APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia
Rationale: 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.
Objectives: Identify individual factors ( e.g. , genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH).
Methods: Associations of individual factors with the magnitude of AIHH (15, 1-min O 2 =9.5%, CO 2 =5% episodes) induced changes in diaphragm motor-evoked potential amplitude (MEP) and inspiratory mouth occlusion pressures (P 0.1 ) 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 ( BDNF, HTR 2A , TPH 2 , MAOA, NTRK 2 ) 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 ) ApoE knock-in rats were performed to test causality.
Results: AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE 4 ( i.e., APOE 3/4 ) allele versus other APOE genotypes (p=0.048). No significant differences were observed between any other SNPs investigated, notably BDNFval/met ( all p>0.05 ). Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (p=0.004). Age was inversely related with change in P 0.1 within the limited age range studied (p=0.007). In hApoE 4 knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE 3 controls (p<0.05).
Conclusions: APOE 4 genotype, sex and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults.
ADDITION TO KNOWLEDGE BASE: 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, APOE ), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.
| Errataetall: |
UpdateIn: Function (Oxf). 2023 Jun 13;4(5):zqad026. - PMID 37575478 |
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| Medienart: |
E-Artikel |
| Erscheinungsjahr: |
2023 |
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| Erschienen: |
2023 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2023 |
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| Enthalten in: |
bioRxiv : the preprint server for biology - (2023) vom: 07. Jan. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Nair, Jayakrishnan [VerfasserIn] |
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Date Revised 18.08.2023 published: Electronic UpdateIn: Function (Oxf). 2023 Jun 13;4(5):zqad026. - PMID 37575478 Citation Status PubMed-not-MEDLINE |
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| doi: |
10.1101/2023.01.06.522840 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Nair, Jayakrishnan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia |
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| 500 | |a Date Revised 18.08.2023 | ||
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| 500 | |a UpdateIn: Function (Oxf). 2023 Jun 13;4(5):zqad026. - PMID 37575478 | ||
| 500 | |a Citation Status PubMed-not-MEDLINE | ||
| 520 | |a Rationale: 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 | ||
| 520 | |a Objectives: Identify individual factors ( e.g. , genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH) | ||
| 520 | |a Methods: Associations of individual factors with the magnitude of AIHH (15, 1-min O 2 =9.5%, CO 2 =5% episodes) induced changes in diaphragm motor-evoked potential amplitude (MEP) and inspiratory mouth occlusion pressures (P 0.1 ) 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 ( BDNF, HTR 2A , TPH 2 , MAOA, NTRK 2 ) 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 ) ApoE knock-in rats were performed to test causality | ||
| 520 | |a Results: AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE 4 ( i.e., APOE 3/4 ) allele versus other APOE genotypes (p=0.048). No significant differences were observed between any other SNPs investigated, notably BDNFval/met ( all p>0.05 ). Males exhibited a greater diaphragm MEP enhancement versus females, regardless of age (p=0.004). Age was inversely related with change in P 0.1 within the limited age range studied (p=0.007). In hApoE 4 knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE 3 controls (p<0.05) | ||
| 520 | |a Conclusions: APOE 4 genotype, sex and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults | ||
| 520 | |a ADDITION TO KNOWLEDGE BASE: 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, APOE ), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity | ||
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| 700 | 1 | |a Marciante, Alexandria B |e verfasserin |4 aut | |
| 700 | 1 | |a Hou, Tingting |e verfasserin |4 aut | |
| 700 | 1 | |a Lu, Qing |e verfasserin |4 aut | |
| 700 | 1 | |a Fox, Emily J |e verfasserin |4 aut | |
| 700 | 1 | |a Mitchell, Gordon S |e verfasserin |4 aut | |
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