Functional and histopathological identification of the respiratory failure in a DMSXL transgenic mouse model of Myotonic Dystrophy

Abstract

SUMMARYAcute and chronic respiratory failure is one of the major and potentially life-threatening features in individuals with myotonic dystrophy type 1 (DM1). Despite several clinical demonstrations showing respiratory problems in DM1 patients, the mechanisms are still not completely understood. This study was designed to investigate whether the DMSXL transgenic mouse model for DM1 exhibits respiratory disorders 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 the CTG repeat in successive generations of DM1 transgenic mice. Statistical analysis of breathing function measurements revealed a significant decrease in the most relevant respiratory parameters in DMSXL mice, indicating impaired respiratory function. 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 breakdown 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. Because 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 might 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.

Abnormal sodium current properties contribute to cardiac electrical and contractile dysfunction in a mouse model of myotonic dystrophy type 1

“…Thus, this is a precious model to study the time course of the disease with aging. It has been previously shown that DMSXL mice have reduced muscle strength, lower motor performances, peripheral neuropathy and respiratory impairments [13][14][15].…”

“…The originality of this model lies in the pattern of expression of the DMPK gene in DMSXL which is similar to DM1 patients including a high level of expression in the heart [13]. This model reproduces the main clinical characteristics observed in the human disease including reduced muscle strength, lower motor performances, peripheral neuropathy and respiratory impairments [13][14][15]. However, nothing is known about the cardiac phenotype of the DMSXL mouse.…”

An anti‐asthmatic activity of natural Toll‐like receptor‐4 antagonist in OVA‐LPS‐induced asthmatic rats

“…Lung function parameters (respiration rate, tidal volume, and airflow rate) were measured using Respiromax, Columbus Instruments . Rats were acclimatized for 15 days before the measurement of lung function parameters.…”

Dosage effect of multiple genes accounts for multisystem disorder of myotonic dystrophy type 1

“…54 They also suggest that the postnatal respiratory insufficiency in CDM patients may be due to the defects of diaphragm muscle. 55 We next characterized the growth profiles of DSMD-QKO SC mice. Interestingly, DSMD-QKO SC pups exhibited growthretarded phenotype (Supplementary information, Fig.…”