Understanding the role of HDACs in Duchenne progression
Fact-checked by In recent years, researchers have come to understand that a group of enzymes called histone deacetylases (HDACs) becomes overactive and contributes to the progression of Duchenne muscular dystrophy (DMD).
While HDACs play a role in normal muscle regeneration and repair, an imbalance in their activity can have the opposite effect, facilitating muscle degeneration and weakness in DMD. Medications to inhibit these enzymes have emerged as a promising class of treatments for slowing DMD progression.
What are HDACs? What do they do in healthy muscles?
HDACs are a group of enzymes that regulate gene activity. They are epigenetic regulators, meaning they help control which genes are turned on or off without altering the underlying DNA sequence. In particular, HDACs help proteins called histones bind more tightly to DNA, effectively silencing or turning off genes.
These enzymes are involved in skeletal muscle remodeling, the process by which muscles adapt their size, structure, and metabolic function in response to exercise and injury.
In healthy muscles, HDAC enzymes help control when genes are turned on and off, so that muscles can grow, repair, and adapt normally. They work with other molecules to help ensure that the right genes for these processes are available when needed.
A naturally occurring molecule called nitric oxide controls HDACs to make sure they don’t become overactive and suppress genes needed for healthy muscles. Nitric oxide production is increased to promote blood flow and muscle function during activity.
What happens to HDACs when dystrophin is missing?
DMD is caused by genetic mutations that disrupt the production of functional dystrophin, a protein important for muscle health. Dystrophin works in a complex with other proteins to act as a shock absorber, protecting muscles against use-related damage. This protein also helps activate other signaling pathways implicated in muscle function.
In DMD, the loss of functional dystrophin leads to the disassembly of the complex and to the disruption of a muscle cell’s normal signaling pathways. Among them is the pathway that leads to nitric oxide production. A lack of nitric oxide consequently allows HDACs to become overactive and start suppressing genes that are necessary for muscle health, which can cause:
- impaired muscle repair
- chronic inflammation and scarring
- the replacement of healthy muscle with fat tissue
- impaired energy production
While dystrophin deficiency causes the initial muscle damage, researchers believe that HDAC overactivity, through the processes listed above, makes it harder for muscles to recover and repair that damage, leading to worsening weakness and wasting over time.
How HDAC inhibitors work to protect muscle health
HDAC inhibitors are a class of treatments that work to prevent the overactivity of HDAC enzymes. They’ve mainly been used to treat certain blood cancers, but now that scientists recognize the role of HDACs in DMD, these medications are of significant interest for treating the neuromuscular disease.
Scientists believe that HDAC inhibition will help prevent muscle loss and reduce inflammation in DMD, ultimately slowing disease progression and preserving physical function.
These medications will not cure DMD. Because the underlying lack of dystrophin still exists, muscles remain vulnerable to damage. Rather, keeping HDACs under control may help muscles repair that damage more easily, ultimately slowing the processes that drive disease progression.
An HDAC inhibitor is approved in the U.S. for some people with DMD, but scientists are still working on developing more selective therapies to maximize the safety and efficacy of these drugs for people with DMD.
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