Neural deficits contribute to respiratory insufficiency in Pompe disease

Proceedings of the National Academy of Sciences of the United States of America - Tập 106 Số 23 - Trang 9419-9424 - 2009
Lara R. DeRuisseau1, David D. Fuller2, Kai Qiu2, Keith C. DeRuisseau3, William H. Donnelly4,5, Cathryn Mah6,5, Paul J. Reier7,5, Barry J. Byrne8
1Department of Physiological Sciences, College of Veterinary Medicine, University of Florida, Gainesville, FL 32610, USA
2Department of Physical Therapy, College of Public Health and Health Professions,
3Department of Applied Physiology and Kinesiology, College of Health and Human Performance; and
4Departments of dPathology,
5University of Florida
6Cellular and Molecular Therapy,
7Neuroscience, and
8Pediatrics, Molecular Genetics, and Microbiology and Powell Gene Therapy Center, College of Medicine, University of Florida, Gainesville, FL 32610

Tóm tắt

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 α-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.

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Proceedings of the National Academy of Sciences of the United States of America

Tập 106 Số 23

9419-9424

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