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First published online May 26, 2006
Journal of Experimental Biology 209, 2276-2292 (2006)
Published by The Company of Biologists 2006
doi: 10.1242/jeb.02088

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The satellite cell as a companion in skeletal muscle plasticity: currency, conveyance, clue, connector and colander

Judy E. Anderson

Department of Human Anatomy and Cell Science, Faculty of Medicine, University of Manitoba, Winnipeg, MB, R3E 0W3, Canada

View larger version (117K): [in a new window]   Fig. 1. An electron micrograph of a satellite cell closely applied to the sarcolemma of an extrafusal fibre. The satellite cell is covered by a thin layer of basement membrane (black arrowheads; also called external lamina), which does not appear between the fibre and satellite cell (original magnification x30 000).

View larger version (97K): [in a new window]   Fig. 2. (A) Normal skeletal muscle in transverse section showing muscle fibres separated by endomysial connective tissue and small profiles of vascular supply. Part of a muscle spindle is visible toward the bottom left of the micrograph. Satellite cells are impossible to identify at this magnification. (Original micrograph x140; Toluidine Blue staining.) (B) Normal muscle in longitudinal section, some 10 min following traumatic injury. Fibres are broken and show hypercontracted myofibrils. There is extravasation of red blood cells from a damaged vessel into the interstitial space. (Original micrograph x140; Toluidine Blue staining.) (C) Micrograph of a section of skeletal muscle from a muscle of a patient with Duchenne muscular dystrophy. While there are some fibres of muscle present (to the left of the field), much of the field is filled with dense collections of collagen bundles and adipocytes (central and right of the field). (Original micrograph x140; Toluidine Blue staining.) Much of the pathology literature on DMD refers to muscle being replaced over time by adipose and connective tissues as muscle fibres are damaged and the disease progresses. However, there is a distinct possibility that the adipocytes and fibroblasts may have differentiated from stem cells in the satellite cell position on fibres, since this alternate differentiation can be observed in tissue culture and in aging muscle (Jozsi et al., 2001; Shefer et al., 2004; Taylor-Jones et al., 2002). Other descriptions of `transdifferentiation' are reported between vascular smooth muscle and skeletal muscle and may relate to the apparent pool of stem cells in the mesangioblast compartment in development (Cossu and Bianco, 2003; Galli et al., 2005; Graves and Yablonka-Reuveni, 2000; Sampaolesi et al., 2003).

View larger version (65K): [in a new window]   Fig. 3. (A) An activated satellite cell on a muscle fibre 10 min following injury (arrow). (Original micrograph taken at x350; H&E staining.) (B) Schematic depicting the relative location of NOS-1-derived nitric oxide release from a muscle fibre and diffusing through satellite cell toward the interstitial space (after Anderson, 2000). (C) Micrograph of NOS-1 expression in an activated satellite cell in skeletal muscle. (Original micrograph x350; in situ hybridization) (after Anderson and Vargas, 2003). (D) A schematic describing potential communication and feedback signaling among various compartments, cells and tissues in skeletal muscle, suggesting that satellite cells are active as filters for signaling during structural and functional plasticity.

View larger version (30K): [in a new window]   Fig. 4. (A) A single normal muscle fibre isolated from the flexor digitorum brevis muscle of a normal mouse. The fibre was maintained in culture for 48 h in the presence of bromodeoxyuridine (BrdU) to label DNA synthesis. Two satellite cells are adherent to the fibre; two additional cells (not identifiable with this staining technique) lie on the surface of the culture dish and have also incorporated BrdU during culture. Note that the post-mitotic nuclei within the muscle fibre have not incorporated BrdU. (Original micrograph x60.) (B) A single normal muscle fibre with BrdU-positive satellite cells beginning to migrate away from the fibre. Again, myonuclei inside the muscle fibre are not BrdU-positive. (Original magnification x140.) A and B after (Anderson and Pilipowicz, 2002). (C) A single normal muscle fibre prepared by immunostaining to demonstrate myogenin expression in activated satellite cells that are undergoing myogenesis on the fibre. The satellite cells have likely divided since the fibres were originally plated for culture, as they are present in pairs and quartets on the fibre surface. Note that the myofibre nuclei do not express myogenin, a muscle-specific regulatory gene expressed during the differentiation phase of myogenesis. (Original magnification x140.) (D) A selected field of myotubes in tissue culture, showing myogenin protein expression by immunostaining and fluorescence microscopy. Cultures are plated satellite cells isolated from skeletal muscle, and may contain `contaminating' cells of the fibroblast, adipocyte and endothelial lineages that are only partly distinguishable from myogenic cells in unstained cultures using structural and behavioural phenotypes. Myotubes form in culture as a result of cell fusion events, meaning that many myogenic cells were contained in a culture. Only those mononuclear cells expressing myogenin would be identified as myogenic. (Original magnification x140.) (E) A single dystrophic muscle fibre isolated from the flexor digitorum brevis muscle of an mdx dystrophic mouse, showing nuclei stained with DAPI (Z. Yablonka-Reuveni and J. E. Anderson, unpublished data). Nuclei are present within the fibre in one of three phenotypes. In the longitudinal regions or segments that have not undergone degeneration and regeneration, the nuclei are apparently `jumbled' and mainly appear out of the plane of focus. In other longitudinal segments of the fibre, the myonuclei are displayed as rows of centrally placed nuclei; these segments have undergone a cycle of degeneration and regeneration, and these central myonuclei originated from the fusion of satellite cell progeny into the muscle fibre remnant. The same regenerated segments are `decorated' with satellite cells, the nuclei of which appear at the periphery of the fibre. These cells lie outside the sarcolemma and within the external lamina that is present on these isolated fibres (Wozniak et al., 2003) and have contributed, through proliferative events, the myonuclei that lie within the adjacent regenerated segments. Note that this technique does not identify the possible heterogeneity between satellite cells regarding the number of cell cycles that have passed, and that the `parent' satellite cell may not lie in the same segment as the central myonucleus that was generated by the previous cell cycle. (Original magnification x140.)

