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Duchenne muscular dystrophy (DMD), and the associated cardiomyopathy, develops from mutations the dystrophin gene. Dystrophin supports the plasma membrane of skeletal myofibres and cardiomyocytes. Nearly all skeletal muscle groups are affected in DMD with preferential early involvement of the limbs and trunk, followed by respiratory muscle compromise and cardiomyopathy. Because of enhanced ventilatory support, DMD patients now survive longer, and cardiac involvement dominates the later stage management. Treatment using β adrenergic blockade and inhibition of angiotensin-converting enzymes (ACEs) has been shown to be effective in promoting favourable remodelling. Management of cardiac arrhythmias presents challenges in the DMD patient.
The majority of DMD-associated mutations result in the complete loss of dystrophin, and the loss of dystrophin protein interrupts the normal link between the actin cytoskeleton and the plasma membrane of muscle.1 Dystrophin associates with a series of membrane-spanning proteins to complete the connection to the extracellular matrix. Disruption of dystrophin or its associated proteins, the sarcoglycans, destabilises the sarcolemma of cardiomyocytes and skeletal myofibres. In both cardiac and skeletal muscle, dystrophin protects cardiomyocytes against contraction-induced damage. Cellular repair mechanisms and regeneration are generally insufficient, yielding progressive loss of skeletal myofibres and cardiomyocytes. Skeletal muscle undergoes a robust regeneration that cannot be sustained, leading to fibrofatty replacement of muscle and progressive muscle weakness. In the heart, there is little to no evidence of ongoing regeneration.
Most DMD boys are diagnosed before the age of 5 …
Competing interests: None.
Funding: EMM is supported as a Distinguished Clinical Scientist of the Doris Duke Charitable Foundation.
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