p=0.007). In knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE controls (p<0.05).
genotype, sex and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults.
Acute intermittent hypoxia (AIH) is a novel rehabilitation strategy to induce functional recovery of respiratory and non-respiratory motor systems in people with chronic spinal cord injury and/or neurodegenerative diseases. Since most AIH trials report considerable inter-individual variability in AIH outcomes, we investigated factors that potentially undermine the response to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH), in healthy humans. We demonstrate that genetics (particularly the lipid transporter, ), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.
急性间歇性低氧（AIH）是一种在慢性脊髓损伤和神经退行性疾病后诱导运动功能恢复的有效策略。尽管已取得显著成果，但人体AIH试验报告显示个体间反应存在相当大的变异性。
确定决定健康成年人对优化的AIH方案（急性间歇性高碳酸血症 - 低氧，AIHH）反应程度的个体因素（ 、基因、年龄和性别）。
在17名健康个体（年龄 = 27±5岁）中，与假手术组相比，评估个体因素与AIHH（15次，每次1分钟，氧气浓度 = 9.5%，二氧化碳浓度 = 5%发作）诱导的膈肌运动诱发电位幅度（MEP）和吸气口闭塞压力（P ）变化之间的关联。测试了与AIH诱导的膈神经运动可塑性（ ）和神经元可塑性（载脂蛋白E， ）机制相关基因中的单核苷酸多态性（SNP）。还分析了AIHH诱导的可塑性随年龄和性别的变化。在人源化（ ） 敲入大鼠中进行了额外实验以测试因果关系。
对于 （ ）等位基因杂合的个体，AIHH诱导的膈肌MEP幅度变化低于其他基因型个体（p = 0.048）。在所研究的任何其他SNP之间未观察到显著差异，特别是 （ ）。无论年龄如何，男性膈肌MEP增强幅度均大于女性（p = 0.004）。在所研究的有限年龄范围内，年龄与P 的变化呈负相关（p = 0.007）。在 敲入大鼠中，AIHH诱导的膈神经运动可塑性显著低于hApoE 对照组（p < 0.05）。
基因型、性别和年龄是健康成年人中AIHH诱导的呼吸运动可塑性的重要生物学决定因素。
急性间歇性低氧（AIH）是一种新型康复策略，可诱导慢性脊髓损伤和/或神经退行性疾病患者呼吸和非呼吸运动系统的功能恢复。由于大多数AIH试验报告显示AIH结果存在相当大的个体间变异性，我们研究了可能削弱健康人对优化的AIH方案（急性间歇性高碳酸血症 - 低氧，AIHH）反应的因素。我们证明基因（特别是脂质转运蛋白， ）、年龄和性别是AIHH诱导的呼吸运动可塑性的重要生物学决定因素。
