Publication Date
1-1-2025
Journal
Acta Physiologica
DOI
10.1111/apha.14243
PMID
39422111
PMCID
PMC11680461
PubMedCentral® Posted Date
1-1-2026
PubMedCentral® Full Text Version
Author MSS
Abstract
Aim: Duchenne muscular dystrophy is a progressive muscle-wasting disease caused by mutations in the dystrophin gene. Despite progress in dystrophin-targeted gene therapies, it is still a fatal disease requiring novel therapeutics that can be used synergistically or alternatively to emerging gene therapy. Defective autophagy and disorganized microtubule networks contribute to dystrophic pathogenesis, yet the mechanisms by which microtubule alterations regulate autophagy remain elusive. The present study was designed to uncover possible mechanisms underpinning the role of microtubules in regulating autophagy in dystrophic mice.
Methods: Mdx mice were also supplemented with Tubastatin A, a pharmacological inhibitor of histone deacetylase 6, and pathophysiology was assessed. Mdx mice with a genetic deletion of the Nox-2 scaffolding subunit p47phox were used to assess redox dependence on tubulin acetylation.
Results: Our data show decreased acetylation of α-tubulin with enhanced histone deacetylase 6 expression. Tubastatin A increases tubulin acetylation and Q-SNARE complex formation but does not alter microtubule organization or density, indicating improved autophagosome-lysosome fusion. Tubastatin A increases the acetylation of peroxiredoxin and protects it from hyper-oxidation, hence modulating intracellular redox status in mdx mice. Tubastatin A reduces muscle damage and enhances force production. Genetic down regulation of Nox2 activity in the mdx mice promotes autophagosome maturation but not autolysosome formation.
Conclusion: Our data highlight that autophagy is differentially regulated by redox and acetylation in mdx mice. By improving autophagy through promoting tubulin acetylation, Tubastatin A decreases the dystrophic phenotype and improves muscle function, suggesting a great potential for clinical translation and treating dystrophic patients.
Keywords
Animals, Acetylation, Mice, Inbred mdx, Microtubules, Autophagosomes, Mice, Histone Deacetylase 6, Lysosomes, Histone Deacetylase Inhibitors, Muscular Dystrophy, Duchenne, Dystrophin, Hydroxamic Acids, Autophagy, Indoles, Male, Tubulin, Mice, Inbred C57BL, Duchenne muscular dystrophy, autophagy, acetylation, microtubule, redox, autolysosome
Published Open-Access
yes
Recommended Citation
Agrawal, Akanksha; Clayton, Erin L; Cavazos, Courtney L; et al., "Histone Deacetylase 6 Inhibition Promotes Microtubule Acetylation and Facilitates Autophagosome-Lysosome Fusion in Dystrophin-Deficient Mdx Mice" (2025). Faculty, Staff and Students Publications. 6597.
https://digitalcommons.library.tmc.edu/baylor_docs/6597