Muscle-specific up-regulation of the ubiquitin-proteasome pathway in a mouse model of nemaline myopathy
(English)Manuscript (preprint) (Other academic)
Nemaline myopathy, the most common congenital myopathy, is characterized by muscle fibre atrophy. This compromises contractile performance and ultimately contributes to muscle weakness. The pathogenic mechanisms remain obscure but may be related to an aberrant protein turnover rate due to an increased activation of the ubiquitin-proteasome pathway. To verify, this hypothesis, in the present study, we used skeletal muscles from a transgenic mouse model of nemaline myopathy. We then evaluated the expression of key proteins such as MuRF1 and atrogin-1. In the slow-twitch soleus muscle, we observed a trend towards a higher level of atrogin-1 whereas in the fast-twitch tibialis anterior muscle, we revealed a greater expression of MuRF1. These led to divergent effects on protein content and muscle fibre size. Indeed, in the soleus, a general protein loss and atrophy was found whilst in tibialis anterior, a preferential myosin loss without any clear reduction in the mean muscle fibre size was noticed. Overall these findings prove for the first time that in nemaline myopathy, the ubiquitin-proteasome pathway (i) is involved in the process of muscle wasting; (ii) is differentially activated in slow- and fast-twitch muscles; (iii) may be targeted as a future therapy to alleviate muscle wasting.
myopathy, muscle wasting, atrophy, Murf1, atrogin-1
Medical and Health Sciences
IdentifiersURN: urn:nbn:se:uu:diva-219403OAI: oai:DiVA.org:uu-219403DiVA: diva2:699769