The specific, nonconventional cytoplasmic histone deacetylase 6 (HDAC6) may be a therapeutic target for patients with Duchenne muscular dystrophy (DMD), according to a study recently published in Nature Communications.

“Our results show that HDAC6 pharmacological inhibition significantly ameliorates several functional, biochemical, and morphological markers in skeletal muscles from dystrophin-deficient mice via three complementary mechanisms,” Alexis Osseni, of the Université de Lyon in France, and colleagues wrote.

This experimental study analyzed the effects of administering tubastatin A, a selective HDAC6 inhibitor, to DMD mouse models. After 40 days of consecutive treatment, the researchers observed an overall improvement in muscle strength and decreased atrophy and fibrosis. Mice that received tubastatin A regained almost all muscle strength.

Continue Reading

Read more about DMD therapies

The authors noted that the effects of tubastatin A could be mediated by inhibiting the subsequent signaling of transforming growth factor-beta. This effect of HDAC6 inhibition is likely due to the activation of Smad3 through acetylation, which in turn decreases Smad2/3 transcriptional activity by interfering with its phosphorylation and nuclear translocation.

Furthermore, tubastatin A interacted with microtubules, stabilizing them. This led to stimulation of the dystrophin-associated glycoprotein complex (DGC) organization and neuromuscular junction, thus enhancing DGC’s role as a shock absorbent molecule and plasma membrane stabilizer.

Finally, the HDAC6 inhibition treatment increased both utrophin A and β-dystroglycan levels in the experimental mice. The authors noted that this mechanism could represent an additional benefit to this therapy due to utrophin A’s structural similarity with the dystrophin molecule, possibly compensating for its absence in DMD.

“Accordingly, HDAC6 inhibition with pharmacological agents represents an attractive therapeutic target for DMD offering many advantages including ease of administration, impact on all muscles, and benefits to all patients regardless of the dystrophin mutations,” the authors concluded.

To conduct this study, the researchers used mice that lacked dystrophin, referred to as mdx, at 7 weeks of age. The treatment group received daily administration of 25 mg/kg/day of tubastatin A by intraperitoneal injections. In contrast, the control group received injections with just a vehicle following the same dosage and scheme. Analysis of alpha-tubulin acetylation was conducted in the anterior tibialis muscle.


Osseni A, Ravel-Chapuis A, Belotti E, et al. Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β viaSmad3 acetylation. Nat Comm. Published online November 19, 2022. doi:10.1038/s41467-022-34831-3