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Distinct Underlying Mechanisms of Limb and Respiratory Muscle Fiber Weaknesses in Nemaline Myopathy
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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2013 (English)In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 72, no 6, 472-481 p.Article in journal (Refereed) Published
Abstract [en]

Nemaline myopathy is the most common congenital myopathy and is caused by mutations in various genes such as ACTA1 (encoding skeletal alpha-actin). It is associated with limb and respiratory muscle weakness. Despite increasing clinical and scientific interest, the molecular and cellular events leading to such weakness remain unknown, which prevents the development of specific therapeutic interventions. To unravel the potential mechanisms involved, we dissected lower limb and diaphragm muscles from a knock-in mouse model of severe nemaline myopathy expressing the ACTA1 His40Tyr actin mutation found in human patients. We then studied a broad range of structural and functional characteristics assessing single-myofiber contraction, protein expression, and electron microscopy. One of the major findings in the diaphragm was the presence of numerous noncontractile areas (including disrupted sarcomeric structures and nemaline bodies). This greatly reduced the number of functional sarcomeres, decreased the force generation capacity at the muscle fiber level, and likely would contribute to respiratory weakness. In limb muscle, by contrast, there were fewer noncontractile areas and they did not seem to have a major role in the pathogenesis of weakness. These divergent muscle-specific results provide new important insights into the pathophysiology of severe nemaline myopathy and crucial information for future development of therapeutic strategies.

Place, publisher, year, edition, pages
2013. Vol. 72, no 6, 472-481 p.
Keyword [en]
Actin, Contractile dysfunction, Limb muscle, Nemaline myopathy, Respiratory muscle, Weakness
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-204291DOI: 10.1097/NEN.0b013e318293b1ccISI: 000319454400003OAI: oai:DiVA.org:uu-204291DiVA: diva2:638343
Available from: 2013-07-30 Created: 2013-07-29 Last updated: 2017-12-06Bibliographically 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.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 977
Keyword
skeletal muscle, skeletal muscle contraction, atrophy, nemaline myopathy, myofibrillar myopathy, myosin, actin
National Category
Clinical Medicine
Identifiers
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)
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Available from: 2014-03-24 Created: 2014-03-02 Last updated: 2014-04-29

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Lindqvist, JohanRenaud, GuillaumeOchala, Julien

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