A respiratory signature of disease progression in the Pompe rat

Early onset Pompe disease occurs due to mutations in the acid α-glucosidase (GAA) gene that result in an absence of functional GAA protein. This results in widespread glycogen accumulation and cardiorespiratory failure early in life. We used a Gaa null ( Gaa -/- ) rat Pompe model and concurrent analysis of diaphragm electromyography (EMG) and plethysmography respiratory waveforms to determine if a unique “respiratory signature” would develop over the lifespan. Intramuscular wires enabled diaphragm EMG recordings during whole body plethysmography. Measurements were taken from 4-10 months of age, and respiratory events were detected by identifying onset and offset of diaphragm EMG bursting. As compared to wild type Sprague-Dawley rats, Pompe rats showed an age-dependent decrease in their frequency of sniffing during exploratory behaviors, potentially due to a decrease in the ability to engage in active expiration. Additionally, Pompe rats exhibited an increased latency from the onset of the diaphragm EMG burst to inspiratory airflow under hypoxic conditions, suggesting dysfunction with neuromuscular coupling. These changes are consistent with a progressive decline in respiratory neuromuscular function, may be predictive of impending respiratory failure, and provide a metric to evaluate the impact of therapies intended to prevent respiratory neuromuscular decline. Additionally, the metrics established here may be useful markers of dysfunction in other models of neuromuscular disease.