In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Pharmacological inhibition of HDAC6 improves muscle phenotypes in dystrophin-deficient mice by downregulating TGF-β via Smad3 acetylation
Today’s pick is from the National Communication Society by Osseni et al on using HDAC6 inhibition in the mdx mouse to improve pathology. Doi 10.1038/s41467-022-34831-3.
Histone deacetylases (HDAC) target the DNA histones (proteins around which DNA is wrapped) and influence how well a gene can be expressed. Like a volume switch or a dimmer. HDAC6 is an odd HDAC because it does not remove acetyl groups from histones and DNA but from proteins.
Ergo it acts in cytoplasm rather than nucleus. It plays a role in atrophy (making muscle smaller). Inhibition of HDAC6 through selective inhibitor Tubustatin A is thought to improve muscle mass. Authors here tested this in the mdx mouse model for Duchenne.
7 weak old mdx mice were treated daily with tubustatin A or vehicle for 30 days. Wild type references were included. After treatment authors saw microtubuli contained more acetyl groups, showing the treatment has the expected impact on HDAC6.
Treatment also improved strength and reduced fatigue in mdx mice, and it increased utrophin levels. With the latter finding the question is whether this is an increase of the amount of utrophin OR whether there is more regeneration per se (see yesterday’s #apaperaday).
Authors claim HDAC6 inhibition by tubustatin A reduces atrophy in the mdx mouse, because they see less small fibers and more large fibers. 2 comments:
- Mdx mouse is quite hypertrophic so I’m not sure it is the best model to pick up an anti-atrophic effect. D2/mdx would be more relevant
- When there is a change from small to larger fibers I wonder about a change in fiber types. Authors look in the soleus, which is a known type 1 (slow twitch) muscle in mouse, but did not study a fiber type switch
Authors also show less central nuclei and fibrotic makers such as collagen. They see an improvement in the organization of microtubuli and neuromuscular junctions. MTor is a protein involved in synthesis of muscle proteins. Tubustatin increased signaling of mTOR.
Again I think showing this in the d2/mdx mouse would be more interesting as muscle is atrophic there. In other words it is good to know whether tubustatin A has the same effects in an atrophic environment (like Duchenne muscle) as in a hypertrophic environment (like mdx mouse).
Finally authors show that tubustatin a increases acetylation of smad3, which appears to impair TGFbeta signaling. However for these studies the effect of tubustatin A treatment is in the wrong direction ( Panel n and m: treated is further from wild type than untreated)
Authors conclude that tubustatin treatment might have therapeutic effects in Duchenne. I would first want to do 2 extra studies:
- See is HDAC6 expression is also expressed in Duchenne muscle like it is in mdx muscle.
- Treat young d2/mdx mice and assess whether therapeutic effects occur in an atrophic environment. So more work is needed.