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Cytoskeletal derangements in hereditary myopathy with a desmin L345P mutation
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB), Anatomy.
Karoloinska Institute.
Karoloinska Institute.
Iowa Statte University.
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2002 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 104, no 5, 493-504 p.Article in journal (Refereed) Published
Abstract [en]

Patients with abnormal accumulations of desmin have been described in myopathies with or without cardiac involvement. Desmin deposits were sometimes associated with abnormal aggregates of other cytoskeletal proteins. In the present study we present how the cytoskeletal organisation of desmin, nestin, synemin, paranemin, plectin and alphaB-crystallin is altered in skeletal muscles from a patient with a L345P mutation in the desmin gene. In general, accumulations of desmin together with synemin, nestin, plectin and alphaB-crystallin were present between myofibrils and beneath the sarcolemma. However, as the biopsy samples were very myopathic, large variability in fibre size and fibre maturation was seen, thus the myofibrillar content and the cytoskeletal organisation varied considerably. In cultured satellite cells from the patient, desmin aggregates were not observed in initial passages, but occurred over time in culture in the form of perinuclear, peripheral or cytoplasmic deposits. Nestin colocalised to the abnormal desmin deposits to a larger extent than did vimentin. alphaB-Crystallin was only present in cells with a disrupted desmin network. Plectin was altered in a subset of cells with a disrupted desmin network, whereas synemin and paranemin were not detected. We conclude that the L345P desmin mutation has a profound influence on the cytoskeletal organisation both in vivo and in vitro, which reflects the pathogenesis of the desmin myopathy.

Place, publisher, year, edition, pages
Springer, 2002. Vol. 104, no 5, 493-504 p.
Keyword [en]
Nestin, Synemin, Paranemin, Plectin, αB-Crystallin
National Category
Other Basic Medicine Health Sciences
URN: urn:nbn:se:umu:diva-81909DOI: 10.1007/s00401-002-0583-zPubMedID: 12410397OAI: diva2:658814
Available from: 2013-10-23 Created: 2013-10-23 Last updated: 2014-03-26Bibliographically approved
In thesis
1. The muscle cytoskeleton of mice and men: Structural remodelling in desmin myopathies
Open this publication in new window or tab >>The muscle cytoskeleton of mice and men: Structural remodelling in desmin myopathies
2001 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The muscle fibre cytoskeleton of skeletal and heart muscle cells is composed mainly of intermediate filaments (IFs), that surround the myofibrils and connect the peripheral myofibrils with the sarcolemma and the nuclear membrane. Desmin is the first muscle specific IF protein to be produced in developing muscles and is the main IF protein in mature muscles. In skeletal muscle, desmin is particularly abundant at myotendinous and neuromuscular junctions. In the heart an increased amount of desmin is found at intercalated discs and in Purkinje fibres of the conduction system. Interactions between the IFs themselves, and between IFs and other structures such as Z-discs and the sarcolemma, are mediated by intermediate filament associated proteins (IFAPs). A transgenic mice model, which lacks the desmin gene have been developed to study the function of desmin. In these mice, morphological abnormalities are observed in both heart and skeletal muscles. Similar defects have been observed in human myopathies, caused by different mutations in the desmin gene. In the present thesis, skeletal and heart muscles of both wild type and desmin knock-out (K/O) mice have been investigated. Furthermore the cytoskeletal organisation in skeletal muscles from human controls and from a patient with desmin myopathy was examined.

In the desmin K/O mice, no morphological alterations were observed during embryogenesis. These mice postnatally developed a cardiomyopathy and a muscle dystrophy in highly used skeletal muscles. Ruptures of the sarcolemma appear to be the primary event leading to muscle degeneration and fibrosis both in cardiac and affected skeletal muscles. In the heart the muscle degeneration gave rise to calcifications, whereas in skeletal muscles regeneration of affected muscle was seen.

In mature wild type mice, the IF proteins synemin and paranemin, and the IFAP plectin were present together with desmin at the myofibrillar Z-discs, the sarcolemma, the neuromuscular junctions and the myotendinous junctions. Nestin was only found in these junctional regions. In desmin K/O mice, all four proteins were detected at neuromuscular and myotendinous junctions. The normal network of synemin and paranemin were not observed, whereas the distribution of plectin was preserved.

In normal human muscles, synemin, paranemin, plectin and αB-crystallin were colocalised with desmin in between the myofibrils, at the sarcolemma and at myotendinous and neuromuscular junctions. In the human desmin myopathy, the distribution of desmin varied considerably. A normal pattern was seen in some fibres areas, whereas other regions either contained large subsarcolemmal and intermyofibrillar accumulations of desmin or totally lacked desmin. Nestin, synemin, paranemin, plectin and αB-crystallin also exhibited an abnormal distribution. They were often aggregated in the areas that contained accumulations of desmin.

In cultured satellite cells from the patient, a normal network of desmin was present in early passages, whereas aggragates of desmin occurred upon further culturing. In the latter, also the nestin network was disrupted, whereas vimentin showed a normal pattern. αB-crystallin was only present in cells with a disrupted desmin network. Plectin was present in a subset of cells, irrespective of whether desmin was aggregated or showed a normal network.

From the present study it can be concluded that an intact desmin network is needed to maintain the integrity of muscle fibres. Desmin may be an important component in the assembly of proteins, which connect the extrasarcomeric cytoskeleton with the extracellular matrix.

Place, publisher, year, edition, pages
Umeå: Umeå universitet, 2001. 45 p.
Umeå University medical dissertations, ISSN 0346-6612 ; 754
desmin, nestin, synemin, paranemin, plectin, αB-crystallin, skeletal muscle, heart muscle, myotendinous junction, motor endplate, costamere
National Category
Basic Medicine
Research subject
Human Anatomy
urn:nbn:se:umu:diva-83451 (URN)91-7305-122-5 (ISBN)
Public defence
2001-11-01, Stora föreläsningssalen, biologihuset, Umeå universitet, Umeå, 09:00 (Swedish)
Available from: 2014-03-26 Created: 2013-11-26 Last updated: 2014-03-26Bibliographically approved

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