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 ( , 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 =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.

RESULTS

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).

CONCLUSIONS

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, ), age and sex are important biological determinants of AIHH-induced respiratory motor plasticity.