View larger version (154K): [in a new window]   Fig. 5. (A) A columnar arcade in which plasticity of function or form is not integrated into the design. (original photograph, Agora, Athens, Greece). (B) This micrograph of skeletal muscle regenerating after traumatic injury contrasts with the arcade of Greek columns in A. A tendon courses through the figure vertically (broken line) and is met by myotubes (arrows) forming in the belly of the damaged muscle. In the damaged region, many myogenic cells (progeny of satellite or stem cells) are present, admixed with numerous mononuclear cells that are only partly identifiable as inflammatory, phagocytic, fibroblastic or angiogenic. The myotubes contain numerous central myonuclei, indicating they have been formed in a regenerative process in the 6 days since injury. The tendon and myotubes, vascular and connective tissues are all involved in the regenerative events that support the plasticity of this skeletal muscle. (Original micrograph at x60.) (C) Myotubes forming by regenerative events at 4 days after injury, showing accretion of nuclei and expansion of the myofibre diameter (arrow). (Original micrograph at x140.) (D) Myotubes and mononuclear cells in the bed of a regenerating muscle following injury. In this field, there is a small central area of ossification (arrow), in a region where no osteogenic progenitors would have been identified prior to injury. The formation of bone in a muscle also demonstrates plasticity of satellite cells in taking direction to be precursors for alternate mesenchymal tissues (Deasy et al., 2004); Lee et al., 2000; Shen et al., 2004). (Original micrograph at x140.) (E) A myotube (arrow) forming through addition of myogenic cells, identified (by in situ hybridization) by their expression of myogenin transcripts, a muscle-specific regulatory gene. The myogenic cells are progeny of the satellite or stem cells that were activated by muscle injury. After proliferation, the cells migrate within the regenerating muscle bed, become aligned in the longitudinal axis of the muscle (which is still attached to the tendons and therefore subject to passive tension during locomotion) and fuse. Long filopodial processes can be observed extending toward the myotube from myogenin-expressing cells in the surrounding region of mononuclear cell infiltration. (Original micrograph at x140.) (F) Micrograph showing a branched myotube (arrow), formed in a regenerating muscle during treatment with a NOS inhibitor. The fusion of myogenic precursors to myotubes or remnant stumps of damaged fibres is mediated in part by the level of nitric oxide in skeletal muscle, and with a low level of nitric oxide, the branched myotube phenotype predominates over the typical slender cylindrical myotubes that form in normal regenerating muscle (Anderson, 2000). (Original micrograph at x140.)

View larger version (61K): [in a new window]   Fig. 6. (A) A region of a myotube around one nucleus (a cytoplasmic domain) that has contributed dystrophin expression to the myotube through fusion during myotube formation. Tissue culture experiments examined the dynamics of domain elongation in culture, using different proportions of co-cultured normal (dystrophin-positive) and dystrophic (dystrophin-negative) satellite cells (Kong and Anderson, 2001). (B) Micrograph showing expression of developmental myosin heavy chain (devMHC) in new myotubes formed over 4 days of regeneration following injury to normal muscle. (C) Micrograph showing laminin immunostaining surrounding skeletal muscle fibres. Laminin is one of the external matrix proteins that is complexed with the dystrophin-associated proteins that are either internal, transmembrane or linked with proteins inside the sarcolemma in normal muscle (Crawford et al., 2000; Ervasti and Campbell, 1993; Ferletta et al., 2003). In muscles affected by mutations in proteins of the dystrophin-associated protein complex, the expression of laminin is reduced; this is also noted in dystrophin-deficient muscle (Ferletta et al., 2003; Kanagawa et al., 2005; Kikkawa et al., 2004; Kim et al., 2004; Saito et al., 2005). Treatment with glucocorticoids increases the expression of laminin in mdx mouse skeletal muscle (Anderson et al., 2000). NOS-1 expression is also reduced secondary to dystrophin deficiency. There is significant alleviation of the dystrophic phenotype (in the mdx dystrophic mouse) by increasing the expression of NOS-1 in mdx mouse skeletal muscle (using transgenic approaches) and the use of a NOS substrate (L-arginine) to reduce the severity and progression of mdx mouse muscular dystrophy (Anderson, 2000; Anderson et al., 2005; Anderson and Vargas, 2003; Archer et al., 2006; Brenman et al., 1995; Brenman et al., 1996; Shiao et al., 2004; Tidball and Wehling-Henricks, 2004a; Tidball and Wehling-Henricks, 2004b; Wehling et al., 2001; Wehling-Henricks et al., 2005). (Original micrographs all x140.)

View larger version (42K): [in a new window]   Fig. 7. A schematic of satellite cells on a regenerating fibre, depicting the roles of the satellite cell as currency to make new muscle; conveyance during migration and to bring therapeutic potential for new gene expression; clue to the processes of development, growth, regeneration and neuromuscular diseases; connector between fibres and signals in the environment; and as a colander to interpret and rectify signaling traffic while communicating with a fibre.

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