Targeting histone deacetylase 6 (HDAC6) in Duchenne muscular dystrophy: New insights into therapeutic potential

Rodney and colleagues provide compelling evidence for the therapeutic potential of selective histone deacetylase 6 (HDAC6) inhibition in mdx mice, a widely used model of Duchenne muscular dystrophy (DMD).¹ Their study reveals that HDAC6 inhibition promotes enhanced autophagy through increased tubulin acetylation, offering new hope for treatment strategies targeting this critical enzyme. This research sheds light on the potential of HDAC6 inhibitors to address some of the key pathological features of DMD.

Duchenne muscular dystrophy is a severe, progressive neuromuscular disorder caused by mutations in the dystrophin gene on the X chromosome.² Affecting approximately 1 in 3500 male births, DMD leads to the absence of dystrophin, a structural protein that connects muscle fibers to the extracellular matrix. Without dystrophin, muscle cells are vulnerable to damage and progressive degeneration. DMD typically presents in early childhood, with delayed motor milestones, muscle weakness, and difficulty standing. As the disease progresses, children develop a characteristic waddling gait, difficulty climbing stairs, and progressive muscle loss, ultimately leading to wheelchair dependence by age 12. Complications such as skeletal deformities, breathing difficulties, and cardiomyopathy arise, and most patients do not survive beyond their 30s due to respiratory and cardiac failure.

Despite two decades of research, no cure for DMD exists, and current treatments remain limited to glucocorticoid therapy. Although innovative genetic approaches, such as exon skipping, gene editing with CRISPR/Cas9, and viral vector-mediated dystrophin delivery, show promise, challenges like inconsistent efficacy, off-target effects, and incomplete dystrophin restoration in muscle tissues—especially in the heart—have slowed progress. As a result, a more comprehensive treatment strategy, combining genetic and pharmacological approaches, is likely necessary to address the multifaceted nature of DMD.

Over the past 20 years, HDAC inhibitors have shown promise in pre-clinical DMD models. Givinostat, a pan-HDAC inhibitor, was recently FDA-approved for its ability to slow disease progression in ambulatory boys with DMD.³ However, pan-HDAC inhibitors can have undesirable side effects, including genotoxicity and impaired DNA repair. To mitigate these risks, more selective HDAC inhibitors have been developed, with HDAC6 emerging as a particularly attractive target. HDAC6-specific inhibitors have been shown to have several advantages over pan-HDAC inhibitors, including a lack of severe side effects. For instance, HDAC6 knockout mice do not exhibit significant pathological features, suggesting that selective inhibition of HDAC6 may be safe and beneficial.⁴

In animal models, HDAC6 inhibition has demonstrated therapeutic effects in a range of disorders, including cancer, neurodegenerative diseases, and cardiomyopathies, without notable adverse outcomes.⁵ In the context of neuromuscular diseases like Charcot–Marie–Tooth disease and Amyotrophic Lateral Sclerosis (ALS), HDAC6 inhibition has been shown to reverse axonal loss, promote muscle reinnervation, and improve survival. In muscular dystrophies, HDAC6 inhibition has been linked to improvements in muscle strength, reduced inflammation and fibrosis, and the partial restoration of the dystrophin-glycoprotein complex and neuromuscular junctions.⁶ These effects are thought to arise from HDAC6-mediated stabilization of microtubules and inhibition of TGF-β signaling respectively due to the inhibition of Smad3 and tubulin deacetylation, both of which are key pathways in muscle regeneration.⁷

One of the key findings of Rodney et al.'s study is the role of autophagy in DMD muscle pathology. In mdx mice and DMD patients, autophagic processes are impaired, leading to an accumulation of damaged cellular components.⁸ The study shows that HDAC6 inhibition restores autophagic function by promoting microtubule acetylation. This process is critical for the proper maturation of autophagosomes, the vesicles that digest and recycle cellular debris.⁹ Specifically, the study highlights two key defects in mdx muscles: impaired vesicle nucleation and phagophore elongation during the early stages of autophagy, as well as compromised fusion of autophagosomes with lysosomes in the later stages. HDAC6 inhibition, particularly through the use of tubastatin A—a selective HDAC6 inhibitor—was shown to reverse these defects, restoring both early and late stages of autophagy in dystrophic muscle cells.

The authors further explore the interplay between acetylation and redox regulation in autophagy. In mdx muscles, increased Nox2 activity disrupts autophagy through the mTOR pathway and microtubule dynamics.¹⁰ However, while Nox2 inhibition preserves the microtubule network, it does not restore autophagosome-lysosome fusion or acetylation, indicating that microtubule acetylation is a critical factor in the fusion process. This finding underscores the importance of acetylation in maintaining autophagic function in DMD muscles (Figure 1).

Rodney and colleagues' study significantly advances our understanding of the mechanisms underlying HDAC6 inhibition's beneficial effects in DMD. By demonstrating that HDAC6 inhibition restores autophagy and promotes muscle recovery, their work paves the way for the development of targeted therapies aimed at modulating autophagic pathways in DMD. Further research will be needed to explore the specific molecular targets of HDAC6, including potential effects on other proteins involved in the autophagic process, and to evaluate the long-term safety and efficacy of HDAC6 inhibitors in clinical settings.

In conclusion, this study highlights the therapeutic potential of HDAC6 inhibition in DMD, offering a promising avenue for further exploration. By addressing critical cellular processes like autophagy, these inhibitors may provide a much-needed complement to existing DMD treatments, helping to slow disease progression and improve the quality of life for affected individuals.

Alexis Osseni: Conceptualization; writing – original draft; writing – review and editing; funding acquisition. Laurent Schaeffer: Conceptualization; writing – original draft; writing – review and editing; funding acquisition.

Funding for this work was obtained via a grant from the Association Française contre les Myopathies (AFM-Téléthon) through strategic MyoNeurALP1 & MyoNeurALP2 alliances. Additional support for this work came from the Fondation Médicale pour la Recherche (FMR) and the Fondation Maladies Rares.

The authors declare no conflict of interest.