Respiratory deficits in the DBA2-mdx mouse model of dystrophin deficiency are not directly associated with diaphragm muscle fibrosis



Poster Number: 133


Jennifer Peterson PhD, William Ross BSc, Kitipong Uaesoontrachoon , Donika Shala MSc, Amanda Mullen BSc, Kanneboyina Nagaraju DVM, PhD


1. Assistant Professor, 2. AGADA Biosciences Inc., 3. AGADA Biosciences Inc., 4. AGADA Biosciences, 6. Binghamton University

Background: D2.B10-Dmdmdx/J (DBA/2-congenic-D2-mdx) is a newer mouse strain developed at Jackson labs by backcrossing C57BL/10ScSn-Dmdmdx/J mice onto the DBA/2J background. We and others have shown that this model recapitulates several human DMD myopathy features, including elevated serum creatine kinase levels, profound muscle weakness, atrophic muscle fibers, and extensive fibrosis in skeletal muscle diaphragm, heart, as well as early deficits in cardiac function. Similar to BL10-mdx mice, this model also shows extensive progressive fibrosis in diaphragm muscle.

Objective: We hypothesized that fibrosis in the diaphragm negatively affects respiratory functions in D2-mdx mice.

Approach: Using male D2-mdx mice at 20, 30, and 40 weeks of age, we systematically performed whole-body plethysmography to assess respiratory function and TGF-beta expression and picrosirius red (PSR) staining to analyze diaphragm fibrosis.

Results: We found significant deficits in tidal volume and peak expiratory function in 20-week-old D2-mdx mice compared to 40-week-old WT controls. Significant peak expiratory function deficits were no longer observed by 30 weeks, a finding that held at 40 weeks. Tidal volume deficits persisted through 30 weeks but rebounded by 40 weeks of age. Comparatively, TGF-beta expression and diaphragm fibrosis (PSR) were both increased in 20-week-old D2-mdx mice compared to WT control and remained elevated through 40 weeks of age.

Conclusions: Our data show that declining respiratory function in D2-mdx mice does not expressly parallel fibrosis in the diaphragm, the primary muscle involved in respiration. These findings suggest that diaphragm fibrosis is not explicitly linked to respiratory function in older D2-mdx mice. Compensatory mechanisms permitting stabilization and even improvement in respiratory function in a fibrotic environment are of great interest for future studies.