APOE4, Age & Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia

Abstract

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 O2=9.5%, CO2=5% episodes) induced changes in diaphragm motor-evoked potential amplitude (MEP) and inspiratory mouth occlusion pressures (P0.1) 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, 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)ApoE knock-in rats were performed to test causality. Results: AIHH-induced changes in diaphragm MEP amplitudes were lower in individuals heterozygous for APOE4 (i.e., APOE3/4) 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 P0.1 within the limited age range studied (p=0.007). In hApoE4 knock-in rats, AIHH-induced phrenic motor plasticity was significantly lower than hApoE3 controls (p<0.05). Conclusions: APOE4 genotype, sex and age are important biological determinants of AIHH-induced respiratory motor plasticity in healthy adults.

BREATHE DMD: boosting respiratory efficacy after therapeutic hypoxic episodes in Duchenne muscular dystrophy

“…This would continue in putative AIH trials in people with DMD, a presumed benefit in the quest to provoke respiratory neuroplasticity. More recently, Nair and colleagues have drawn attention to the fact that individual characteristics such as age, sex and genetics can modify acute intermittent hypercapnic hypoxia‐induced changes in MEP amplitudes (Nair et al., 2023), and it is established that there are important state and circadian influences on the expression of AIH‐induced respiratory plasticity (Puri et al., 2021).…”