Dystrophic cardiomyopathy is the consequence of diseases that affect the protein dystrophin. Dystrophin forms part of the dystrophin glycoprotein complex and is postulated to act as a membrane stabilizer, protecting the sarcolemma from contractioninduced damage. Duchenne muscular dystrophy (DMD) is the most severe dystrophinopathy, caused by a total absence of dystrophin. Patients with DMD present with progressive skeletal muscle weakness and due to advances in treatment, which increase life span, a cardiac component of the disease has been unmasked. Many patients with DMD now succumb to heart failure. As such this study aims to address a knowledge gap relating to the cardiac myofilament involvement in DMD. To assess the effects of DMD upon cardiomyocyte function, isolated permeabilized cardiomyocytes of wild-type and DMDmdx-4cv mice were attached between a force transducer and motor and subjected to a range of contractile assays. Maximal tension and force development rates (indexed by the rate constant, ktr) were similar between the wild-type and DMDmdx-4cv cardiac myocyte preparations. Interestingly, it was found that DMDmdx-4cv cardiac myocytes had a greater sarcomere length dependence of peak power output when compared to the cardiac myocytes of wild-type littermates. These results suggest dystrophin mitigates length dependence of activation and augmented sarcomere length dependence of myocyte contractility which may accelerate the progression of ventricular myocyte damage in dystrophic hearts. Following this first study, the effects of mavacamten, a novel small molecule modulator of the thick filament activation, were assessed upon contractile properties in wild-type and DMDmdx-4cv murine permeabilized cardiomyocytes. Mavacamten decreased maximal tension and ktr in both wild-type and DMDmdx-4cv cardiomyocytes, while also normalizing the length dependence of peak power between DMDmdx-4cv cardiac myocytes and wild-type preparations. These results highlight the potential benefits of mavacamten (i.e., reduced overall contractility while maintaining exquisite sarcomere length dependence of power output) as a treatment for dystrophic cardiomyopathy associated with DMD.Includes bibliographical references
