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Eric N Olson - One of the best experts on this subject based on the ideXlab platform.
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defining the regulatory networks for muscle development
Current Opinion in Genetics & Development, 1996Co-Authors: Jeffery D Molkentin, Eric N OlsonAbstract:The formation of skeletal muscle during vertebrate embryogenesis requires commitment of mesodermal precursor cells to the skeletal muscle lineage, withdrawal of myoblasts from the cell cycle, and transcriptional activation of dozens of muscle structural genes. The myogenic basic helix-loop-helix (bHLH) factors - MyoD, Myogenin, Myf5, and MRF4 - act at multiple points in the myogenic lineage to establish myoblast identity and to control terminal differentiation. Recent studies have begun to define the inductive mechanisms that regulate myogenic bHLH gene expression and muscle cell determination in the embryo. Myogenic bHLH factors interact with components of the cell cycle machinery to control withdrawal from the cell cycle and act combinatorially with other transcription factors to induce skeletal muscle transcription. Elucidation of these aspects of the myogenic program is leading to a detailed understanding of the regulatory circuits controlling muscle development.
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cooperative activation of muscle gene expression by mef2 and myogenic bhlh proteins
Cell, 1995Co-Authors: Jeffery D Molkentin, Brian L Black, James F Martin, Eric N OlsonAbstract:Members of the myocyte enhancer factor-2 (MEF2) family of MADS domain transcription factors cannot induce myogenesis in transfected fibroblasts, but when coexpressed with the myogenic basic-helix-loop-helix (bHLH) proteins MyoD or Myogenin they dramatically increase the extent of myogenic conversion above that seen with either myogenic bHLH factor alone. This cooperativity required direct interactions between the DNA-binding domains of MEF2 and the myogenic bHLH factors, but only one of the factors needed a transactivation domain, and only one of the factors needed to be bound to DNA. These interactions allow either factor to activate transcription through the other's binding site and reveal a novel mechanism for indirect activation of gene expression via protein-protein interactions between the DNA-binding domains of heterologous classes of transcription factors.
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fgf inactivates myogenic helix loop helix proteins through phosphorylation of a conserved protein kinase c site in their dna binding domains
Cell, 1992Co-Authors: Jumin Zhou, Guy James, Robin A Hellerharrison, Michael P Czech, Eric N OlsonAbstract:Myogenin belongs to a family of myogenic helix-loop-helix (HLH) proteins that activate muscle transcription through binding to a conserved DNA sequence associated with numerous muscle-specific genes. Fibroblast growth factor (FGF) inhibits myogenesis by inactivating myogenic HLH proteins. We show that activated protein kinase C (PKC) can substitute for FGF and inhibit transcriptional activity of myogenic HLH proteins. In transfected cells, FGF induces phosphorylation of a conserved site in the DNA-binding domain of Myogenin. This site is phosphorylated by PKC in vivo and in vitro and mediates repression of the myogenic program through a loss in DNA binding activity. A Myogenin mutant lacking the PKC phosphorylation site is not repressed by FGF, confirming this site as a molecular target for FGF-dependent repression of muscle transcription. These results establish a direct link between the signal transduction pathways that inhibit myogenesis and the transcription factors directly activating muscle-specific genes.
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mhox a mesodermally restricted homeodomain protein that binds an essential site in the muscle creatine kinase enhancer
Development, 1992Co-Authors: Peter Cserjesi, Brenda Lilly, Laura Bryson, Yaoqi Wang, David Sassoon, Eric N OlsonAbstract:Myogenic helix-loop-helix (HLH) proteins, such as Myogenin and MyoD, can activate muscle-specific transcription when introduced into a variety of nonmuscle cell types. Whereas cells of mesodermal origin are especially permissive to the actions of these myogenic regulators, many other cell types are refractory to myogenic conversion by them. Here we describe a novel homeodomain protein, MHox, that binds an A+T-rich element in the muscle creatine kinase (MCK) enhancer that is essential for muscle-specific transcription and trans-activation by myogenic HLH proteins. MHox is completely restricted to mesodermally derived cell types during embryogenesis and to established cell lines of mesodermal origin. In contrast to most other homeobox genes, MHox expression is excluded from the nervous system, with the highest levels observed in limb bud and visceral arches. In adult mice, MHox is expressed at high levels in skeletal muscle, heart and uterus. The DNA-binding properties and pattern of MHox expression are unique among homeobox genes and suggest a role for MHox as a transcriptional regulator that participates in the establishment of diverse mesodermal cell types.
