Neural deficits contribute to respiratory insufficiency in Pompe disease.
Pompe disease is a severe form of muscular dystrophy due to glycogen accumulation in all tissues, especially striated muscle. Disease severity is directly related to the deficiency of acid alpha-glucosidase (GAA), which degrades glycogen in the lysosome. Respiratory dysfunction is a hallmark of the disease, muscle weakness has been viewed as the underlying cause, and the possibility of an associated neural contribution has not been evaluated previously. Therefore, we examined behavioral and neurophysiological aspects of breathing in 2 animal models of Pompe disease--the Gaa(-/-) mouse and a transgenic line (MTP) expressing GAA only in skeletal muscle, as well as a detailed analysis of the CNS in a Pompe disease patient. Glycogen content was elevated in the Gaa(-/-) mouse cervical spinal cord. Retrograde labeling of phrenic motoneurons showed significantly greater soma size in Gaa(-/-) mice vs. isogenic controls, and glycogen was observed in Gaa(-/-) phrenic motoneurons. Ventilation, assessed via plethysmography, was attenuated during quiet breathing and hypercapnic challenge in Gaa(-/-) mice (6 to >21 months of age) vs. controls. We confirmed that MTP mice had normal diaphragmatic contractile properties; however, MTP mice had ventilation similar to the Gaa(-/-) mice during quiet breathing. Neurophysiological recordings indicated that efferent phrenic nerve inspiratory burst amplitudes were substantially lower in Gaa(-/-) and MTP mice vs. controls. In human samples, we demonstrated similar pathology in the cervical spinal cord and greater accumulation of glycogen in spinal cord compared with brain. We conclude that neural output to the diaphragm is deficient in Gaa(-/-) mice, and therapies targeting muscle alone may be ineffective in Pompe disease.
DeRuisseau
Lara R
LR
Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USA.
Fuller
David D
DD
Qiu
Kai
K
DeRuisseau
Keith C
KC
Donnelly
William H
WH
Mah
Cathryn
C
Reier
Paul J
PJ
Byrne
Barry J
BJ
D017668:Age of Onset; D000818:Animals; D005260:Female; D006009:Glycogen Storage Disease Type II / Q000473:pathology / Q000503:physiopathology*; D006801:Humans; D007223:Infant; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010791:Phrenic Nerve / Q000166:cytology / Q000502:physiology*; D012131:Respiratory Insufficiency / Q000503:physiopathology*; D012132:Respiratory Muscles / Q000502:physiology; D013116:Spinal Cord / Q000473:pathology; D000520:alpha-Glucosidases / Q000235:genetics
D000520:alpha-Glucosidases