Molecular modulation in Pompe disease following acute intermittent hypoxia

Pompe disease results in cardiorespiratory distress secondary to glycogen accumulation in the lysosomes of all muscle types and motor neurons. The only approved treatment is enzyme replacement therapy (ERT), which improves survival, however, it cannot completely correct skeletal muscle or motor neuron pathology, therefore respiratory failure persists. To prevent respiratory distress effectively in Pompe patients, there is a need to develop novel approaches that can improve respiratory muscle and motor neuron function. Acute intermittent hypoxia (AIH) is a non-invasive therapy capable of improving respiratory motor function and has has been successful in studies of spinal cord injury and ALS. The hypothesis of this study is that AIH will promote plasticity in skeletal muscle and motor neurons to improve respiration in Pompe mice. 2-month-old Pompe and wildtype (WT) mice were exposed to 10 cycles of alternating room air (21% O 2 ) and hypoxia (10% O 2 ) for 5 minutes each, once per day for 7 consecutive days. After the initial week of exposures, mice were given a reminder dose twice per week through 4 and 6 months of age. An additional group of Pompe and WT mice were only exposed to room air to serve as untreated controls. Whole-body plethysmography under hypoxic (10% O 2 ) and hypercapnic (7% CO 2 ) gas challenges indicate respiratory improvement in AIH-treated WT and Pompe mice. Post-mortem, we evaluated molecular profiles of the medullas as well as respiratory skeletal muscle (tongue and diaphragm). First, bulk proteomics were analyzed in the medullas. ~450 proteins are altered in sham-treated Pompe mice compared to sham-treated WT mice, and in AIH-treated Pompe mice, ~34% of these proteins are normalized. Normalized proteins are associated with biological processes of metabolic processes and transport and organization; within the cell they are localized to mitochondria and cell-cell junctions. Next, phrenic nerve-diaphragm neuromuscular junctions (NMJs) were measured. Sham-treated Pompe mice have reduced colocalization of the axon terminals and acetyl choline receptors as well as increased fragmentation, measured by area. In AIH-treated Pompe mice, however, colocalization is improved and is attributed to an increase in presynaptic plate overlap with the postsynaptic plate. There is also a slight (n.s.) decrease in area in these mice. Lastly, we sought to understand the impact of AIH on autophagy in Pompe. Secondary to lysosomal glycogen accumulation autophagy is disrupted in Pompe skeletal muscle. In WT mice, there is nearly no change in autophagy when comparing sham-treated and AIH-treated mouse diaphragm, tongue, and tibialis anterior. However, in Pompe mice, there is a robust activation of autophagy in all three muscles. Our preliminary conclusions are that despite increased vesicle accumulation in respiratory muscles, improvements to motor unit communication in the diaphragm and metabolic process normalization in the medulla lead to respiration function maintenance. NIH/NHLBI R00HL161420 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.