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repression of Myogenin function by tgf β1 is targeted at the basic helix loop helix motif and is independent of e2a products
Journal of Biological Chemistry, 1992Co-Authors: James F Martin, Eric N Olson, L LiAbstract:Abstract The muscle-specific helix-loop-helix (HLH) proteins Myogenin, MyoD, myf5, and MRF4 form hetero-oligomers with ubiquitous HLH proteins encoded by the E2A gene and activate muscle transcription by binding to a DNA sequence known as an E-box (CANNTG). Transforming growth factor-beta (TGF-beta) can inhibit muscle differentiation by silencing the transcription-activating potential of myogenic HLH proteins without affecting their ability to bind DNA. We show that repression by TGF-beta is directed at the basic-HLH motif of Myogenin and is independent of E2A products. Using a series of reporter genes as targets for trans-activation by Myogenin, transcriptional repression by TGF-beta is also shown to map to the E-box motif and to not require heterologous DNA sequence elements. These results demonstrate that TGF-beta represses muscle-specific transcription through a post-translational mechanism that renders the basic-HLH regions of the myogenic regulators nonfunctional. The selective repression of myogenic HLH proteins by TGF-beta indicates that the TGF-beta signaling system can discriminate between different classes of HLH proteins and implies that myogenic HLH proteins activate muscle-specific transcription through a unique mechanism.
Stephen J Tapscott - One of the best experts on this subject based on the ideXlab platform.
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myod and the transcriptional control of myogenesis
Seminars in Cell & Developmental Biology, 2005Co-Authors: Charlotte A Berkes, Stephen J TapscottAbstract:The basic helix-loop-helix myogenic regulatory factors MyoD, Myf5, Myogenin and MRF4 have critical roles in skeletal muscle development. Together with the Mef2 proteins and E proteins, these transcription factors are responsible for coordinating muscle-specific gene expression in the developing embryo. This review highlights recent studies regarding the molecular mechanisms by which the muscle-specific myogenic bHLH proteins interact with other regulatory factors to coordinate gene expression in a controlled and ordered manner.
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molecular distinction between specification and differentiation in the myogenic basic helix loop helix transcription factor family
Molecular and Cellular Biology, 2001Co-Authors: Donald A. Bergstrom, Stephen J TapscottAbstract:Myogenesis is regulated by a family of four transcription factors (Myf5, MyoD, Myogenin, and MRF4) that share a common dimerization and DNA binding domain (DBD), the basic helix-loop-helix (bHLH) motif. Genetic studies have demonstrated that MyoD and Myf5 act to establish the skeletal muscle lineage in mice, since disruption of both of these genes resulted in complete absence of skeletal muscle cells (16). In contrast, Myogenin is required for the normal differentiation of the myoblasts established by the prior expression of Myf5 or MyoD (6, 12). In this regard, MyoD and Myf5 can be considered determination or specification factors and Myogenin can be considered a differentiation factor. MRF4 has been difficult to study because of its proximity to Myf5, but null mutations of MRF4 result in increased expression of Myogenin with relatively normal muscle cell differentiation (13, 25). The difference between the specification of the muscle lineage by MyoD and Myf5 and the terminal differentiation mediated by Myogenin might be due to differences in protein sequence or the temporal pattern of gene expression, or both. During embryogenesis, expression of either Myf5 or MyoD is the earliest marker of myoblast specification in the dorsal or ventral dermomyotome, respectively, and precedes expression of Myogenin in any given cell (7). Similarly, during the regeneration of adult skeletal muscle, the activated satellite cells initially express Myf5 and MyoD and