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A myopathy-related actin mutation increases contractile function
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
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2012 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 123, no 5, 739-746 p.Article in journal (Refereed) Published
Abstract [en]

Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Despite increasing clinical and scientific interest, the contractile consequences of these subtle amino acid substitutions remain obscure. To decipher them, in the present study, we originally recorded and analysed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibres with a particular peptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an unexpected cascade of molecular and cellular events. During contraction, p.Phe352Ser greatly enhances the strain of individual cross-bridges. Paradoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by altering the rate of myosin head attachment to actin monomers. Overall, at the cell level, these divergent mechanisms conduct to an improved steady-state force production. Such results provide new surprising scientific insights and crucial information for future therapeutic strategies.

Place, publisher, year, edition, pages
2012. Vol. 123, no 5, 739-746 p.
Keyword [en]
Nemaline myopathy, ACTA1 mutation, Skeletal muscle, Force, Actin, Myosin cross-bridge
National Category
Medical and Health Sciences
URN: urn:nbn:se:uu:diva-173318DOI: 10.1007/s00401-012-0962-zISI: 000302255000009OAI: oai:DiVA.org:uu-173318DiVA: diva2:523488
Available from: 2012-04-25 Created: 2012-04-23 Last updated: 2014-04-29Bibliographically approved
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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