Reversing mdx cardiomyocyte hypertrophy in vitro

Several promising therapies aimed at treating Duchenne muscular dystrophy (DMD) are under investigation at various pre-clinical and clinical stages. Unfortunately, many of these approaches, including exon skipping and viral-mediated gene therapy, have shown to be more efficient in skeletal muscle than in the heart. In addition to this, there is a growing need to treat dystrophin-deficient cardiomyopathy as patient life expectancy is increasing and symptoms of cardiomyopathy in the patient population are becoming more prevalent. Despite the primary genetic defect being identical in skeletal and cardiac muscle, the symptoms and severity often differ suggesting the involvement of secondary organ-specific pathways that are yet to be fully understood. In order to more efficiently screen treatments in the dystrophic heart, we have developed an in vitro model of cardiomyocyte hypertrophy using primary embryonic cardiomyocytes isolated from mdx hearts. Using this newly developed model, we have been able to utilise various pharmacological and gene therapy approaches to decrease the hypertrophic phenotype seen in the model. This model could be a fast and efficient way to screen new and existing pharmaceutical compounds in addition to gene editing and gene replacement approaches for potential therapeutic efficacy in dystrophin-deficient cardiomyopathy. In addition to the screening of therapeutic compounds, using transcriptomics and proteomic approaches, this model can be used to deepen our understanding of the secondary organ-specific pathways involved in the pathophysiology of the heart in DMD and potentially identify novel therapeutic targets. RNA-sequencing of hypertrophic mdx cardiomyocytes identified differential regulation of genes and pathways both across the time course of the hypertrophic response and in comparison to wild-type controls. Identified genes include those involved in calcium ion handling, fibrosis and angiogenesis.