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Myonuclear domain size and myosin isoform expression in muscle fibres from mammals representing a 100 000-fold difference in body size
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.
Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
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2009 (English)In: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 94, no 1, 117-129 p.Article in journal (Refereed) Published
Abstract [en]

This comparative study of myonuclear domain (MND) size in mammalian species representing a 100 000-fold difference in body mass, ranging from 25 g to 2500 kg, was undertaken to improve our understanding of myonuclear organization in skeletal muscle fibres. Myonuclear domain size was calculated from three-dimensional reconstructions in a total of 235 single muscle fibre segments at a fixed sarcomere length. Irrespective of species, the largest MND size was observed in muscle fibres expressing fast myosin heavy chain (MyHC) isoforms, but in the two smallest mammalian species studied (mouse and rat), MND size was not larger in the fast-twitch fibres expressing the IIA MyHC isofom than in the slow-twitch type I fibres. In the larger mammals, the type I fibres always had the smallest average MND size, but contrary to mouse and rat muscles, type IIA fibres had lower mitochondrial enzyme activities than type I fibres. Myonuclear domain size was highly dependent on body mass in the two muscle fibre types expressed in all species, i.e. types I and IIA. Myonuclear domain size increased in muscle fibres expressing both the β/slow (type I; r= 0.84, P < 0.001) and the fast IIA MyHC isoform (r= 0.90; P < 0.001). Thus, MND size scales with body size and is highly dependent on muscle fibre type, independent of species. However, myosin isoform expression is not the sole protein determining MND size, and other protein systems, such as mitochondrial proteins, may be equally or more important determinants of MND size.

Place, publisher, year, edition, pages
2009. Vol. 94, no 1, 117-129 p.
National Category
Physiology
Identifiers
URN: urn:nbn:se:uu:diva-87940DOI: 10.1113/expphysiol.2008.043877ISI: 000261961800014PubMedID: 18820003OAI: oai:DiVA.org:uu-87940DiVA: diva2:133943
Available from: 2009-01-15 Created: 2009-01-15 Last updated: 2017-12-14Bibliographically approved
In thesis
1. Myonuclear Organization and Regulation of Muscle Contraction in Single Muscle Fibres: Effects of Ageing, Gender, Species, Endocrine Factors and Muscle Size
Open this publication in new window or tab >>Myonuclear Organization and Regulation of Muscle Contraction in Single Muscle Fibres: Effects of Ageing, Gender, Species, Endocrine Factors and Muscle Size
2012 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The skeletal muscle fibre is a syncitium where each myonucleus regulates the gene products in a finite volume of cytoplasm i.e., the myonuclear domain (MND). A novel image analysis algorithm applied to confocal images, analyzing MND size and myonuclear spatial distribution in 3-dimensions in single skeletal muscle fibres has been used in this project. The goal was to explore the modulation of myonuclei count and MND size in response to muscle adaptation processes. The effects of ageing, gender, hormones, muscle hypertrophy and body size were investigated on MND size.

A strong linear relationship was found between MND size and body size in the muscle fibres from mammals representing a 100,000-fold difference in body size. Independent of species, MND size was highly dependent on MyHC isoform type and mitochondrial contents of skeletal muscle fibres. In hypertrophic mice, a significant effect of MND size on specific force and myosin content was observed. This effect was muscle fibre type-specific and shows that the bigger MNDs in fast-twitch EDL muscle fibres are optimally tuned for force production while smaller MNDs in slow-twitch soleus muscle fibres have a much more dynamic range of hypertrophy without functional compromise. This indicates a critical volume individual myonuclei can support efficiently for a proportional gain in muscle fibre force and size. In human muscle fibres, spatial organization of myonuclei was affected by both ageing and MyHC isoform expression. In fibres expressing type I MyHC isoform, an increased MND size variability and myonuclear aggregates were observed in old age although average MND size was unchanged. In contrast, in type IIa fibres, the average MND size was smaller reflecting smaller size of muscle fibres. Those changes may influence the transcriptional activity per myonucleus and/or local cooperatively of myonuclei in a gender and muscle fibre-type specific manner. Finally, hormone replacement therapy was shown to negate menopause-related functional impairment in skeletal muscle fibres. The positive effect on force was due to quantitative effect in fibres expressing fast myosin isoform while the effect was both quantitative and qualitative in fibres expressing slow myosin isoform. The effect on MND size was fibre type dependent and was achieved by significantly reducing domain size in slow- but not the fast-twitch muscle fibres.

