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#apaperaday: Mitochondria and Reactive Oxygen Species: The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy

In today’s #apaperaday, Prof. Aartsma-Rus reads and comments on the paper titled: Mitochondria and Reactive Oxygen Species: The Therapeutic Balance of Powers for Duchenne Muscular Dystrophy

The pick is from @Cells_MDPI by Casati et al, a review on mitochondria and reactive oxygen species (ROS) in Duchenne DOI: 10.3390/cells13070574

Dystrophinopathies are caused by lack of dystrophin (Duchenne) or lack of fully functional dystrophin (Becker). This leads to chronic muscle damage and loss of muscle tissue and function. dystrophin restoration is a therapeutic approach that is approved now in various regions.

However, restored dystrophins are partially functional and therefore will not fully protect muscles from being damaged. Furthermore, restoring dystrophin will not restore the muscle tissue that is already lost. In fact, dystrophin will only be restored in muscle that is left.

Thus there is a need to also target downstream pathology. Here authors focus on mitochondria dysfunction in dystrophinopathies (mainly Duchenne) and how therapies may target this to slow down pathology. Mitochondria are small organelles in our cells that produce energy.

They do this by burning fat and glucose/glycogen. When this does not go properly reactive oxygen species can be produced that can react with other components in the cell (DNA, proteins etc), which will cause damage. In Duchenne there are metabolic changes.

It is known already that the glycolytic pathway (burning sugars) is compromised and there is an accumulation of fatty acids as well. Not having enough energy will exacerbate pathology as muscle needs energy to maintain itself, to contract and (for Duchenne) to repair.

The improper functioning of mitochondria means Duchenne patients are exercise intolerant and that muscle cannot do the metabolic adaptation to training properly. Mitochondria likely are damaged because there is too much Calcium ions floating around in dystrophic muscle.

There are therapeutic compounds that can improve the buffer capacity of mitochondria, e.g. cyclosporin A (though that was tested in Duchenne and did not have a therapeutic effect on function). Givinostat can improve the metabolic adaptation by de-repressing genes involved.

Givinostat DID show a therapeutic effect but it should be mentioned that givinostat does not only act by improving mitochondria health. Authors introduce normally damaged mitochondria self destruct (mitophagy) – this is because damaged mitochondria produce toxic oxygen species.

So this is a protective mechanism. However, when there are too much mitochondria damaged for too long at some point damaged mitochondria start accumulating (like in Duchenne) and that will lead to damage as the reactive oxygen reacts with DNA, proteins etc.

Therapeutic compound that improve mitophagy could help – however, this only works if enough new mitochondria can be produced or there will be an energy crisis in the muscles. Another approach is to try and buffer the reactive oxygens before they can do irreversible damage.

There are many genes in our body that actually already do this buffering as a fail safe. The hope is that producing more of the proteins they code for will be enough to overcome the higher production of reactive oxygens.

There are compounds that can acts as a buffer, e.g. n-acetyl cysteine (NAC, indeed, this was in #apaperaday this week). Authors outline the positive findings with NAC but do not outline the recent publication (likely before it was not yet published when they wrote the review).

Other antioxidants have shown positive effects in mdx mice as well, e.g. curcumin and resveratrol. However, there is so far no antioxidant that showed a clinical effect in Duchenne patients in a clinical trial. Authors focus on those that are currently in trials.

However, I think they should also have listed the many that were tested and failed (halofuginone, idebenone, pentoxyfilin to name but a few). Authors do outline that the metformin and L-citrulline trial failed recently.

Authors end by stressing the need for combination therapy. I agree, but I’m not sure only addressing mitochondria health/reactive oxygens will be enough. It is interesting so far the only secondary treatments that work target multiple pathways (steroids/vamorolone/givinostat).