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 the 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 whether a unique "respiratory signature" would develop over the lifespan. Intramuscular wires enabled diaphragm EMG recordings during whole body plethysmography. Measurements were taken from 4 to 10 mo of age, and respiratory events were detected by identifying the onset and offset of diaphragm EMG bursting. As compared with 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. In addition, 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. In addition, the metrics established here may be useful markers of dysfunction in other models of neuromuscular disease.NEW & NOTEWORTHY We used a novel algorithm for breath-by-breath detection on concurrent plethysmography and diaphragm EMG recordings to identify shifts in breathing throughout the lifespan of Pompe rats. We identified a "respiratory signature" of disease progression in the Pompe rat comprising a decrease in the frequency of sniffing behaviors and increased latency from diaphragm activation to inspiratory flow during hypoxia. This signature offers new metrics to evaluate the effectiveness of potential therapies.