Respiration and Swallow in Pompe Disease: Results from a Neuromechanical Computational Model

Late onset Pompe disease (LOPD) is a genetic, metabolic myopathy caused by alterations in the gene that encodes acid alpha-glucosidase (GAA). The absence of GAA contributes to glycogen buildup throughout muscle, visceral organs, and neural regions. These accumulations translate to weaknesses in the respiratory neuromuscular systems that affect breathing and breathing-coordinated behaviors (i.e., swallowing). The progression of LOPD leads to increasingly severe pulmonary dysfunction and eventual respiratory failure, which is the major cause of death in LOPD. Emerging evidence indicates significant respiratory neuron dysfunction, altering pulmonary and swallow function in humans and animal models. It has been suggested that respiratory and swallow insufficiency observed in LOPD may be attributed to medullary motoneurons potentially associated with the respiratory and swallow pattern generators. However, the precise neural mechanisms that suppress breathing and swallowing are not fully understood. One possible target for LOPD respiratory/swallow insufficiencies may be reduced medullary inspiratory neurons within this network, which result in decreased phrenic motoneuron output and disfacilitation of breath-swallow coordination. We expect global decreased neural bursts, suppressed inspiratory motor drive, discoordination of respiratory-swallowing behavior, and/or suppressed swallow motoneuron output. Using a stochastic neural network simulator that consisted of discrete “integrate and fire” populations, we simulated a systematic decrease in excitability of three medullary inspiratory neuron populations inspiratory driver (I-Driver), inspiratory decrementing (I-Dec), or inspiratory augmenting (I-Aug) neurons. These medullary inspiratory neurons excite swallow motoneurons within the model. We simulated breathing and three swallow trials. Simulations indicated that when the number of I-Dec neurons was decreased by 30% phrenic/lumbar bursting patterns were reduced in frequency. Additionally, swallow motoneuron patterns exhibited decreased burst magnitudes and shortened durations. Reducing the number of I-Aug neurons by 30% resulted in longer inspiratory phase durations (T I ) and a decreased respiratory rate. Swallow motoneuron burst magnitudes were depressed. During cough, there was a decrease in the duration and amplitudes of the expiratory motoneurons associated with cough and pulmonary stretch fibers. When the number of I-Driver neurons were reduced by 30%, T I decreased and swallow motoneuron burst magnitudes were depressed. During swallow, lumbar and phrenic motoneuron discharge duration and amplitude decreased. These results are consistent with previously reported in vivo data. Overall, our simulation data support the plausibility of glycogen storage impairing medullary motoneurons within the inspiratory network. Our results also suggest that some motoneurons, within the medulla, may be more sensitive to glycogen storage and affect the phase timing of respiratory-swallow execution within the model. Supported by NHLBI L30HL165496 and 3OT2OD023854. 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.