Researchers Review Duchenne Muscular Dystrophy As a Mitochondrial Metabolic Disease

Christine Traxler, MD avatar

by Christine Traxler, MD |

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In a recent study entitled “Revisiting the dystrophin-ATP connection: How half a century of research still implicates mitochondrial dysfunction in Duchenne Muscular Dystrophy aetiology“, published in the journal Medical Hypotheses, researchers explored the hypothesis that Duchenne Muscular Dystrophy (DMD) is characterised by a systemic mitochondrial impairment central to disease aetiology, instead of a secondary pathophysiological consequence of dystrophin-deficiency.

DMD is the most common type of muscular dystrophy affecting as many as one out of 3,500 males, and because it is an x-linked genetic disorder females are relatively unaffected. This condition is uniformly fatal when males are in their twenties, as it affects muscle strength including the respiratory muscles. DMD patients develop muscle weakness early in life and most become wheelchair-bound by the time they reach twelve years of age.  The disease progresses further so that the patient eventually succumbs to respiratory failure.

DMD was once thought to be a metabolic disease due to the many different metabolic dysfunctions observed during disease progression. Researchers noted that DMD patients had very low levels of dystrophin, a key protein for muscle strength, and the idea that DMD was a metabolic disease was quickly abandoned. Additionally, Duchenne patients also present lipids in their muscle fibers, some of them leach out as a consequence of damage. The cause behind this phenomenon was initially unknown but researchers eventually discovered it to be due to isocitrate dehydrogenase deficiency/dysfunction. This pointed to a metabolic problem as the underlying cause of DMD, however, the lipid buildup was seen as a consequence of dystrophin deficiency.

There have been multiple metabolic findings in Duchenne muscular dystrophy research, which included abnormalities in macronutrient uptake and availability, glycolysis, glycogen storage and utilization, fat oxidation, the creatine phophagen system and the purine nucleotide cycle. The presence of such a high number of abnormal metabolic systems was the reason DMD was initially thought to be of metabolic origin. What was confusing to scientists was that there was no link between dystrophin deficiency and the many metabolic findings in DMD, with the exception of the metabolic pathway associated with neuronal nitric oxide synthase.

More recently, it was found that the lack of dystrophin in DMD is not the cause of the disease per se as was once thought, but a secondary finding that goes along with the metabolic problems observed in the disease. In fact, patients with certain types of muscular dystrophy have no dystrophin in their system whatsoever and have a milder form of the disease due to the metabolic dysfunctions found in muscular dystrophy.

It seems that scientific views are changing once again, with DMD being classified once again as a metabolic disease and not a consequence of dystrophin abnormality. These insights hold important implications in future research to find a potential cure for this disease.