How Does Mature Skeletal Muscle Repair Damage?
Adult skeletal muscle generates force in a controlled and directed fashion through the contraction of highly specialized, postmitotic, multinucleated myofibers. Life-long muscle function relies on maintenance and regeneration of myofibers through a highly regulated process beginning with activation of normally quiescent musculus precursor cells and proceeding with formation of proliferating progenitors that fuse to generate differentiated myofibers. In this review, nosotros depict the historical basis and current evidence for the identification of satellite cells as developed musculus stem cells, critically evaluate contributions of other cells to adult myogenesis, and summarize existing data regarding the origins, genetic markers, and molecular regulation of satellite cells in normal, diseased, and aged muscle.
Main Text
Satellite Cells as Adult Muscle Precursor Cells and Candidate Muscle Stem Cells
Adult skeletal musculus possesses remarkable regenerative capacity, and large numbers of new myotubes normally are formed in only a few days after acute muscle damage (
,
,
,
). Early hypotheses proposed that new myofibers were generated via budding of myotubes from existing, injured fibers (
,
); however, further study has demonstrated instead that this rapid repair occurs through the differentiation and subsequent prison cell fusion of myogenically specified mononuclear precursor cells contained within a population of "satellite cells" positioned betwixt the plasma membrane and the surrounding basal lamina of mature, differentiated muscle fibers (
,
). Alexander Mauro first proposed in 1961 that satellite cells might represent "dormant myoblasts" left over from embryonic muscle development and capable of recapitulating the developmental program of skeletal myogenesis in response to musculus damage (
). Subsequent studies, in both the chick (
) and mouse (
), demonstrated that multinucleated myotubes could indeed be generated in vitro from unmarried myogenic precursor cells, and that these precursors ultimately derived from muscle satellite cells (
). Furthermore, in vivo-labeled (
), and clonally cultured in vitro-labeled (
), satellite cells were shown to participate in the regeneration of damaged muscle when transplanted in vivo, contributing well-nigh exclusively via fusion with pre-existing myofibers. Pulse-chase experiments using a single dose of tritiated thymidine to label dividing cells indicated that DNA synthesis among sublaminar nuclei was limited to satellite cell nuclei, and that true muscle nuclei practise non undergo mitosis (
). Although these methods labeled satellite cells relatively infrequently, indicating the relative quiescence of satellite cells (
), in some cases Dna label from satellite cells marked during the pulse phase eventually appeared in myonuclei during the chase phase, demonstrating the capacity of at least some satellite cell progeny to incorporate into existing myofibers, even in the absence of astute tissue injury (
). Such studies formed the basis for our current view of muscle satellite cells as the principal mediators of postnatal musculus growth and repair. These cells reply to regenerative cues, such as injury or exercise, by proliferating to grade myoblasts, which divide a limited number of times before terminally differentiating and fusing to form multinucleated myotubes (reviewed in
,
) (see Effigy 1A ). The life-long regenerative capacity of satellite cells implies that they can be robustly and perpetually renewed while maintaining the ability to generate differentiated progeny and suggests that they may represent an developed stem jail cell population for skeletal muscle.
Stem cells are thought to exist in many adult tissues capable of regeneration and are defined by their unique chapters to both self-renew and differentiate. Adult stalk cells take been all-time characterized in the mammalian claret-forming system, where clonogenic, multipotent hematopoietic stem cells (HSC) have been prospectively isolated from bone marrow and demonstrate at the single-cell level the capacity to regenerate the entire hematopoietic system (reviewed in
Kondo et al., 2003
- Kondo M.
- Wagers A.J.
- Manz Grand.G.
- Prohaska S.Due south.
- Scherer D.C.
- Beilhack G.F.
- Shizuru J.A.
- Weissman I.L.
Biology of hematopoietic stem cells and progenitors: implications for clinical awarding.
- Crossref
- PubMed
- Scopus (759)
- Google Scholar
). While it is clear that satellite cells also contain unspecified precursor cells capable of all-encompassing proliferation and differentiation to generate mature myofibers, to formally constitute that they indeed part equally adult stem cells, it volition be necessary to demonstrate that private cells within the satellite cell pool maintain both self-renewal and differentiation potential in vivo. Although this clonal analysis is still lacking, every bit outlined below, multiple lines of prove from in vitro and in vivo studies exercise suggest that musculus stalk cells are contained within at least a subset of satellite cells.
First, every bit noted in a higher place, satellite jail cell number and regenerative capacity normally remain nearly constant through multiple cycles of injury and repair, suggesting satellite jail cell cocky-renewal. In addition, studies of isolated unmarried myofibers and chief satellite cells maintained in culture have revealed that some cultured satellite cells form clusters that contain both differentiated progeny and cells that regain a phenotype characteristic of quiescent satellite cells (Pax-7+ and MyoD− or myogenin−) (
,
). Furthermore, populations of neonatal, satellite jail cell-derived myoblasts have been shown to generate both differentiated myofibers and functional satellite cells in vivo following intramuscular transplantation (
,
). In ex vivo explant cultures, satellite cells activated past muscle injury give rise to intermediate progenitor cells expressing the myogenic transcription gene Pax-3, which carve up asymmetrically and differentiate into Pax-three−, Myf-5hi, desminhi myoblasts (
). This progression forth a myogenic lineage in developed muscle resembles embryonic myogenesis, where Pax-three induces the expression of Myf-5 and MyoD (
), and Pax-3+ pre-myoblast progenitor cells delaminate from somites and migrate into the limb buds to generate fusion-competent myoblasts (
Goulding et al., 1994
- Goulding M.
- Lumsden A.
- Paquette A.J.
Regulation of Pax-3 expression in the dermomyotome and its role in musculus development.
- PubMed
- Google Scholar
). Finally, the most compelling evidence for the stem prison cell nature of satellite cells comes from recent studies in which rigorously purified, single, intact myofibers, containing an average of merely 7–22 associated satellite cells, were transplanted into the radiation-ablated muscle of immunocompromised, dystrophic (mdx-nude) hosts (
). The grafted fibers could give rise to over 100 new myofibers, contributing an estimated 25,000–30,000 differentiated myonuclei and, moreover, could regenerate substantially expanded (upwards to 10-fold) numbers of functional Pax-seven+ satellite cells in vivo. These donor-derived satellite cells persisted in the skeletal musculus for at least several weeks and could exist reactivated and expanded in response to additional musculus injury (
).
Taken together, these data strongly suggest that satellite cells represent self-renewing developed muscle stem cells and alone are sufficient for musculus repair. This conclusion likely will be strengthened past ongoing studies of the chapters for and regulation of satellite jail cell self-renewal, specially those testing the continued regenerative potential of single or clonally marked satellite cells in series transplantations.
Developmental Origins of Skeletal Muscle and Satellite Cells
Myogenic precursors are specified during development past signals emanating from neighboring cells of the notochord, neural tube, and dorsal ectoderm. This specification depends critically on the part of myogenic transcription factors, such as Pax-3 and Pax-7 (
,
Cossu et al., 1996a
- Cossu G.
- Kelly R.
- Tajbakhsh S.
- Di Donna Due south.
- Vivarelli E.
- Buckingham M.
Activation of different myogenic pathways: myf-5 is induced by the neural tube and MyoD by the dorsal ectoderm in mouse paraxial mesoderm.
- PubMed
- Google Scholar
,
,
). Once committed, somite-derived cells migrate to multiple sites of embryonic myogenesis, begin to express the myogenic basic helix-loop-helix transcription factors Myf-five and MyoD (
), and differentiate into muscle fibers. Somite-derived myogenic progenitors that do not differentiate into myofibers at this time have been suggested instead to be retained into adulthood as musculus satellite cells (
,
,
). This concept recently has been confirmed in two papers in which myogenic reporter strains and prison cell-lineage tracing experiments demonstrated that avian (
) and mouse (
) embryonic and fetal myogenic progenitor cells ascend from the central dermomyotome, following generation of the main myotome. Importantly, neonatal Pax-7+ progenitor cells establish in the satellite cell position were shown to originate besides from the avian embryonic dermomyotome, indicating that some of the precursor cells that contribute to embryonic and fetal muscle are retained later nativity as satellite cells (
). In quickly growing neonatal muscle, nuclei of satellite cells and myoblasts comprise ∼thirty% of myofiber-associated nuclei, simply after abeyance of muscle growth, quiescent satellite cells stand for only ∼5% of adult myofiber nuclei (
). Information technology remains to exist adamant, however, whether the quiescent satellite cells in developed muscle have the same developmental origin as embryonic, fetal, and neonatal cells, or, alternatively, if proliferating dermomyotome-derived myofibers-associated progenitors are exhausted during the musculus growth, and subsequent regeneration of the adult muscle invokes a distinct lineage of precursor cells. Additional analysis of myogenic reporter markers (
) in older animals, and subsequently repeated rounds of muscle injury and regeneration, will be particularly informative to address this issue and also may give farther insight into the self-renewal potential of embryonically specified dermomyotome-derived satellite cells.
Phenotypic and Functional Heterogeneity of Satellite Cells
Satellite cells are classically defined by their position beneath the basal lamina and past their ability to undergo myogenic differentiation (
,
). Notwithstanding, accumulating testify suggests that the satellite cell compartment contains cells of distinct ontogeny and function. Kickoff, although several markers have been associated with satellite cells, no unmarried marker defines all satellite cells. For example, while most satellite cells express the surface poly peptide CD34 (
,
,
), they can variably express other surface markers (
), as well every bit myogenic transcription factors, such as Pax-7, MyoD, and Myf-5 (
,
,
). CD34 and Pax-7 identify quiescent satellite cells, and Pax-seven, Grand-Cadherin, MyoD, and Myf-5 are really upregulated with differentiation of satellite cells into myoblasts (
,
,
). This heterogeneity of marking expression may reflect functional differences among satellite cells or distinct stages of myogenic lineage specification or may distinguish myogenic from nonmyogenic jail cell types within myofiber compartment. In this regard, it is interesting that in vitro studies accept shown that some cells emerging from explanted unmarried myofibers can express markers of osteocytes or adipocytes, rather than myogenic markers (
,
). Recent studies from our group (
) and others (
) have indicated that single cells from within the satellite-cell compartment showroom mutually exclusive abilities to generate either myogenic or fibroblastic and adipogenic colonies in clonal in vitro assays. Importantly, activated immune or inflammatory cells may besides populate the satellite-cell compartment, infiltrating beneath the basal lamina of damaged muscle fibers (
), although such infiltrating hematopoietic cells display no myogenic activity (
). Finally, intrinsic differences in proliferation (
,
Rantanen et al., 1995
- Rantanen J.
- Hurme T.
- Lukka R.
- Heino J.
- Kalimo H.
Satellite jail cell proliferation and the expression of myogenin and desmin in regenerating skeletal muscle: evidence for ii different populations of satellite cells.
- PubMed
- Google Scholar
,
,
), differentiation (
Rantanen et al., 1995
- Rantanen J.
- Hurme T.
- Lukka R.
- Heino J.
- Kalimo H.
Satellite jail cell proliferation and the expression of myogenin and desmin in regenerating skeletal muscle: evidence for two different populations of satellite cells.
- PubMed
- Google Scholar
,
), and fusogenic chapters (
Rouger et al., 2004
- Rouger K.
- Brault G.
- Daval Due north.
- Leroux I.
- Guigand 50.
- Lesoeur J.
- Fernandez B.
- Cherel Y.
Muscle satellite cell heterogeneity: in vitro and in vivo evidences for populations that fuse differently.
- Crossref
- PubMed
- Scopus (43)
- Google Scholar
) amongst private satellite cells have been reported. More detailed studies employing prospective isolation and/or clonal marking to further delineate the precise lineage relationships, cellular interaction, and myogenic capacities of these distinct populations of myofiber-associated cells will greatly enhance our understanding of their normal roles and relative importance during muscle regeneration.
Adult Myogenic Cells Distinct from Satellite Cells
Contempo reports accept suggested that developed skeletal musculus progenitors distinct from satellite cells may function in some models of muscle injury and repair. For example, muscle-resident side population (muSP) cells, defined past their ability to exclude Hoechst 33342 (
), have been shown to contribute to myofibers when injected intramuscularly (
) or when cocultured with myoblasts (
), although these cells lack myogenic activity when cultured alone (
). Similarly, although they do not generate myogenic cells when cultured lone, interstitial muscle-resident CD45+Sca-1+ cells reportedly acquire myogenic activity when cocultured with primary myoblasts or in response to musculus injury or Wnt signaling (
). Finally, cells with high proliferative potential and surprisingly wide differentiation capacity, and thus termed "musculus-derived stem cells" (MDSC) or "multipotent adult progenitor cells" (MAPC), have been isolated following prolonged civilization of cells from muscle (
,
,
).
Descriptions of these singled-out subsets of myogenic cells have raised the possibility that multiple mechanisms may support adult skeletal muscle regeneration. Yet, as compared to conventional satellite cells, many of these populations, with the notable exception of cultured MDSC (
Qu-Petersen et al., 2002
- Qu-Petersen Z.
- Deasy B.
- Jankowski R.
- Ikezawa M.
- Cummins J.
- Pruchnic R.
- Mytinger J.
- Cao B.
- Gates C.
- Wernig A.
- Huard J.
Identification of a novel population of muscle stem cells in mice: potential for musculus regeneration.
- Crossref
- PubMed
- Scopus (717)
- Google Scholar
), brandish vanishingly small myogenic potential. In addition, in all cases, the contribution of these cells to the maintenance or repair of skeletal muscle under physiologic conditions is uncertain, and their therapeutic potential has not been conspicuously established. Moreover, recent information suggest that satellite cells are lonely sufficient to mediate extensive regeneration of damaged developed skeletal muscle in vivo (
). Thus, in farther assessing the intrinsic myogenic office of these populations, it volition be essential to exclude the possibility that their activity derives from "contagion" with a small subset of highly myogenic satellite cells or their progeny or from a change in developmental potential induced by cell civilisation. The use of lineage-tracing methods (
,
) and single myofiber transplantation (
) volition exist a cardinal first footstep in determining the myogenicity of these populations in relationship to conventional satellite cells.
Bone marrow cells (
,
Fukada et al., 2002
- Fukada S.
- Miyagoe-Suzuki Y.
- Tsukihara H.
- Yuasa K.
- Higuchi S.
- Ono Due south.
- Tsujikawa K.
- Takeda S.
- Yamamoto H.
Muscle regeneration by reconstitution with bone marrow or fetal liver cells from green fluorescent poly peptide-factor transgenic mice.
- PubMed
- Google Scholar
,
,
), and even single hematopoietic stem cells (
,
,
), also accept been reported to contribute to myofibers when injected direct into injured muscle or intravenously into irradiated injured or dystrophic animals. The frequency with which these unexpected contributions to skeletal muscle take been detected has varied widely and, while generally quite depression (<1% of total myofibers;
,
,
,
,
), has been reported in some cases to achieve levels of 5%–12% of differentiated cells (
,
). In this regard, it is worth noting that the method of detection of donor-derived myofibers can significantly influence the interpretation of donor contributions, and assay systems employing highly diffusible markers, such as GFP (
), cannot accurately quantify the numbers of donor myonuclei incorporated due to spread of the marking throughout the myofiber. In any example, such observations initially generated a great deal of excitement, suggesting that bone marrow could represent a reasonably accessible, novel source of regenerative cells for muscle repair; all the same, equally with other nonsatellite cell populations, the physiological significance of os marrow contributions to skeletal musculus remains uncertain (
,
Gussoni et al., 2002
- Gussoni E.
- Bennett R.R.
- Muskiewicz One thousand.R.
- Meyerrose T.
- Nolta J.A.
- Gilgoff I.
- Stein J.
- Chan Y.M.
- Lidov H.Thousand.
- Bonnemann C.G.
- et al.
Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation.
- Crossref
- PubMed
- Scopus (170)
- Google Scholar
), and accumulating prove suggests that these events may in fact represent an accidental or even pathological response elicited by severe musculus damage and inflammation (meet below).
Interestingly, while early efforts aimed at eliciting myogenic activity from bone marrow cells focused largely on the hematopoietic lineages, recent studies take suggested that nonhematopoietic elements isolated from developed os marrow or from embryonic sites of hematopoietic development might somewhen be harnessed for therapeutic skeletal muscle regeneration. For instance, cultured "mesangioblasts" (
Minasi et al., 2002
- Minasi Yard.Chiliad.
- Riminucci M.
- De Angelis Fifty.
- Borello U.
- Berarducci B.
- Innocenzi A.
- Caprioli A.
- Sirabella D.
- Baiocchi Thousand.
- De Maria R.
- et al.
The meso-angioblast: a multipotent, self-renewing cell that originates from the dorsal aorta and differentiates into nigh mesodermal tissues.
- PubMed
- Google Scholar
), a subset of claret vessel-associated cells originating from the embryonic dorsal aorta region, which have been shown to generate multiple mesodermal cell types following in vivo transplantation, tin, when injected intra-arterially into dystrophic α-sarcoglycan knockout mice, contribute to myofiber germination and significantly improve muscle function (
Sampaolesi et al., 2003
- Sampaolesi M.
- Torrente Y.
- Innocenzi A.
- Tonlorenzi R.
- D'Antona Chiliad.
- Pellegrino M.A.
- Barresi R.
- Bresolin N.
- De Angelis M.G.
- Campbell Thousand.P.
- et al.
Jail cell therapy of alpha-sarcoglycan nada dystrophic mice through intra-arterial delivery of mesoangioblasts.
- Crossref
- PubMed
- Scopus (522)
- Google Scholar
). In addition, clonal, cultured marrow-derived stromal cells, lacking expression of CD34, c-Kit, and CD45, have been shown to participate in myogenesis in vitro and in vivo, regenerating myofibers and sublaminar Pax-7+ satellite cells in immunocompromised dystrophic mice (
). Significantly, the myogenic contributions from marrow stromal cells observed in this study were much more robust than those typical of BM-derived HSC or hematopoietic progenitor cell subsets; however, it is important to annotation that the activation of a myogenic plan by these stromal cells absolutely required in vitro induction, showtime by culturing the cells with certain growth factors and then past ectopic expression of constitutively active Notch-1 (
). Thus, while this work suggests a promising therapeutic potential of marrow stromal cells, these data do non necessarily propose that coordinating populations of marrow cells unremarkably contribute to physiologic muscle regeneration.
In summary, while nether particular conditions some cells apparently distinct from satellite cells can contribute to muscle tissue, the preponderance of testify indicates that the myogenic activity normally responsible for robust developed muscle regeneration is largely restricted to sublaminar CD34+ satellite cells.
Mechanisms of Bone Marrow Contribution to Skeletal Muscle: Cell Fusion or Transdifferentiation?
In most studies in which hematopoietic or bone marrow-derived contributions to skeletal muscle accept been detected, significant musculus injury has been necessary, except in item muscles (e.g., panniculus carnosus) (
,
). The mechanisms underlying these contributions take been an surface area of intense enquiry. While initial reports appeared to favor the direct "transdifferentiation" of transplanted BM cells to generate satellite cells (
Fukada et al., 2002
- Fukada South.
- Miyagoe-Suzuki Y.
- Tsukihara H.
- Yuasa Yard.
- Higuchi S.
- Ono S.
- Tsujikawa K.
- Takeda S.
- Yamamoto H.
Muscle regeneration past reconstitution with os marrow or fetal liver cells from green fluorescent protein-factor transgenic mice.
- PubMed
- Google Scholar
,
), more than recent studies accept indicated that donor-marker-expressing myofibers arise via fusion of donor hematopoietic cells with host musculus cells (
,
,
) (Effigy 1B). While the precise prison cell types involved in these fusion events accept not been fully defined, transplantation of BM cells from transgenic mice expressing Cre in a hematopoietic lineage-restricted manner suggests that at least one of the fusion partners is probable to exist a committed claret myeloid prison cell (
,
). The stage of differentiation at which musculus-lineage cells participate in heterotypic cell fusions with infiltrating hematopoietic cells remains unknown (Figure 1B). However, when because the mechanism by which hematopoietic cells fuse with musculus cells, it is important to remember that normally muscle is repaired by fusion of myoblasts with each other, with nascent myotubes, and/or with damaged multinucleated fibers. Thus, macrophages and other inflammatory cells known to infiltrate injured muscle fibers (
) almost certainly are exposed to physiologic fusogenic signals. Significantly, macrophages themselves are known to undergo cell-jail cell fusion both physiologically, to generate osteoclasts, and pathologically, to generate multinucleated giant cells (
). Therefore, heterotypic cell fusion between endogenous muscle cells and infiltrating claret cells may occur via mechanisms that normally allow the homotypic fusion of these cells in the context of tissue maintenance and repair. At present the molecular mediators, likewise as the overall significance, of these rare events remain unclear. Future studies using coculture or transplantation models will be required to identify the secreted factors, cell-surface receptors, and signaling pathways involved in blood-prison cell/musculus-cell fusion. Knowledge of these mechanisms ultimately should allow experiments to block its occurrence and thereby test its physiologic importance.
Prospective Isolation of Muscle Precursor Cells
Nosotros recently reported a methodology that permits the prospective isolation past fluorescence-activated jail cell sorting (FACS) of highly myogenic musculus precursor cells from other prison cell populations independent within the satellite-cell compartment (
). Combinatorial assay of multiple cell-surface markers indicated that autonomously myogenic colony-forming cells (CFC) were highly enriched among the CD45−Sca-i−Mac-ane−CXCR4+β1-integrin+ (CSM4B) subset of myofiber-associated satellite cells, and that individual CSM4B cells efficiently grade myogenic colonies, which limited myosin heavy chain (MyHC) upon induction of myogenic differentiation in vitro. CSM4B cells are contained inside a population of cells (CD45−Sca-1−CD34+) that also generates myofibers in vivo upon intramuscular injection and expresses mRNA encoding the myogenic transcription factors MyoD, Myf-v, and Pax-7 (
).
The precise relationship of the CSM4B subset of myofiber-associated cells to previously described satellite cells is conspicuously of interest in synthesizing recent literature and developing a further understanding of skeletal muscle biology and regeneration. These cells coexpress CD34 and c-met, previously reported satellite-prison cell surface markers (
,
), just are not contained in c-kit+, CD13+, CD71+, Flk-i+, CD105+, CD44+, α1-integrin+, or α6-integrin+ populations of myofiber-associated cells. They besides fail to express the pan-hematopoietic marker CD45 and the surface protein Sca-1, in either resting or regenerating (2 days following cardiotoxin injection) muscle; both CD45 and Sca-1 have been reported by others (
) to identify a subset of Wnt-responsive musculus-regenerative cells singled-out from satellite cells and likely residing in the muscle interstitium. Finally, CSM4B cells are not derived from transplanted bone marrow cells and are not repopulated from the circulation at detectable levels, indicating that they probable ascend from and are maintained by a lineage of cells distinct from bone marrow-derived, hematopoietic, and fibroblastic cells also present in musculus. These information are consequent with previous studies in muscle transplantation systems indicating that muscle repair does not generally involve the recruitment of regenerative cells from a distance (
,
).
Other groups similarly have undertaken phenotypic analysis and prospective isolation of myogenic satellite-cell populations. Using Pax-3/GFP "knockin" mice, in which a GFP marker reports transcriptional activity of the Pax-3 locus, Montarras and colleagues likewise isolated a highly regenerative population of myogenic forerunner cells. Similar CSM4B cells, these Pax-3+ cells are largely CD34+, CD45−, and Sca-i− (
Montarras et al., 2005
Montarras, D., Morgan, J., Collins, C., Relaix, F., Zaffran, S., Cumano, A., Partridge, T., and Buckingham, M. (2005). Straight isolation of muscle satellite cells demonstrates their major role in skeletal muscle self renewal. Science. Published online September one, 2005. x.1126/science.1114758.
- Google Scholar
). In these studies, intramuscular delivery of only a few thousand freshly sorted CD34+CD45−Sca-1− cells yielded substantial regeneration of normal myofibers in irradiated mdx-nude recipients; notwithstanding, strikingly, prison cell culture prior to transplant dramatically reduced the efficiency of muscle engraftment (by as much every bit 10-fold).
Biochemical Pathways Regulating Musculus Regeneration
Muscle remodeling involves myogenesis, reinnervation, and revascularization and is regulated by multiple biochemical pathways, including those initiated by inflammatory cytokines, growth factors, and the evolutionarily conserved Notch, Wnt, and Sonic Hedgehog (Shh) signaling pathways (
,
,
,
,
). Muscle repair coincides with injury-induced inflammation, and some inflammatory cytokines, such as IL-4, LIF, TGF-β, IL-6, and TNF-α regulate myogenic potential (
). Damaged muscle produces monocyte and macrophage chemoattractants, and blockade of inflammatory jail cell infiltration impairs muscle regeneration (
,
,
), perhaps due to a reduction in macrophage-secreted factors inducing myoblast proliferation (
,
).
In add-on to initiating the inflammatory response, injury promotes the release of growth factors that bind to extracellular matrix (ECM) proteins, such equally proteoheparan sulfates (
). This procedure involves the activeness of matrix metalloproteinases, recently shown to play a role in musculus repair (
). The virtually studied growth factors participating in muscle maintenance and regeneration are FGFs, HGF, IGF-one, and GDF8/myostatin (
,
,
,
Miller et al., 2000
- Miller K.J.
- Thaloor D.
- Matteson S.
- Pavlath G.K.
Hepatocyte growth gene affects satellite cell activation and differentiation in regenerating skeletal musculus.
- PubMed
- Google Scholar
). FGF-ii and HGF promote proliferation of myogenic progenitors and filibuster their differentiation, in role past inhibiting the expression of myogenic regulatory factors, such as MyoD (
,
Miller et al., 2000
- Miller K.J.
- Thaloor D.
- Matteson S.
- Pavlath Grand.Grand.
Hepatocyte growth factor affects satellite cell activation and differentiation in regenerating skeletal muscle.
- PubMed
- Google Scholar
). Both growth factors require heparan sulfate proteoglycans for signaling via their receptors, and syndecan-3 and -four have been identified as the relevant cell-surface proteoglycans expressed by satellite cells (
Cornelison et al., 2001
- Cornelison D.D.
- Filla One thousand.S.
- Stanley H.Grand.
- Rapraeger A.C.
- Olwin B.B.
Syndecan-iii and syndecan-four specifically mark skeletal muscle satellite cells and are implicated in satellite prison cell maintenance and muscle regeneration.
- Crossref
- PubMed
- Scopus (285)
- Google Scholar
). IGF-1 promotes myogenic differentiation and enhances protein synthesis in differentiated myofibers past activating the translation gene 4E-BP and the ribosomal protein S6 kinase (p70S5K) and by inhibiting musculus-specific E3 ligases that promote protein degradation (reviewed in
). These mechanisms and the antiapoptotic effects of IGF-i via the suppression of caspases and activation of Akt (
,
) likely explain why IGF-1 attenuates experimentally induced muscle wasting (
). On the other finish of the proliferative spectrum, the musculus-specific TGF-β family member, GDF8, inhibits cell-cycle progression in myogenic progenitors during embryonic development and in adult muscle via induction of p21 and suppression of the cyclin-dependent kinase CDK25 (
,
,
,
).
The appropriate expansion followed by the timely differentiation of myogenic progenitor cells during muscle repair appear to be regulated past the same conserved mechanisms that orchestrate embryonic organogenesis. Namely, proliferation of satellite cells in response to muscle injury is positively regulated by the Notch pathway, while terminal myogenic differentiation of these cells requires the inhibition of Notch by its intracellular antagonist Numb (
). Notch receptor is expressed in quiescent satellite cells, and Notch betoken transduction responsible for satellite-cell activation is initiated by the upregulation of Notch ligand, Delta, on the fibers adjacent to the damaged muscle and on the satellite cells themselves (
,
). The contempo demonstration that BM-derived stromal cells become myogenic after stable expression of constitutively active Notch-1 (
) may propose that activation of the Notch pathway generally regulates specification of organ forerunner cells toward a myogenic lineage when other myogenic factors, such as FGF-2, are nowadays.
In improver to Notch, Shh mRNA and protein, as well equally the Patched receptor, become upregulated in regenerating skeletal muscle (
Pola et al., 2003
- Pola R.
- Ling L.E.
- Aprahamian T.R.
- Barban E.
- Bosch-Marce Yard.
- Curry C.
- Corbley One thousand.
- Kearney Grand.
- Isner J.Grand.
- Losordo D.W.
Postnatal recapitulation of embryonic hedgehog pathway in response to skeletal muscle ischemia.
- Crossref
- PubMed
- Scopus (166)
- Google Scholar
). Moreover, ectopic Shh appears to ameliorate experimentally induced musculus cloudburst (
Alzghoul et al., 2004
- Alzghoul Grand.B.
- Gerrard D.
- Watkins B.A.
- Hannon K.
Ectopic expression of IGF-I and Shh past skeletal musculus inhibits decay-mediated skeletal musculus atrophy and bone osteopenia in vivo.
- PubMed
- Google Scholar
), thus demonstrating that yet another classic regulator of embryonic development likely as well participates in adult myogenesis. Additionally, Wnt signaling has been reported to be important for the presence of CD45+ cells in regenerating adult musculus, although the physiologic myogenic potential of these cells remains unclear (
,
). Futurity experiments that decipher how muscle regulates its own inflammatory response and clarify the temporal and spatial crosstalk between Notch, Shh, and Wnt pathways volition exist instrumental for providing a better agreement of how cell fate is adamant during musculus repair.
Satellite-Cell Action in Diseased Muscle
In sure pathological states, including congenital myopathies, denervation, and muscle atrophy, satellite-prison cell numbers and proliferative potential may decrease (
). In muscular dystrophy (MD), repeated cycles of musculus regeneration, brought on by repeated loss of differentiated tissue, may pb to an early loss of the proliferative potential of satellite cells in these patients, and a subsequent failure to maintain musculus homeostasis (
). Although the underlying mechanism for this loss of satellite-cell responsiveness in diseased musculus has not been fully elucidated, these findings indicate that under detail circumstances satellite cells may be functionally exhausted. Satellite-jail cell burnout may relate, at to the lowest degree in part, to shortening of telomere ends after repeated rounds of Dna replication (
,
Di Donna et al., 2003
- Di Donna S.
- Mamchaoui K.
- Cooper R.N.
- Seigneurin-Venin S.
- Tremblay J.
- Butler-Browne G.S.
- Mouly V.
Telomerase can extend the proliferative capacity of human myoblasts, but does non lead to their immortalization.
- PubMed
- Google Scholar
), to recurrent exposure to inflammatory conditions and/or oxidative stress (
), to an aggregating of mutations in central satellite-cell regulatory genes, introduced during repeated rounds of proliferation, or to a combination of these and other factors. Nonmyogenic cells in the muscle may as well contribute to failed muscle regeneration, as fibroblasts in dystrophic patients have been shown to secrete increased levels of IGF-1 binding proteins, which could sequester this cytokine away from myogenic cells (
Melone et al., 2000
- Melone M.A.
- Peluso G.
- Galderisi U.
- Petillo O.
- Cotrufo R.
Increased expression of IGF-binding protein-5 in Duchenne muscular dystrophy (DMD) fibroblasts correlates with the fibroblast-induced downregulation of DMD myoblast growth: An in vitro analysis.
- Crossref
- PubMed
- Scopus (29)
- Google Scholar
). A better understanding of the dynamic coaction among distinct populations of cells resident in the muscle and recruited by musculus damage will aid in developing a full picture of the complex cellular networks responsible for myogenesis in healthy and diseased muscle and for designing therapeutic strategies to promote muscle repair.
Age-Related Changes in the Molecular Regulation of Satellite Cell Activeness
One characteristic of crumbling is a turn down in the ability of organ stalk cells to repair damaged tissues. Developed skeletal muscle is a perfect case of a tissue that robustly regenerates throughout adult life but fails to exercise so in one-time age (
). The reason for this reject in regenerative potential is non completely understood and may involve both intrinsic molecular changes in the stem cells themselves and/or alterations in their aged environs.
Every bit mentioned above, muscle repair relies on Notch action, which is necessary and sufficient for the activation of satellite cells (
,
,
). Chiefly, Notch receptor continues to be expressed in anile satellite cells, while injury-specific induction of the Notch ligand Delta, and therefore subsequent signal transduction, fail with age, resulting in grossly inefficient regeneration of old muscle tissue (
). Strikingly, productive tissue repair tin can be restored to old muscle by enforced activation of Notch, while the repair of immature musculus is severely perturbed when Notch signaling is inhibited (
). Therefore, information technology seems that Notch is the key age-related determinant of musculus regenerative potential.
Is the age-related decline in satellite cell regenerative potential intrinsic or dependent on the cell environment? In early muscle transplantation studies, small minced or intact muscle from young or old rodents was transplanted into either young or old muscle beds, and the ability of donor muscle pieces to regenerate in the center of either immature or old host limbs was examined. Amazingly, the efficiency of musculus regeneration was clearly determined in these experiments by the historic period of the host surroundings, rather than by the age of the muscle donor (
,
). In these important studies, the pocket-sized transplanted muscle was physically isolated from the host satellite cells, revealing the effects of prevalent local and organismal environments on the regenerative potential of the donor satellite cells.
In more recent studies, the age of the systemic environment likewise dominated over the intrinsic age-related regenerative properties of satellite cells when the efficiency of muscle repair was examined in immature and old mice with a shared blood circulation (
). Significantly, regeneration-specific Delta-Notch signaling, appropriate activation of satellite cells, and general success in muscle repair were all rejuvenated by the exposure of aged tissue to a young systemic milieu (
). In concert with the above-mentioned pivotal part of satellite cells as muscle stem cells, the anile satellite cells endogenous to the old muscle successfully engaged in tissue repair without any recruitment of immature cells from the shared apportionment (
). These data strongly suggest that the molecular pathways responsible for muscle repair are regulated past systemic factors and that these factors alter with age in ways precluding the activation of satellite cells.
Multiple lines of show advise that many cell-intrinsic changes occur with tissue aging, including the aggregating of oxidative impairment, a reject in genome maintenance, and macerated mitochondrial role (
,
,
). The rejuvenation of anile stem and progenitor cells past the young extrinsic milieu, fifty-fifty in the presence of these age-related changes, suggests the intriguing possibility that the crumbling of organ stalk cells might be regulated extrinsically and that the molecular changes underlying the loss of the tissue-regenerative potential with age tin can be reversed or overcome if the stem cell niche is young. Future identification of the relevant extrinsic age-related components will exist instrumental for therapies aimed at enhancing the regenerative potential of organ stem cells in aged individuals.
Future Avenues and Perspectives
It is quite clear that endogenous skeletal muscle satellite cells associated with myofibers account for nearly, if non all, physiologic muscle-regenerative potential and likely represent musculus stem cells. Contempo advances have immune a more than refined determination of their origin, position in the myogenic cell lineage, and molecular pathways regulating their function. Other avenues of musculus repair, e.g., by bone marrow-derived cells, may be; however, unambiguous determination of the precise cell types and specific fusion and reprogramming mechanisms involved in this procedure will be needed in order to establish whether such cells form muscle tissue under physiologic conditions or tin can be used therapeutically. Electric current advances in our understanding of the cellular and molecular mechanisms regulating cell-fate determination and tissue specification during adult muscle repair accept indicated a remarkable conservation of developmentally regulated point transduction pathways, and age-related analysis of these pathways indicates that at to the lowest degree some of them deteriorate in old muscle, causing ineffective tissue repair. The identification of historic period-related systemic factors that regulate the regenerative capacity of organ stalk cells will improve our understanding of aging equally a conserved biological process and will aid to develop therapies for the enhancement of the regenerative potential often lost in sometime age or disease.
Acknowledgments
We give thanks T. Partridge and D. Montarras for communication of unpublished data and for helpful discussions. This work was supported in office past a Burroughs Wellcome Fund Career Award and a Harvard Stalk Cell Establish Seed Funding Grant to A.J.W. and NIA KO-ane AG25652 to I.G.C.
References
-
Robust conversion of marrow cells to skeletal musculus with germination of marrow-derived muscle cell colonies: a multifactorial process.
Exp. Hematol. 2004; 32 : 426-434 -
Ectopic expression of IGF-I and Shh by skeletal muscle inhibits decay-mediated skeletal musculus cloudburst and bone osteopenia in vivo.
FASEB J. 2004; xviii : 221-223 -
Delaying the mitochondrial decay of crumbling.
Ann. Due north Y Acad. Sci. 2004; 1019 : 406-411 -
Origin of satellite cells in avian skeletal muscles.
Arch. Anat. Microsc. Morphol. Exp. 1983; 72 : 163-181 -
Notch signaling: cell fate command and bespeak integration in development.
Science. 1999; 284 : 770-776 -
Muscle satellite cells are multipotential stalk cells that exhibit myogenic, osteogenic, and adipogenic differentiation.
Differentiation. 2001; 68 : 245-253 -
Myogenic specification of side population cells in skeletal muscle.
J. Cell Biol. 2002; 159 : 123-134 -
Dynamics of myoblast transplantation reveal a discrete minority of precursors with stem cell-like properties as the myogenic source.
J. Cell Biol. 1999; 144 : 1113-1122 -
Expression of CD34 and Myf5 defines the majority of quiescent developed skeletal muscle satellite cells.
J. Cell Biol. 2000; 151 : 1221-1234 -
Radioautographic study of skeletal muscle regeneration.
Am. J. Anat. 1960; 106 : 233 -
Genes that command the development of migrating muscle precursor cells.
Curr. Opin. Cell Biol. 2000; 12 : 725-730 -
Regeneration of single skeletal muscle fibers in vitro.
Anat. Rec. 1975; 182 : 215-235 -
Patterns of repair of dystrophic mouse musculus: studies on isolated fibers.
Dev. Dyn. 1999; 216 : 244-256 -
The COX-2 pathway is essential during early stages of skeletal muscle regeneration.
Am. J. Physiol. Cell Physiol. 2004; 287 : C475-C483 -
Pax3 functions in cell survival and in pax7 regulation.
Development. 1999; 126 : 1665-1674 -
Unmarried hematopoietic stem cells generate skeletal muscle through myeloid intermediates.
Nat. Med. 2003; 9 : 1520-1527 -
Muscle stalk cells differentiate into haematopoietic lineages merely retain myogenic potential.
Nat. Cell Biol. 2003; v : 640-646 -
An analysis of nuclear numbers in individual muscle fibers during differentiation and growth: a satellite prison cell-musculus fiber growth unit.
J. Exp. Zool. 1975; 191 : 347-358 -
Muscle transplantation betwixt young and old rats: historic period of host determines recovery.
Am. J. Physiol. 1989; 256 : C1262-C1266 -
Matrix metalloproteinases and skeletal muscle: a cursory review.
Muscle Nerve. 2004; 29 : 191-197 -
Satellite cells attract monocytes and use macrophages as a back up to escape apoptosis and enhance muscle growth.
J. Cell Biol. 2003; 163 : 1133-1143 -
Stem prison cell function, cocky-renewal, and behavioral heterogeneity of cells from the adult muscle satellite cell niche.
Jail cell. 2005; 122 : 1-thirteen -
Athletes with practise-associated fatigue have abnormally short muscle DNA telomeres.
Med. Sci. Sports Exerc. 2003; 35 : 1524-1528 -
The regulation of Notch signaling controls satellite cell activation and jail cell fate decision in postnatal myogenesis.
Dev. Cell. 2002; 3 : 397-409 -
Notch-mediated restoration of regenerative potential to aged muscle.
Scientific discipline. 2003; 302 : 1575-1577 -
Rejuvenation of aged progenitor cells by exposure to a young systemic environment.
Nature. 2005; 433 : 760-764 -
Contribution of hematopoietic stem cells to skeletal muscle.
Nat. Med. 2003; 9 : 1528-1532 -
Syndecan-3 and syndecan-4 specifically mark skeletal musculus satellite cells and are implicated in satellite jail cell maintenance and muscle regeneration.
Dev. Biol. 2001; 239 : 79-94 -
Single-jail cell analysis of regulatory gene expression in quiescent and activated mouse skeletal muscle satellite cells.
Dev. Biol. 1997; 191 : 270-283 -
Activation of different myogenic pathways: myf-5 is induced by the neural tube and MyoD past the dorsal ectoderm in mouse paraxial mesoderm.
Development. 1996; 122 : 429-437 -
How is myogenesis initiated in the embryo?.
Trends Genet. 1996; 12 : 218-223 -
Oxygen-mediated regulation of skeletal muscle satellite jail cell proliferation and adipogenesis in culture.
J. Cell. Physiol. 2001; 189 : 189-196 -
Os marrow stromal cells generate muscle cells and repair musculus degeneration.
Science. 2005; 309 : 314-317 -
Telomerase tin can extend the proliferative capacity of human myoblasts, but does non lead to their immortalization.
Mol. Cancer Res. 2003; one : 643-653 -
PI three-kinase, Akt and prison cell survival.
Semin. Prison cell Dev. Biol. 2004; 15 : 177-182 -
Hematopoietic contribution to skeletal muscle regeneration past myelomonocytic precursors.
Proc. Natl. Acad. Sci. Usa. 2004; 101 : 13507-13512 -
Muscle regeneration past os marrow-derived myogenic progenitors.
Science. 1998; 279 : 1528-1530 -
Failure to correct murine muscular dystrophy.
Nature. 2001; 411 : 1014-1015 -
Muscle regeneration past reconstitution with bone marrow or fetal liver cells from dark-green fluorescent protein-gene transgenic mice.
J. Prison cell Sci. 2002; 115 : 1285-1293 -
Oxidative stress and aging: beyond correlation.
Aging Cell. 2002; 1 : 117-123 -
Regulation of Pax-3 expression in the dermomyotome and its role in musculus development.
Evolution. 1994; 120 : 957-971 -
A common somitic origin for embryonic musculus progenitors and satellite cells.
Nature. 2005; 435 : 954-958 -
Age-associated changes in the response of skeletal muscle cells to do and regeneration.
Ann. N Y Acad. Sci. 1998; 854 : 78-91 -
Dystrophin expression in the mdx mouse restored by stem prison cell transplantation.
Nature. 1999; 401 : 390-394 -
Long-term persistence of donor nuclei in a Duchenne muscular dystrophy patient receiving bone marrow transplantation.
J. Clin. Invest. 2002; 110 : 807-814 -
Aging and genome maintenance: lessons from the mouse?.
Science. 2003; 299 : 1355-1359 -
Transplanted primary neonatal myoblasts can give rise to functional satellite cells as identified using the Myf5nlacZl+ mouse.
Cistron Ther. 2001; 8 : 778-783 -
Insulin-similar growth factor I: the yin and yang of musculus cloudburst.
Endocrinology. 2004; 145 : 4803-4805 -
Growth factors in skeletal musculus regeneration.
Cytokine Growth Factor Rev. 1996; vii : 249-258 -
Satellite cell depletion in degenerative skeletal muscle.
Apoptosis. 2003; 8 : 573-578 -
Pluripotency of mesenchymal stalk cells derived from adult marrow.
Nature. 2002; 418 : 41-49 -
Migration of developed myogenic precursor cells equally revealed past GFP/nLacZ labelling of mouse transplantation chimeras.
J. Cell Sci. 2003; 116 : 1611-1616 -
Biological science of hematopoietic stalk cells and progenitors: implications for clinical application.
Annu. Rev. Immunol. 2003; 21 : 759-806 -
Clonal analysis of myogenesis.
Science. 1963; 140 : 1273-1284 -
Biological progression from adult bone marrow to mononucleate muscle stem cell to multinucleate muscle fiber in response to injury.
Cell. 2002; 111 : 589-601 -
Coordinate control of muscle cell survival by distinct insulin-like growth factor activated signaling pathways.
J. Cell Biol. 2000; 151 : 1131-1140 -
Regulation of muscle mass past myostatin.
Annu. Rev. Cell Dev. Biol. 2004; twenty : 61-86 -
An experimental study of regeneration of mammalian striped muscle.
J. Anat. 1946; 80 : 24-36 -
Blood borne macrophages are essential for the triggering of muscle regeneration following muscle transplant.
Neuromuscul. Disord. 1999; 9 : 72-80 -
Developmental fate of skeletal muscle satellite cells.
Science. 1979; 205 : 1292-1294 -
Dumb regeneration of dystrophin-scarce muscle fibers is caused by exhaustion of myogenic cells.
Braz. J. Med. Biol. Res. 2002; 35 : 691-695 -
Intrinsic differences in MyoD and myogenin expression between primary cultures of SJL/J and BALB/C skeletal musculus.
Exp. Prison cell Res. 1994; 211 : 99-107 -
Ectopic Pax-3 activates MyoD and Myf-five expression in embryonic mesoderm and neural tissue.
Cell. 1997; 89 : 139-148 -
Satellite cells of muscle skeletal fibers.
J. Biophys. Biochem. 1961; nine : 493-495 -
Myostatin negatively regulates satellite cell activation and self-renewal.
J. Jail cell Biol. 2003; 162 : 1135-1147 -
Muscle-derived hematopoietic stalk cells are hematopoietic in origin.
Proc. Natl. Acad. Sci. U.s.. 2002; 99 : 1341-1346 -
Regulation of skeletal musculus mass in mice past a new TGF-beta superfamily member.
Nature. 1997; 387 : 83-90 -
Increased expression of IGF-binding protein-5 in Duchenne muscular dystrophy (DMD) fibroblasts correlates with the fibroblast-induced downregulation of DMD myoblast growth: An in vitro analysis.
J. Cell. Physiol. 2000; 185 : 143-153 -
Hepatocyte growth factor affects satellite cell activation and differentiation in regenerating skeletal muscle.
Am. J. Physiol. Cell Physiol. 2000; 278 : C174-C181 -
The meso-angioblast: a multipotent, self-renewing jail cell that originates from the dorsal aorta and differentiates into virtually mesodermal tissues.
Development. 2002; 129 : 2773-2783 -
Montarras, D., Morgan, J., Collins, C., Relaix, F., Zaffran, Southward., Cumano, A., Partridge, T., and Buckingham, K. (2005). Direct isolation of muscle satellite cells demonstrates their major role in skeletal muscle self renewal. Science. Published online September one, 2005. 10.1126/science.1114758.
-
Muscle satellite cells.
Int. J. Biochem. Cell Biol. 2003; 35 : 1151-1156 -
Nature of dividing nuclei in skeletal muscle of growing rats.
J. Cell Biol. 1970; 44 : 459-462 -
Pax-7 up-regulation inhibits myogenesis and cell wheel progression in satellite cells: a potential machinery for cocky-renewal.
Dev. Biol. 2004; 275 : 375-388 -
Postnatal recapitulation of embryonic hedgehog pathway in response to skeletal muscle ischemia.
Circulation. 2003; 108 : 479-485 -
Wnt signaling induces the myogenic specification of resident CD45+ developed stem cells during muscle regeneration.
Cell. 2003; 113 : 841-852 -
Identification of a novel population of musculus stem cells in mice: potential for muscle regeneration.
J. Cell Biol. 2002; 157 : 851-864 -
Satellite cell proliferation and the expression of myogenin and desmin in regenerating skeletal muscle: evidence for ii different populations of satellite cells.
Lab. Invest. 1995; 72 : 341-347 -
A Pax3/Pax7-dependent population of skeletal muscle progenitor cells.
Nature. 2005; 435 : 948-953 -
Human skeletal musculus satellite cells: aging, oxidative stress and the mitotic clock.
Exp. Gerontol. 2002; 37 : 1229-1236 -
The office of macrophages in skeletal musculus regeneration with particular reference to chemotaxis.
Exp. Cell Res. 1993; 207 : 321-331 -
Musculus satellite cell heterogeneity: in vitro and in vivo evidences for populations that fuse differently.
Cell Tissue Res. 2004; 317 : 319-326 -
Cell therapy of alpha-sarcoglycan cipher dystrophic mice through intra-arterial delivery of mesoangioblasts.
Science. 2003; 301 : 487-492 -
Insulin-similar growth factor I slows the rate of denervation induced skeletal muscle cloudburst.
Neuromuscul. Disord. 2005; 15 : 139-146 -
Satellite cells are mitotically quiescent in mature mouse musculus: an EM and radioautographic study.
J. Exp. Zool. 1978; 206 : 451-456 -
Pax7 is required for the specification of myogenic satellite cells.
Jail cell. 2000; 102 : 777-786 -
Muscle satellite prison cell-specific genes identified by genetic profiling of MyoD-deficient myogenic jail cell.
Dev. Biol. 2004; 275 : 287-300 -
Skeletal muscle satellite cells tin spontaneously enter an alternative mesenchymal pathway.
J. Cell Sci. 2004; 117 : 5393-5404 -
Isolation of adult mouse myogenic progenitors; functional heterogeneity of cells inside and engrafting skeletal muscle.
Cell. 2004; 119 : 543-554 -
Determinants of skeletal muscle contribution from circulating cells, bone marrow cells, and hematopoietic stem cells.
Stalk Cells. 2004; 22 : 1292-1304 -
Skeletal muscle: regeneration and transplantation studies.
Br. Med. Bull. 1980; 36 : 153-158 -
An autoradiographic report of satellite cell differentiation into regenerating myotubes following transplantation of muscles in young rats.
Cell Tissue Res. 1978; 186 : 535-540 -
Characterization of muscles injured by forced lengthening. I. Cellular infiltrates.
Med. Sci. Sports Exerc. 1988; 20 : 345-353 -
Myostatin, a negative regulator of muscle growth, functions past inhibiting myoblast proliferation.
J. Biol. Chem. 2000; 275 : 40235-40243 -
Inflammatory processes in muscle injury and repair.
Am. J. Physiol. Regul. Integr. Comp. Physiol. 2005; 288 : R345-R353 -
Osteoclasts and giant cells: macrophage-macrophage fusion mechanism.
Int. J. Exp. Pathol. 2000; 81 : 291-304 -
Uber dice regeneration des quergestrieften muskelgewebes beim menschen und saugetier.
Bieitr. Path. Anat. 1893; 12 : 233-332 -
The response of the normal, the denervated and the dystrophic muscle-prison cell to injury.
J. Pathol. Bacterol. 1956; 72 : 273-298 -
Nonmuscle stem cells neglect to significantly contribute to regeneration of normal musculus.
Gene Ther. 2004; 11 : 1724-1728 -
Ueber die regeneration quergestreifter muskelfasern.
Zentrabl. Med. Wis. 1863; 1 : 529-531 -
Isolation and clonal analysis of satellite cells from craven pectoralis muscle.
Dev. Biol. 1987; 119 : 252-259 -
Cellular aspects of muscle differentiation in vitro.
Curr. Peak. Dev. Biol. 1969; 4 : 37-77 -
Age-related impeded regeneration of mouse minced anterior tibial muscle.
Muscle Nerve. 1982; 5 : 152-161 -
Muscle satellite cells adopt divergent fates: a mechanism for self-renewal?.
J. Cell Biol. 2004; 166 : 347-357 -
Induction of cachexia in mice past systemically administered myostatin.
Science. 2002; 296 : 1486-1488
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