subsequently express Myogenin and MRF4 (19, 24). It is possible that the requirement for MyoD or Myf5 in specifying the muscle lineage reflects gene regulatory sequences that appropriately initiate expression, whereas the proteins encoded by each of the myogenic bHLH genes might have similar functions. Indeed, there is considerable evidence that each of the myogenic bHLH proteins have largely redundant functions. For example, each can initiate myogenesis when artificially expressed in nonmuscle cells, such as fibroblasts (1, 2, 11, 23). Experiments in the developing mouse embryo, however, have shown that Myogenin cannot efficiently promote myogenesis when substituted for Myf5 (21). This result suggested that the myogenic specification factors MyoD and Myf5 encode protein functions distinct from the differentiation protein Myogenin. Since one critical aspect of lineage specification is the initiation of tissue-restricted gene expression, we hypothesized that the lineage specification factors may possess a greater intrinsic ability to initiate the expression of silent genes than differentiation factors. Indeed, our previous work demonstrated that MyoD and Myf5 were more efficient than Myogenin at initiating expression of endogenous muscle genes (5). In the present study, we extend this initial observation to identify the molecular attributes of MyoD and Myogenin that confer the function of specification factor and differentiation factor, respectively. We discovered that a cysteine-rich region amino terminal to the bHLH domain and previously shown necessary for MyoD-mediated chromatin remodeling was functionally conserved in Myogenin and was not sufficient to account for their different activities. The major difference between the activities of MyoD and Myogenin was encoded in a carboxy-terminal amphipathic alpha-helix conserved during the evolution of the myogenic bHLH proteins. This alpha-helix appears to have evolved distinct functions in MyoD and Myogenin, functioning as a specification domain in MyoD, i.e., a domain critical for the efficient initiation of skeletal muscle gene expression, and as a general transcription activation domain in Myogenin.
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A conserved motif N-terminal to the DNA-binding domains of myogenic bHLH transcription factors mediates cooperative DNA binding with Pbx-Meis1/Prep1
Nucleic Acids Research, 1999Co-Authors: Paul S. Knoepfler, Donald A. Bergstrom, Taichi Uetsuki, L. A. Korytko, Woodring E. Wright, Stephen J Tapscott, Mark P KampsAbstract:The t(1;19) chromosomal translocation of pediatric pre-B cell leukemia produces chimeric oncoprotein E2a-Pbx1, which contains the N-terminal transactivation domain of the basic helix-loop-helix (bHLH) transcription factor, E2a, joined to the majority of the homeodomain protein, Pbx1. There are three Pbx family members, which bind DNA as heterodimers with both broadly expressed Meis/Prep1 homeo-domain proteins and specifically expressed Hox homeodomain proteins. These Pbx heterodimers can augment the function of transcriptional activators bound to adjacent elements. In heterodimers, a conserved tryptophan motif in Hox proteins binds a pocket on the surface of the Pbx homeodomain, while Meis/Prep1 proteins bind an N-terminal Pbx domain, raising the possibility that the tryptophan-interaction pocket of the Pbx component of a Pbx-Meis/Prep1 complex is still available to bind trypto-phan motifs of other transcription factors bound to flanking elements. Here, we report that Pbx-Meis1/Prep1 binds DNA cooperatively with heterodimers of E2a and MyoD, Myogenin, Mrf-4 or Myf-5. As with Hox proteins, a highly conserved tryptophan motif N-terminal to the DNA-binding domains of each myogenic bHLH family protein is required for cooperative DNA binding with Pbx-Meis1/Prep1. In vivo, MyoD requires this tryptophan motif to evoke chromatin remodeling in the Myogenin promoter and to activate Myogenin transcription. Pbx-Meis/Prep1 complexes, therefore, have the potential to cooperate with the myogenic bHLH proteins in regulating gene transcription.
