Therapy for muscular dystrophy?
A new study in PLOS Biology raises the possibility that vitamin B3 might be worth assessing as a therapy for muscular dystrophies. This is tantalising, because this group of human genetic diseases includes some severely disabling and ultimately lethal forms, including Duchenne muscular dystrophy (DMD), which affects one boy in every 3000 born. However, the study rang a faint bell in a dusty 20-year-old room…
Back in the early ’90s as part of my PhD thesis on DMD, I wrote a section for the introductory chapter in which I catalogued all the attempted therapeutic interventions that I could dig out of the literature. There were a large number, many based on rather questionable rationale, and most with no demonstrable effect, but then desperate diseases warrant desperate measures. Among them I recall several studies that involved dietary vitamins – E and Q10.
Nowadays most therapeutic efforts for DMD seem to be aimed at rectifying the underlying genetic defect in muscular dystrophy, whether at the DNA level (gene therapy), RNA level (antisense oligonucleotide-induced exon-skipping) or protein level (translational read-through); mercifully, several of these approaches are at last a source of some genuine optimism.
But a new study just published online in PLOS Biology by Michelle Goody, Clarissa Henry and colleagues (and discussed in an accompanying Synopsis by Richard Robinson) hints at a potential parallel route towards improving the symptoms of muscular dystrophies, rather than tackling the root genetic cause. And it involves another vitamin…
How muscular dystrophies work
To appreciate this, you need to know a little about how muscular dystrophies are thought to work. The most generally accepted idea is that this group of diseases, which arise from a variety of genetic mutations, share a common disastrous effect on the robustness of muscle cells.
Cells, and the gossamer two-molecule-thick membranes that enclose them, are shockingly fragile things, but next time you’re pumping iron (no, I don’t either, but bear with me) just think of the forces that muscle fibres are subjected to. How do they cope with this? The short answer is that they’re each enclosed within a tough tube of extracellular matrix, and that minuscule but crucial protein clusters anchor the cell membrane to the tube. It’s these protein anchors that go wrong in muscular dystrophies, with devastating consequences for the patients.
The new study in PLOS Biology
I won’t go into the science much here (see the Synopsis if you want more detail), but building on a previous paper of theirs, the authors checked out their hunch that boosting levels of a common cellular chemical, NAD+ (see picture at top), could help organise and strengthen the extracellular matrix in zebrafish that have a severe (congenital) form of muscular dystrophy. This might enable any remaining protein anchors (there are several different types, some affected, some spared, by the mutation) to rescue the fish from the disease.
To cut to the chase, the results are quite spectacular, with NAD+ significantly improving not only the state of the animals’ muscles, but also enhancing their swimming performance. The authors also start to tease apart the mechanism by which NAD+ might be having these effects. As an extra twist, because cells make NAD+ out of vitamin B3 (niacin), the authors took the bizarre step of adding a proprietary B3-rich vitamin supplement (Emergen-C) to the fishes’ environment. Incredibly, this also seemed to work.
Science, and especially translational science, tends to progress in a series of steps; some in the right direction, and others not so fruitful, so I’ll end this piece with a list of caveats. In terms of a rationale on which to base further investigations, the results of this study
look much more promising than the historical trials with vitamins E and Q10. But here are three reasons not to reach for the B3 supplements just yet:
- Humans and zebrafish last shared a common ancestor 500 million years ago; what happens in one animal may not happen in the other.
- The study addresses young developing fish, and presumably the authors will go on to see whether these findings can be replicated in older animals. Most human muscular dystrophy patients are not diagnosed until after birth, and (depending on the type of muscular dystrophy) often much later in life. We can’t assume that this treatment would work if it were to be initiated long after the extracellular matrix has been made.
- The study looks at the very severest types of muscular dystrophy – the congenital ones. It may be that the commonest form of muscular dystrophy, Duchenne, which is less severe (but still deadly), is not significantly improved by this treatment.
So my pressing question for the future is: “This works (spectacularly well) for fish embryos with congenital muscular dystrophy; will it work for a five year-old boy who’s just been diagnosed with Duchenne muscular dystrophy?” Only time and future research into these promising findings will tell.