Together, our data suggest that modulation of myonuclei count and MND size is a mechanism contributing to remodelling of skeletal muscle in muscle adaptation process. These findings should be considered when developing therapeutic approaches towards restoring muscle mass and strength in muscle wasting conditions.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2012. 62 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 737
Keyword
single muscle cells, muscle nuclei, specific force, species, hypertrophy, mammals, ageing, gender
National Category
Neurosciences
Research subject
Physiology
Identifiers
urn:nbn:se:uu:diva-167723 (URN)978-91-554-8264-0 (ISBN)
Public defence
2012-03-15, Hedstrandsalen, Ingång 70, bv,AS Akademiska sjukhuset, Uppsala, 09:15 (English)
Opponent
Supervisors
Available from: 2012-02-28 Created: 2012-02-01 Last updated: 2012-03-01Bibliographically approved
2. Methods and models for 2D and 3D image analysis in microscopy, in particular for the study of muscle cells
Open this publication in new window or tab >>Methods and models for 2D and 3D image analysis in microscopy, in particular for the study of muscle cells
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Alternative title[sv]
Metoder och modeller för två- och tredimensionell bildanalys inom mikroskopi, speciellt med inrikting mot muskelceller
Abstract [en]

Many research questions in biological research lead to numerous microscope images that need to be evaluated. Here digital image cytometry, i.e., quantitative, automated or semi-automated analysis of the images is an important rapidly growing discipline. This thesis presents contributions to that field. The work has been carried out in close cooperation with biomedical research partners, successfully solving real world problems.

The world is 3D and modern imaging methods such as confocal microscopy provide 3D images. Hence, a large part of the work has dealt with the development of new and improved methods for quantitative analysis of 3D images, in particular fluorescently labeled skeletal muscle cells.

A geometrical model for robust segmentation of skeletal muscle fibers was developed. Images of the multinucleated muscle cells were pre-processed using a novel spatially modulated transform, producing images with reduced complexity and facilitating easy nuclei segmentation. Fibers from several mammalian species were modeled and features were computed based on cell nuclei positions. Features such as myonuclear domain size and nearest neighbor distance, were shown to correlate with body mass, and femur length. Human muscle fibers from young and old males, and females, were related to fiber type and extracted features, where myonuclear domain size variations were shown to increase with age irrespectively of fiber type and gender.

A segmentation method for severely clustered point-like signals was developed and applied to images of fluorescent probes, quantifying the amount and location of mitochondrial DNA within cells. A synthetic cell model was developed, to provide a controllable golden standard for performance evaluation of both expert manual and fully automated segmentations. The proposed method matches the correctness achieved by manual quantification.

An interactive segmentation procedure was successfully applied to treated testicle sections of boar, showing how a common industrial plastic softener significantly affects testosterone concentrations.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2008. 76 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Science and Technology, ISSN 1651-6214 ; 544
Keyword
medical image analysis, image segmentation, fluorescence microscopy, cytometry, human skeletal muscle
National Category
Natural Sciences
Identifiers
urn:nbn:se:uu:diva-9201 (URN)978-91-554-7255-9 (ISBN)
Public defence
2008-09-19, Polhemsalen, Ångströmlaboratoriet, Polacksbacken, Uppsala, 13:15
Opponent
Supervisors
Available from: 2008-08-29 Created: 2008-08-29 Last updated: 2013-07-03Bibliographically approved

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