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selective accumulation of myod and Myogenin mrnas in fast and slow adult skeletal muscle is controlled by innervation and hormones
Development, 1993Co-Authors: Simon M Hughes, Stephen J Tapscott, Jane M Taylor, Cathy M Gurley, William J Carter, Charlotte A PetersonAbstract:Each of the myogenic helix-loop-helix transcription factors (MyoD, Myogenin, Myf-5, and MRF4) is capable of activating muscle-specific gene expression, yet distinct functions have not been ascribed to the individual proteins. We report here that MyoD and Myogenin mRNAs selectively accumulate in hindlimb muscles of the adult rat that differ in contractile properties: MyoD is prevalent in fast twitch and Myogenin in slow twitch muscles. The distribution of MyoD and Myogenin transcripts also differ within a single muscle and correlate with the proportions of fast glycolytic and slow oxidative muscle fibres, respectively. Furthermore, the expression of a transgene consisting of a muscle-specific cis-regulatory region from the myoD gene controlling lacZ was primarily associated with the fast glycolytic fibres. Alteration of the fast/slow fibre type distribution by thyroid hormone treatment or by cross-reinnervation resulted in a corresponding alteration in the MyoD/Myogenin mRNA expression pattern. These findings show that the expression of specific myogenic helix-loop-helix regulators is under the control of innervation and humoral factors and may mediate differential control of contractile protein gene expression in adult muscle.
S G Velleman - One of the best experts on this subject based on the ideXlab platform.
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effect of the timing of posthatch feed restrictions on broiler breast muscle development and muscle transcriptional regulatory factor gene expression
Poultry Science, 2014Co-Authors: S G Velleman, D A EmmersonAbstract:Abstract The effect of the timing of an immediate posthatch feed restriction on broiler pectoralis major muscle development was studied by applying a 20% feed restriction either the first or second week after hatch. Pectoralis major muscle morphological structure and the expression of the myogenic transcriptional regulatory factors, myogenic determination factor 1 (MyoD), myogenic regulatory factor 4 (MRF4), and Myogenin, were measured. Broiler chicks at hatch were divided into a full-fed (control) group and a 20% feed restriction treatment administered either the first or second week posthatch. At the end of the feed restriction, the chicks were placed on a full feed ad libitum diet with no further restrictions. Muscle fiber diameter and fiber bundle size of the pectoralis major muscle were smaller in the wk 1 restricted group than the control group by 7 d of age. By 15 d of age through the duration of the study, d 43, both endomysial and perimysial connective tissue spacing were diminished in the wk 1 feed-restricted group. The expression of MyoD, MRF4, and Myogenin was affected by the wk 1 feed restriction. The expression of MyoD and MRF4 was significantly increased during the first week posthatch. Both of the genes have been shown to be expressed during proliferation especially MyoD, which is required for muscle cell proliferation. In contrast, Myogenin expression was significantly decreased. Myogenin expression is required for differentiation to occur. The morphological changes and gene expression changes observed with the wk 1 feed restriction were eliminated by moving the 20% feed restriction to wk 2, which is after the period of maximal myogenic satellite cell mitotic activity. Taken together, these results demonstrate that the timing of early posthatch feed restrictions to chicks is critical for the morphological development of the pectoralis major muscle and the expression of genes required for muscle satellite cell proliferation and differentiation.
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the effect of nutritional status and myogenic satellite cell age on turkey satellite cell proliferation differentiation and expression of myogenic transcriptional regulatory factors and heparan sulfate proteoglycans syndecan 4 and glypican 1
Poultry Science, 2014Co-Authors: Laura B Harthan, Douglas C Mcfarland, S G VellemanAbstract:ABSTRACT Posthatch satellite cell mitotic activity is a critical component of muscle development and growth. Satellite cells are myogenic stem cells that can be induced by nutrition to follow other cellular developmental pathways, and whose mitotic activity declines with age. The objective of the current study was to determine the effect of restricting protein synthesis on the proliferation and differentiation, expression of myogenic transcriptional regulatory factors myogenic determination factor 1, Myogenin, and myogenic regulatory factor 4, and expression of the heparan sulfate proteoglycans syndecan-4 and glypican-1 in satellite cells isolated from 1-d-, 7-wk-, and 16-wk-old turkey pectoralis major muscle (1 d, 7 wk, and 16 wk cells, respectively) by using variable concentrations of Met and Cys. Four Met concentrations—30 (control), 7.5, 3, or 0 mg/L with 3.2 mg/L of Cys per 1 mg/L of Met—were used for culture of satellite cells to determine the effect of nutrition and age on satellite cell behavior during proliferation and differentiation. Proliferation was reduced by lower Met and Cys concentrations in all ages at 96 h of proliferation. Differentiation was increased in the 1 d Met-restricted cells, whereas the 7 wk cells treated with 3 mg/L of Met had decreased differentiation. Reduced Met and Cys levels from the control did not significantly affect the 16 wk cells at 72 h of differentiation. However, medium with no Met or Cys suppressed differentiation at all ages. The expression of myogenic determination factor 1, Myogenin, myogenic regulatory factor 4, syndecan-4, and glypican-1 was differentially affected by age and Met or Cys treatment. These data demonstrate the age-specific manner in which turkey pectoralis major muscle satellite cells respond to nutritional availability and the importance of defining optimal nutrition to maximize satellite cell proliferation and differentiation for subsequent muscle mass accretion.
