Diaphragm degeneration and cardiac structure in mdx mouse: potential clinical implications for Duchenne muscular dystrophy

Abstract

We examined the effects of exercise on diaphragm degeneration and cardiomyopathy in dystrophin-deficient mdx mice. Mdx mice (11 months of age) were exercised (swimming) for 2 months to worsen diaphragm degeneration. Control mdx mice were kept sedentary. Morphological evaluation demonstrated increased fibrosis in the diaphragm of exercised mdx mice (33.3 ± 6.0% area of fibrosis) compared with control mdx mice (20.9 ± 1.7% area of fibrosis). Increased (26%) activity of MMP-2, a marker of fibrosis, was detected in the diaphragms from exercised mdx mice. Morphological evaluation of the heart demonstrated a 45% increase in fibrosis in the right ventricle (8.3 ± 0.6% in sedentary vs. 12.0 ± 0.6% of fibrosis in exercised) and in the left ventricle (35% increase) in the exercised mdx mice. The density of inflammatory cells-degenerating cardiomyocytes increased 95% in the right ventricle (2.3 ± 0.6 in sedentary vs. 4.5 ± 0.8 in exercised) and 71% in the left ventricle (1.4 ± 0.6 sedentary vs. 2.4 ± 0.5 exercised). The levels of both active MMP-2 and the pro-fibrotic factor transforming growth factor beta were elevated in the hearts of exercised compared with sedentary mdx mice. The wall thickness to lumen diameter ratio of the pulmonary trunk was significantly increased in the exercised mdx mice (0.11 ± 0.04 in sedentary vs. 0.28 ± 0.12 in exercised), as was the thickness of the right ventricle wall, which suggests the occurrence of pulmonary hypertension in those animals. It is suggested that diaphragm degeneration is a main contributor to right ventricle dystrophic pathology. These findings may be relevant for future interventional studies for Duchenne muscular dystrophy-associated cardiomyopathy.

Long-Term Quercetin Dietary Enrichment Partially Protects Dystrophic Skeletal Muscle

“…Utrophin, a dystrophin-like protein, participates in DGC formation, stability, and function in the absence of dystrophin [3, 4], hence utrophin upregulation remains an area of intense research interest [5–8]. Utrophin transcription can be driven by the exercise-sensitive PGC-1α pathway [9], however, attempts to use various exercise modalities as interventions for DMD have been met with mixed results [10–13]. Direct activation of the PGC-1α pathway using transgenic and gene transfer approaches yields consistently positive results using both prevention and rescue paradigms [14–18].…”

Mild Aerobic Exercise Training Hardly Affects the Diaphragm of mdx Mice

“…Chronic volitional running was associated with decreased tension of the diaphragm in mdx mice (Selsby et al, ). More recently, Barbin et al () in swimming‐trained, 11‐month‐old mice found increased fibrosis of the diaphragm and increased activity of the fibrosis marker MMP‐2. Differently from these results, no evidence for diaphragmatic fibrosis was found after 6 weeks of low‐intensity running in our mice.…”

Association between pulmonary function and left ventricular volume and function in duchenne muscular dystrophy

“…The dystrophin‐deficient mdx mouse model has been used to examine the heart–lung association in DMD. Barbin et al . demonstrated that biventricular dystrophy with pulmonary hypertension was prevalent in such mice, due in part to degeneration of the diaphragm.…”