Acute and chronic respiratory failure is one of the major and potentially life-threatening features in patients with Myotonic Dystrophy type 1 (DM1). Despite the several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely known. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibit respiratory disorder, and if so to identify the pathological changes underlying these respiratory problems. Using pressure plethysmography we assessed the breathing function in control mice and DMSXL mice generated after large expansions of CTG repeat in successive generations of DM1 transgenic mice. The statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. The histological and morphometric analysis showed pathological changes in diaphragmatic muscle of DMSXL mice characterized by an increase in the percentage of type I muscle fibers, the presence of central nuclei, partial denervation of end-plates (EPs) and a significant reduction in their size, shape complexity and density of acetylcholine receptors, all of which reflect a possible break down in communication between the diaphragmatic muscles fibers and the nerve terminals. Diaphragm muscle abnormalities were accompanied by an accumulation of mutant DMPK RNA foci in muscle fiber nuclei. Moreover, in DMSXL mice, the unmyelinated phrenic afferents are significantly lower. Also in these mice, significant neuronopathy was not detected in either cervical phrenic motor neurons or brainstem respiratory neurons. Since EPs are involved in the transmission of action potentials and the unmyelinated phrenic afferents exert a modulating influence on the respiratory drive, the pathological alterations affecting these structures may underlie the respiratory impairment detected in DMSXL mice. Understanding mechanisms of respiratory deficiency should guide pharmaceutical and clinical research towards better therapy for the respiratory deficits associated with DM1.
- Received July 11, 2012.
- Accepted November 19, 2012.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License (http://creativecommons.org/licenses/by-nc-sa/3.0), which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.