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changes in proliferation differentiation fibroblast growth factor 2 responsiveness and expression of syndecan 4 and glypican 1 with turkey satellite cell age
Development Growth & Differentiation, 2013Co-Authors: Laura B Harthan, Douglas C Mcfarland, S G VellemanAbstract:Myogenic satellite cells are heterogeneous multipotential stem cells that are required for muscle repair, maintenance, and growth. The membrane-associated heparan sulfate proteoglycans syndecan-4 and glypican-1 differentially regulate satellite cell proliferation, differentiation, fibroblast growth factor 2 (FGF2) signal transduction, and expression of the myogenic regulatory factors MyoD and Myogenin. The objective of the current study was to determine the effect of age on syndecan-4 and glypican-1 satellite cell populations, proliferation, differentiation, FGF2 responsiveness, and expression of syndecan-4, glypican-1, MyoD, and Myogenin using satellite cells isolated from the pectoralis major muscle of 1-day-old, 7-week-old and 16-week-old turkeys. Proliferation was significantly reduced in the 16-week-old satellite cells, while differentiation was decreased in the 7-week-old and the 16-week-old cells beginning at 48 h of differentiation. Fibroblast growth factor 2 responsiveness was highest in the 1-day-old and 7-week-old cells during proliferation; during differentiation there was an age-dependent response to FGF2. Syndecan-4 and glypican-1 satellite cell populations decreased with age, but syndecan-4 and glypican-1 were differentially expressed with age during proliferation and differentiation. MyoD and Myogenin mRNA expression was significantly decreased in 16-week-old cells compared to the 1-day-old and 7-week-old cells. MyoD and Myogenin protein expression was higher during proliferation in the 16-week-old cells and decreased with differentiation. These data demonstrate an age-dependent effect on syndecan-4 and glypican-1 satellite cell subpopulations, which may be associated with age-related changes in proliferation, differentiation, FGF2 responsiveness, and the expression of the myogenic regulatory factors MyoD and Myogenin.
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heparan sulfate proteoglycans syndecan 4 and glypican 1 differentially regulate myogenic regulatory transcription factors and paired box 7 expression during turkey satellite cell myogenesis implications for muscle growth
Poultry Science, 2012Co-Authors: Jonghyun Shin, Douglas C Mcfarland, S G VellemanAbstract:ABSTRACT The heparan sulfate proteoglycans have been shown to play essential roles in the proliferation and differentiation of myogenic satellite cells. Myogenic regulatory factors (MRF) and paired box 7 (Pax7) are essential transcription factors for satellite cell myogenesis. The objective of the current study was to investigate whether the expression of the MRF and Pax7 is, in part, regulated by the heparan sulfate proteoglycans, syndecan-4, and glypican-1, whose expression has been shown to differentially affect satellite cell proliferation and differentiation. To test this objective, small interfering RNA was used to knockdown the gene expression of glypican-1 and syndecan-4. The effect on the expression of MRF and Pax7 was measured at the mRNA level by real-time quantitative PCR. The knockdown of the glypican-1 gene decreased mRNA expression of MyoD, Myogenin, MRF4, and Pax7 expression during proliferation and differentiation of turkey satellite cells; whereas knockdown of the syndecan-4 gene increased mRNA expression of MyoD and MRF4 expression during cell proliferation but not during differentiation and had no effect on Myogenin and Pax7 expression. These data suggested that the precise expression of the MRF are dependent upon the appropriate expression of glypican-1 and syndecan-4 during satellite cell proliferation and differentiation, and Pax7 expression is influenced by glypican-1.
