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Muscle-specific up-regulation of the ubiquitin-proteasome pathway in a mouse model of nemaline myopathy
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
(English)Manuscript (preprint) (Other academic)
Abstract [en]

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.

Keyword [en]
myopathy, muscle wasting, atrophy, Murf1, atrogin-1
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-219403OAI: oai:DiVA.org:uu-219403DiVA: diva2:699769
Available from: 2014-02-28 Created: 2014-02-28 Last updated: 2014-04-29
In thesis
1. Cellular and Molecular Mechanisms Underlying Congenital Myopathy-related Weakness
Open this publication in new window or tab >>Cellular and Molecular Mechanisms Underlying Congenital Myopathy-related Weakness
2014 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Congenital myopathies are a rare and heterogeneous group of diseases. They are primarily characterised by skeletal muscle weakness and disease-specific pathological features. They harshly limit ordinary life and in severe cases, these myopathies are associated with early death of the affected individuals. The congenital myopathies investigated in this thesis are nemaline myopathy and myofibrillar myopathy. These diseases are usually caused by missense mutations in genes encoding myofibrillar proteins, but the exact mechanisms by which the point mutations in these proteins cause the overall weakness remain mysterious. Hence, in this thesis two different nemaline myopathy-causing actin mutations and one myofibrillar myopathy-causing myosin-mutation found in both human patients and mouse models were used to investigate the cascades of molecular and cellular events leading to weakness.

I performed a broad range of functional and structural experiments including skinned muscle fibre mechanics, small-angle X-ray scattering as well as immunoblotting and histochemical techniques. Interestingly, according to my results, point mutations in myosin and actin differently modify myosin binding to actin, cross-bridge formation and muscle fibre force production revealing divergent mechanisms, that is, gain versus loss of function (papers I, II and IV). In addition, one point mutation in actin appears to have muscle-specific effects.  The presence of that mutant protein in respiratory muscles, i.e. diaphragm, has indeed more damaging consequences on myofibrillar structure than in limb muscles complexifying the pathophysiological mechanisms (paper II).

As numerous atrophic muscle fibres can be seen in congenital myopathies, I also considered this phenomenon as a contributing factor to weakness and characterised the underlying causes in presence of one actin mutation. My results highlighted a direct muscle-specific up-regulation of the ubiquitin-proteasome system (paper III).

All together, my research work demonstrates that mutation- and muscle-specific mechanisms trigger the muscle weakness in congenital myopathies. This gives important insights into the pathophysiology of congenital myopathies and will undoubtedly help in designing future therapies.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2014. 45 p.
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 977
skeletal muscle, skeletal muscle contraction, atrophy, nemaline myopathy, myofibrillar myopathy, myosin, actin
National Category
Clinical Medicine
urn:nbn:se:uu:diva-219460 (URN)978-91-554-8894-9 (ISBN)
Public defence
2014-04-16, Hedstrandssalen, Akademiska sjukhuset, ing 70, b.v., Uppsala, 09:15 (English)
Available from: 2014-03-24 Created: 2014-03-02 Last updated: 2014-04-29

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