Histone deacetylase 6 inhibition promotes microtubule acetylation and facilitates autophagosome-lysosome fusion in dystrophin-deficient mdx mice

Duchenne Muscular Dystrophy (DMD) is a severe X-linked genetic disorder. Defective autophagy and disorganized microtubule network contributes to DMD pathogenesis, yet the mechanisms by which microtubule alterations regulate autophagy remain elusive. We show decreased acetylated α-tubulin and enhanced histone deacetylase (HDAC6) expression in mdx mice. Pharmacological inhibition of HDAC6 increases tubulin acetylation and enhances Q-SNARE complex formation, leading to improved autophagosome-lysosome fusion. HDAC6 inhibition reduces apoptosis, inflammation, muscle damage and prevents contraction induced force loss. HDAC6 inhibition restores peroxiredoxin (PrxII) by increasing its acetylation and protecting it from hyper-oxidation, hence modulating intracellular redox status in mdx mice. Genetic inhibition of Nox2 activity in mdx mice promotes autophagosome maturation. Our data highlight that autophagy is differentially regulated by redox and acetylation in mdx mice. By restoring tubulin acetylation HDAC6 inhibition enhances autophagy, ameliorates the dystrophic phenotype and improves muscle function, suggesting a potential therapeutic target for treating DMD.