Michael A. Rudnicki - One of the best experts on this subject based on the ideXlab platform.
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The myogenic regulatory factors, determinants of muscle development, cell identity and regeneration.
Seminars in cell & developmental biology, 2017Co-Authors: J. Manuel Hernández-hernández, Estela G. García-gonzález, Caroline E. Brun, Michael A. RudnickiAbstract:The Myogenic Regulatory Factors (MRFs) Myf5, MyoD, Myogenin and MRF4 are members of the basic helix-loop-helix family of transcription factors that control the determination and differentiation of skeletal muscle cells during embryogenesis and postnatal myogenesis. The dynamics of their temporal and spatial expression as well as their biochemical properties have allowed the identification of a precise and hierarchical relationship between the four MRFs. This relationship establishes the myogenic lineage as well as the maintenance of the terminal myogenic phenotype. The application of genome-wide technologies has provided important new information as to how the MRFs function to activate muscle gene expression. Application of combined functional genomics technologies along with single cell lineage tracing strategies will allow a deeper understanding of the mechanisms mediating myogenic determination, cell differentiation and muscle regeneration.
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myod synergizes with the e protein hebβ to induce myogenic differentiation
Molecular and Cellular Biology, 2006Co-Authors: Maura H Parker, Charlotte A Berkes, Robert L S Perry, Melanie C Fauteux, Michael A. RudnickiAbstract:The MyoD family of basic helix-loop-helix transcription factors function as heterodimers with members of the E-protein family to induce myogenic gene activation. The E-protein HEB is alternatively spliced to generate alpha and beta isoforms. While the function of these molecules has been studied in other cell types, questions persist regarding the molecular functions of HEB proteins in skeletal muscle. Our data demonstrate that HEB alpha expression remains unchanged in both myoblasts and myotubes, whereas HEB beta is upregulated during the early phases of terminal differentiation. Upon induction of differentiation, a MyoD-HEB beta complex bound the E1 E-box of the Myogenin promoter leading to transcriptional activation. Importantly, forced expression of HEB beta with MyoD synergistically lead to precocious Myogenin expression in proliferating myoblasts. However, after differentiation, HEB alpha and HEB beta synergized with Myogenin, but not MyoD, to activate the Myogenin promoter. Specific knockdown of HEB beta by small interfering RNA in myoblasts blocked differentiation and inhibited induction of Myogenin transcription. Therefore, HEB alpha and HEB beta play novel and central roles in orchestrating the regulation of myogenic factor activity through myogenic differentiation.
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the transition from proliferation to differentiation is delayed in satellite cells from mice lacking myod
Developmental Biology, 1999Co-Authors: Zipora Yablonkareuveni, Michael A. Rudnicki, Anthony J Rivera, Michael Primig, Judy E Anderson, Priscilla NatansonAbstract:Satellite cells from adult rat muscle coexpress proliferating cell nuclear antigen and MyoD upon entry into the cell cycle, suggesting that MyoD plays a role during the recruitment of satellite cells. Moreover, the finding that muscle regeneration is compromised in MyoD−/− mice, has provided evidence for the role of MyoD during myogenesis in adult muscle. In order to gain further insight into the role of MyoD during myogenesis in the adult, we compared satellite cells from MyoD−/− and wildtype mice as they progress through myogenesis in single-myofiber cultures and in tissue-dissociated cell cultures (primary cultures). Satellite cells undergoing proliferation and differentiation were traced immunohistochemically using antibodies against various regulatory proteins. In addition, an antibody against the mitogen-activated protein kinases ERK1 and ERK2 was used to localize the cytoplasm of the fiber-associated satellite cells regardless of their ability to express specific myogenic regulatory factor proteins. We show that during the initial days in culture the myofibers isolated from both the MyoD−/− and the wildtype mice contain the same number of proliferating, ERK+ satellite cells. However, the MyoD−/− satellite cells continue to proliferate and only a very small number of cells transit into the Myogenin+ state, whereas the wildtype cells exit the proliferative compartment and enter the Myogenin+ stage. Analyzing tissue-dissociated cultures of MyoD−/− satellite cells, we identified numerous cells whose nuclei were positive for the Myf5 protein. In contrast, quantification of Myf5+ cells in the wildtype cultures was difficult due to the low level of Myf5 protein present. The Myf5+ cells in the MyoD−/− cultures were often positive for desmin, similar to the MyoD+ cells in the wildtype cultures. Myogenin+ cells were identified in the MyoD−/− primary cultures, but their appearance was delayed compared to the wildtype cells. These “delayed” Myogenin+ cells can express other differentiation markers such as MEF2A and cyclin D3 and fuse into myotubes. Taken together, our studies suggest that the presence of MyoD is critical for the normal progression of satellite cells into the Myogenin+, differentiative state. It is further proposed that the Myf5+/MyoD− phenotype may represent the myogenic stem cell compartment which is capable of maintaining the myogenic precursor pool in the adult muscle.
