APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia.
APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia.
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APOE4、年龄
DOI：
10.1101/2023.01.06.522840
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Mitchell,GordonS
中科院分区：
文献类型：
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作者：
Nair,Jayakrishnan;Welch,JosephF;Marciante,AlexandriaB;Hou,Tingting;Lu,Qing;Fox,EmilyJ;Mitchell,GordonS
急性间歇性缺氧（AIH）有望促进慢性脊髓损伤和神经退行性疾病的运动恢复。然而，AIH的人体试验报告了个体反应的显著差异。（例如，遗传学、年龄和性别），其确定健康成人对优化的AIH方案（急性间歇性高碳酸血症-缺氧（AIHH））的反应幅度。（年龄= 27 ± 5岁），个体因素与AIHH幅度变化之间的关联评价了（15，1分钟O2 = 9.5%，CO2 = 5%发作）引起的膈肌运动诱发电位（MEP）振幅和吸气口闭合压（P0.1）的变化。检测与AIH诱发的膈运动可塑性（BDNF、HTR 2A、TPH 2、MAOA、NTRK 2）和神经可塑性（载脂蛋白E、APOE）相关基因的单核苷酸多态性（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（h）ApoE敲入大鼠中进行另外的实验以测试因果关系。结果AIHH诱导的膈肌MEP振幅的变化在APOE 4杂合的个体中较低（即，APOE 3/4基因型（P= 0.048）与其他基因型和其他SNP相比，APOE 3/4基因型与APOE 3/4基因型之间差异无显著性（P= 0.048）。男性表现出更大的隔膜MEP增强与女性相比，无论年龄（P= 0.004）。此外，年龄与P0.1的变化呈负相关（P= 0.007）。在hApoE 4基因敲入大鼠中，AIHH诱导的膈运动可塑性显著低于hApoE 3对照组结论APOE 4基因型、性别、AIH是一种新的康复策略，可诱导慢性脊髓损伤和/或慢性脊髓损伤患者呼吸和非呼吸运动系统的功能恢复。或神经退行性疾病。图5由于大多数AIH试验报告AIH结局存在相当大的个体间差异，我们研究了可能破坏健康人对优化AIH方案AIHH反应的因素。我们证明遗传（特别是脂质转运蛋白APOE）、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
RationaleAcute intermittent hypoxia (AIH) shows promise for enhancing motor recovery in chronic spinal cord injuries and neurodegenerative diseases. However, human trials of AIH have reported significant variability in individual responses.ObjectivesIdentify individual factors (eg, genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH).MethodsIn 17 healthy individuals (age = 27 ± 5 yr), associations between individual factors and changes in the magnitude of AIHH (15, 1-min O2 = 9.5%, CO2 = 5% episodes) induced changes in diaphragm motor-evoked potential (MEP) amplitude and inspiratory mouth occlusion pressures (P0.1) were evaluated. Single nucleotide polymorphisms (SNPs) in genes linked with mechanisms of AIH induced phrenic motor plasticity (BDNF, HTR2A, TPH2, MAOA, NTRK2) and neuronal plasticity (apolipoprotein E,APOE) were tested. Variations in AIHH induced plasticity with age and sex were also analyzed. Additional experiments in humanized (h)ApoEknock-in rats were performed to test causality.ResultsAIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous forAPOE4(i.e.,APOE3/4) compared to individuals with otherAPOEgenotypes (P= 0.048) and the other tested SNPs. Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (P= 0.004). Additionally, age was inversely related with change in P0.1 (P= 0.007). In hApoE4knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE3controls (P< 0.05).ConclusionsAPOE4genotype, sex, and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults.Addition to Knowledge BaseAIH 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 disease. Figure 5 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, AIHH, in healthy humans. We demonstrate that genetics (particularly the lipid transporter,APOE), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity