Downstream Pathways of Dystrophin Deficiency in Duchenne Muscular Dystrophy: Implications for Muscle Degeneration and...

Duchenne muscular dystrophy (DMD) is the most common and severe form of muscular dystrophy, primarily affecting skeletal muscle and leading to premature death. Although the loss of dystrophin has long been recognised as the primary cause of the disease, no definitive cure is currently available. As a consequence, therapeutic efforts have largely focused on mitigating disease progression rather than correcting the primary genetic defect. In this context, extensive research focuses on secondary pathological mechanisms, downstream cellular and molecular alterations triggered by dystrophin deficiency, that contribute to disease progression, particularly by affecting muscle degeneration and regeneration. While therapeutic strategies have traditionally aimed to enhance muscle regeneration, accumulating evidence indicates that limiting chronic degeneration and the associated degeneration-regeneration cycles may represent a more effective approach to preserve muscle integrity. Here, we examine the published evidence to delineate this shift in therapeutic perspective.

This narrative review summarises preclinical and clinical strategies for DMD. We considered over 100 published articles, 85% from the last 15 years and analysing 40 different approaches, grouping them based on pathways targeted. For each study, therapeutic efficacy was assessed by focusing on the impact on promoting muscle regeneration versus limiting degeneration, based on morphological features, including muscle architecture, inflammation and fibrosis, as well as functional outcomes.

Our analysis revealed pathway-specific benefits in skeletal muscle. Among calcium- and mitochondrial-targeted interventions, 94.4% preserved muscle morphology and slowed down muscle regeneration. Myofibre stability approaches were evenly split, with 50% promoting regeneration and 50% delaying muscle wasting. Satellite cell-targeted therapies affecting proliferation and fusion enhanced muscle regeneration in most cases, while anti-inflammatory strategies slowed muscle degeneration in 63.6% and promoted new myofibre formation in 36.4% of cases. Oxidative stress modulation preserved muscle structure in 85.7% of cases, while boosting muscle regeneration in the remaining therapies.

Emerging evidence indicates a shift in DMD therapeutic focus, from strategies aimed primarily at enhancing muscle regeneration to approaches that limit repeated degeneration-regeneration cycles. Most current interventions act by modulating pathological processes that drive chronic muscle damage rather than by directly stimulating regeneration. Importantly, targeting multiple disease-relevant pathways within skeletal muscle has shown beneficial effects in preclinical models, supporting the concept that coordinated and temporally controlled modulation of key biological processes may represent an effective strategy to stabilise muscle tissue and delay disease progression.