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the myod family of transcription factors and skeletal myogenesis
BioEssays, 1995Co-Authors: Michael A. Rudnicki, Rudolf JaenischAbstract:Gene targeting has allowed the dissection of complex biological processes at the genetic level. Our understanding of the nuances of skeletal muscle development has been greatly increased by the analysis of mice carrying targeted null mutations in the Myf-5, MyoD and Myogenin genes, encoding members of the myogenic regulatory factor (MRF) family. These experiments have elucidated the hierarchical relationships existing between the MRFs, and established that functional redundancy is a feature of the MRF regulatory network. Either MyoD or Myf-5 is sufficient for the formation or survival of skeletal myoblasts. Myogenin acts later in development and plays an essential in vivo role in the terminal differentiation of myotubes.
Erik A Richter - One of the best experts on this subject based on the ideXlab platform.
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oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in humans
The Journal of Physiology, 2001Co-Authors: Peter Hespel, Valery Labarque, Steven Dymarkowski, Bert O. Eijnde, Birgitte Ursø, Paul L Greenhaff, Marc Van Leemputte, Paul Van Hecke, Erik A RichterAbstract:Muscle disuse due to physical inactivity, ageing and many disease conditions results in muscle atrophy and reduced muscle functional capacity, which may impair activities of daily living. Strategies that may prevent or reverse these effects are of considerable functional significance to the individual. Recent evidence suggests that oral creatine supplementation is an effective intervention to prevent or reverse neuromuscular degeneration in humans. Since Harris and his co-workers (1992) reported that high-dose oral creatine supplementation can significantly increase muscle total creatine content, the potential of creatine supplementation to boost muscular performance has been widely acknowledged. It has become well established in healthy subjects that oral creatine supplementation can improve muscle power output during high-intensity exercise (Balsom et al. 1993; Greenhaff et al. 1993; Vandenberghe et al. 1996; American College of Sports Medicine, 2000) and enhance the increments of muscle mass and muscle strength that result from heavy resistance training (Vandenberghe et al. 1997; Kreider et al. 1998). These findings, which were obtained in experiments involving athletes and healthy subjects, have also prompted interest in the potential of oral creatine supplementation to treat muscular pathologies. In this respect, creatine supplementation was recently found to enhance muscle functional capacity in patients with various forms of neuromuscular diseases or muscular dystrophies (Tarnopolsky & Martin, 1999; Walter et al. 2000) as well as in McArdle's disease (Vorgerd et al. 2000). Conversely, creatine supplementation was found to be ineffective in improving functional capacity in patients afflicted by chronic progressive external ophthalmoplegia or mitochondrial myopathy (Klopstock et al. 2000). Still, the precise physiological mechanism underlying the described beneficial effects of creatine supplementation on skeletal musculature remains largely unexplained. There is evidence from experiments in rats that the expression of the myogenic transcription factors MyoD, Myogenin, Myf5 and MRF4 is involved in determining structural and metabolic phenotype in adult skeletal muscle cells (Eftimie et al. 1991; Voytik et al. 1993; Megeney & Rudnicki, 1995; Hughes et al. 1999), in particular during episodes of muscle catabolism or anabolism (Hughes et al. 1993; Loughna & Brownson, 1996; Marsh et al. 1997; Mozdziak et al. 1998; Adams et al. 1999). Thus, disuse atrophy was found to cause fibre-specific alterations in mRNA expression of the various myogenic factors (Loughna & Brownson, 1996). Compensatory hypertrophy