- Therapeutic characterization in mouse models
Capucine Trollet is a post-doctoral research associate in Gillian Butler-Browne’s team. She is working on oculopharyngeal muscular dystrophy (OPMD) after 4 years of post-doc in George Dickson’s lab in Royal Holloway, London.
What is the importance of this study?
I would like first to mention that I have worked on this study both in George Dickson’s lab in the UK and then in Gillian’s team here in Paris. We have carried out a molecular and phenotypic characterisation of the skeletal muscle of a mouse model for OPMD (previously described by David Rubinsztein, Cambridge). I think the main importance of this study is that we have shown that the expression of triplet-repeat expanded PABPN1 leads to a massive gene deregulation with muscle atrophy as a major consequence. Functional and histological analysis of skeletal muscle confirmed a severe and progressive muscular atrophy and reduction in muscle strength. What was also exciting was that at the fibre-type level, we observed differences between different types of fibres, some were affected and others not, even though they all expressed the mutant PAPBN1. This is similar in OPMD patients where some muscles are not affected at all and others are. So it is quite interesting. In conclusion, this mouse recapitulates several pathological observations seen in OPMD patients: progressive muscle weakness, muscle atrophy, fibrosis, mitochondrial defects, ubiquitin-proteasome pathway dysregulation, and affected and unaffected muscles all expressing mutant PABPN1.
What do you think is the significance of this fibre type specificity?
We can’t really translate this so easily into humans because the muscles that are affected in patients are not only fast muscles, as we found in the mouse. So it’s not as simple as ‘ fast muscles are affected, slow muscles are not affected.’ But it’s interesting that for some reason, whether it be resistance or some other parameters that we have not yet deciphered, there is a muscle that has all the features necessary for it be affected but yet it is not affected whereas other muscles are greatly affected. So for the moment I can’t explain this observation but at least we possess a mouse model that contains aggregates in this muscle but no phenotype and others have aggregates and are atrophied.
Do you intend to study this in more detail?
Yes, that’s the plan now. It was not the first thing that we initially found but after looking in detail at the fibre types, we found that there really was a difference between the oxidative and glycolytic fibres. We performed a transcriptomic analysis but this was done in the whole quadriceps muscle, which is a mixture of fibre types, so now it would be really interesting to compare glycolytic fibres and oxidative fibres but that’s not a simple task considering the differences in these two types of muscle. So the muscle type differences need to be distinguished as well, according to what is specific for OPMD. But yes, it is important to investigate these two fibre types now. More generally, the molecular and pathological changes found in this study provide targets for future therapeutic strategies that may reverse some or all of these modified pathways, which are essential for muscle homeostasis and normal function.
Could there be a relationship between the mitochondrial abnormalities and fibre type specificity?
We only looked at the activity of the complex in the mitochondria, where we found differences. However, we looked in the TA (tibialis anterior). So similarly it would be interesting to now study and compare, for example, the soleus muscle (a ‘slow’ muscle) versus the EDL (extensor digitorum longus, a ‘fast’ muscle) to determine whether there are differences in the mitochondria. This is exciting because thus far, all of the papers that describe OPMD patients have just highlighted abnormal mitochondrial structures, mainly using electron microscopy. In our study we really show a difference in mitochondrial activity in this mouse model. Whether it has any significance for OPMD or not, whether it is just age-related, is yet to be revealed, but at least with the transcriptomic data and this mitochondrial activity, we demonstrate that there are significant differences.