Accelerating the Mdx Heart Histo-Pathology through Physical Exercise

Abstract

Chronic cardiac muscle inflammation and fibrosis are key features of Duchenne Muscular Dystrophy (DMD). Around 90% of 18-year-old patients already show signs of DMD-related cardiomyopathy, and cardiac failure is rising as the main cause of death among DMD patients. The evaluation of novel therapies for the treatment of dystrophic heart problems depends on the availability of animal models that closely mirror the human pathology. The widely used DMD animal model, the mdx mouse, presents a milder cardiac pathology compared to humans, with a late onset, which precludes large-scale and reliable studies. In this study, we used an exercise protocol to accelerate and worsen the cardiac pathology in mdx mice. The mice were subjected to a 1 h-long running session on a treadmill, at moderate speed, twice a week for 8 weeks. We demonstrate that subjecting young mdx mice (4-week-old) to “endurance” exercise accelerates heart pathology progression, as shown by early fibrosis deposition, increases necrosis and inflammation, and reduces heart function compared to controls. We believe that our exercised mdx model represents an easily reproducible and useful tool to study the molecular and cellular networks involved in dystrophic heart alterations, as well as to evaluate novel therapeutic strategies aimed at ameliorating dystrophic heart pathology.

Inhibition of PKCθ Improves Dystrophic Heart Phenotype and Function in a Novel Model of DMD Cardiomyopathy

“…It is worth mentioning that C20 treatment also reduced the frequency of treadmill exhaustion during the exercise protocol. This fact could be attributed mainly to the preserved heart function since, as we described previously, the lower limb and diaphragm muscle are only slightly affected by this exercise protocol [46].…”

“…We used the exercised mdx mice we recently characterised in order to test pharmacological approaches, because they display an accelerated and worsened dystrophic heart phenotype [46]. In the mdx mouse model in fact, the cardiac workload induced by the exercise is not tolerated because of the absence of dystrophin.…”

“…To assess whether C20 could ameliorate dystrophic heart phenotype and function, we used the exercised mdx model (ex-mdx) we previously described and characterised [46]. As summarised in Figure 1A, mdx mice were divided into three groups at 3 weeks of age.…”

“…A third group of non-exercised, non-treated, age-matched mdx were used as control. Vehicle and C20-treated groups were exercised as previously described [46], starting at 4 weeks of age, with two 1-h long sessions per week, at the speed of 20 cm/s, for 8 weeks. Since in the present study the C20 treatment needed to be administered for the duration of 9 weeks, a much longer duration than in our previous works, we first tested the efficacy of daily (as we used before) versus twice-a-week administration of C20 (5 mg/kg) in lowering the number of circulating CD3 + and CD11b + immune cells.…”

“…We, therefore, wondered whether this therapeutic approach could also be used to ameliorate DMD cardiomyopathy. Since the commonly used mdx mouse model presents a much milder cardiac pathology that develops late in the mice lifespan [43][44][45], we used our recently described "exercised mdx" (ex mdx) mouse model, which is characterised by accelerated heart pathology, with clear signs of cardiomyopathy, such as diffuse ventricular fibrosis, appearing as early as 12 weeks of age [46].…”