in overloaded plantaris muscle led to markedly increased expression of Myogenin, whereas the expression of MyoD was only slightly and transiently increased (Adams et al. 1999). The regeneration of muscle fibres after bupivacaine injection led to a rapid and marked increase in mRNA expression of Myogenin and MyoD, whereas the expression of MRF4 first decreased and then increased at the time when expression of Myogenin and MyoD decreased (Marsh et al. 1997). Furthermore, long-term administration of the anabolic compound clenbuterol and/or thyroid hormone decreased the expression of Myogenin (Loughna & Brownson, 1996; Mozdziak et al. 1998). However, the protein expression of myogenic factors has yet to be determined in human skeletal muscle; nor has the effect of altered activity level on this expression been studied. It is thus well established that oral creatine supplementation can stimulate muscle hypertrophy. In addition, the expression of myogenic transcription factors has been implicated in the regulation of muscle fibre adaptations during hypertrophy. Therefore, in the present study we investigated the effects of oral creatine supplementation on both the functional and structural adaptations of skeletal muscle and the expression of myogenic transcription factors during leg-immobilization-induced disuse atrophy and subsequent exercise rehabilitation. The data presented in this paper demonstrate for the first time that oral creatine supplementation is an effective therapeutic strategy with which to enhance rehabilitation from muscle disuse atrophy. This effect may be mediated by a creatine-induced change in myogenic transcription factor expression.
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Oral creatine supplementation facilitates the rehabilitation of disuse atrophy and alters the expression of muscle myogenic factors in human
Journal of Physiology, 2001Co-Authors: Peter Hespel, Marc Van Leemputte, Valery Labarque, Steven Dymarkowski, Bert O. Eijnde, Birgitte Ursø, P Van Hecke, Paul L Greenhaff, Erik A RichterAbstract:1. We investigated the effect of oral creatine supplementation during leg immobilization and rehabilitation on muscle volume and function, and on myogenic transcription factor expression in human subjects. 2. A double-blind trial was performed in young healthy volunteers (n = 22). A cast was used to immobilize the right leg for 2 weeks. Thereafter the subjects participated in a knee-extension rehabilitation programme (3 sessions x week(-1), 10 weeks). Half of the subjects received creatine monohydrate (CR; from 20 g down to 5 g daily), whilst the others ingested placebo (P; maltodextrin). 3. Before and after immobilization, and after 3 and 10 weeks of rehabilitation training, the cross-sectional area (CSA) of the quadriceps muscle was assessed by NMR imaging. In addition, an isokinetic dynamometer was used to measure maximal knee-extension power (Wmax), and needle biopsy samples taken from the vastus lateralis muscle were examined to asses expression of the myogenic transcription factors MyoD, Myogenin, Myf5, and MRF4, and muscle fibre diameters. 4. Immobilization decreased quadriceps muscle CSA (approximately 10 %) and Wmax (approximately 25 %) by the same magnitude in both groups. During rehabilitation, CSA and Wmax recovered at a faster rate in CR than in P (P < 0.05 for both parameters). Immobilization changed myogenic factor protein expression in neither P nor CR. However, after rehabilitation Myogenin protein expression was increased in P but not in CR (P < 0.05), whilst MRF4 protein expression was increased in CR but not in P (P < 0.05). In addition, the change in MRF4 expression was correlated with the change in mean muscle fibre diameter (r = 0.73, P < 0.05). 5. It is concluded that oral creatine supplementation stimulates muscle hypertrophy during rehabilitative strength training. This effect may be mediated by a creatine-induced change in MRF4 and Myogenin expression.
