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PubMed1992

Formation of highly organized skeletal muscle fibers in vitro. Comparison with muscle development in vivo.

Two methods were developed in which long-term cultures of quail skeletal muscle were established so that all of the muscle fibers develop in a highly oriented manner. The muscle fibers became spontaneously and vigorously contractile and established strong connections with the extracellular matrix at their ends that closely duplicate the structure of the myotendinous junction. A continuous basal lamina was formed around each muscle fiber that contained type IV collagen, laminin and heparan sulfate proteoglycan. With one of the methods, an extensive extracellular matrix developed around each muscle fiber that was highly organized with the formation of a distinctive epimysium, perimysium and endomysium. Analysis of the cultures by both methods for different isoforms of myosin showed expression of an adult form of myosin by some of the muscle cells. The results therefore demonstrate that muscle development in the present culture systems proceeds extensively for several weeks. It will now be possible to investigate directly the structure of the connections between muscle fibers and the extracellular matrix.

Animals↗
PubMed1996

Pax3 modulates expression of the c-Met receptor during limb muscle development.

Pax3 is a transcription factor whose expression has been used as a marker of myogenic precursor cells arising in the lateral somite destined to migrate to and populate the limb musculature. Accruing evidence indicates that the embryologic origins of axial and appendicular muscles are distinct, and limb muscle abnormalities in both mice and humans harboring Pax3 mutations support this distinction. The mechanisms by which Pax3 affects limb muscle development are unknown. The tyrosine kinase receptor for hepatocyte growth factor/scatter factor encoded by the c-met protooncogene is also expressed in limb muscle progenitors and, like Pax-3, is required in the mouse for limb muscle development. Here, we show that c-met expression is markedly reduced in the lateral dermomyotome of Splotch embryos lacking Pax3. We show that Pax3 can stimulate c-met expression in cultured cells, and we identify a potential Pax3 binding site in the human c-MET promoter that may contribute to direct transcriptional regulation. In addition, we have found that several cell lines derived from patients with rhabdomyosarcomas caused by a t(2;13) chromosomal translocation activating PAX3 express c-MET, whereas those rhabdomyosarcoma cell lines examined without the translocation do not. These results are consistent with a model in which Pax3 modulates c-met expression in the lateral dermomyotome, a function that is required for the appropriate migration of these myogenic precursors to the limb where the ligand for c-met (hepatocyte growth factor/scatter factor) is expressed at high levels.

Animals↗
PubMed1994

Temporal differences in the induction of dihydropyridine receptor subunits and ryanodine receptors during skeletal muscle development.

The expression of the dihydropyridine (DHP) and ryanodine receptors in skeletal muscle was investigated during development of rat myotubes in culture as well as during embryonic and postnatal development in the rat. Through the use of specific gene probes, antibodies and radioligand binding ([3H]PN 200-110 (DHP) and [3H]ryanodine), we identified a significant difference between the time course of appearance of the DHP receptor and the ryanodine receptor during muscle development. Although the number of DHP receptors dramatically increased at early stages of development (up to day 7 in tissue culture and day 20 postnatal), increase in the ryanodine receptor density occurred comparatively later at day 10 in culture and day 30 postnatal. This process was associated with parallel changes in the expression of the mRNA encoding the alpha 1, alpha 2, and beta subunits of the DHP receptor and the skeletal muscle ryanodine receptor. The genes encoding the DHP receptor subunits were activated in a temporally distinct transcript appeared and plateaued first, at the onset of myoblast fusion and day 16 embryonic. This was followed closely by an increase in expression of the mRNAs for alpha 1 and alpha 2 subunits which coincided with the sharp rise in the DHP receptor density. Ryanodine receptor gene expression was induced well after the DHP receptor gene expression had plateaued. The temporal appearance of the polypeptides comprising the DHP receptor subunits and the ryanodine receptor paralleled the induction of the genes encoding these receptors. These results imply that gene expression is a major mechanism that contributes to the regulation of DHP and ryanodine receptor numbers during muscle development. The temporal differences in the induction of the genes encoding the DHP receptor subunits and the ryanodine receptor suggests that these genes are under the control of distinct endogenous factors. These differences in expression of the DHP receptor and the ryanodine receptor may contribute to the different mechanisms of excitation-contraction coupling in immature versus adult skeletal muscle.

Animals↗
PubMed2003

Peroxisome proliferator-activated receptor delta controls muscle development and oxidative capability.

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors exerting several functions in development and metabolism. The physiological functions of PPARdelta remain elusive. By using a CRE-Lox recombination approach, we generated an animal model for muscle-specific PPARdelta overexpression to investigate the role of PPARdelta in this tissue. Muscle-specific PPARdelta overexpression results in a profound change in fiber composition due to hyperplasia and/or shift to more oxidative fiber and, as a consequence, leads to the increase of both enzymatic activities and genes implicated in oxidative metabolism. These changes in muscle are accompanied by a reduction of body fat mass, mainly due to a large reduction of adipose cell size. Furthermore, we demonstrate that endurance exercise promotes an accumulation of PPARdelta protein in muscle of wild-type animals. Collectively, these results suggest that PPARdelta plays an important role in muscle development and adaptive response to environmental changes, such as training exercise. They strongly support the idea that activation of PPARdelta could be beneficial in prevention of metabolic disorders, such as obesity or type 2 diabetes.

Adipose Tissue↗
PubMed2001

Control of muscle development by dueling HATs and HDACs.

Skeletal muscle cells have provided an especially auspicious system in which to dissect the roles of chromatin structure in the control of cell growth, differentiation, and development. The MyoD and MEF2 families of transcription factors act cooperatively to regulate the expression of skeletal muscle-specific genes. Recent studies have shown that these two classes of transcription factors associate with histone acetyltransferases and histone deacetylases to control the activation and repression, respectively, of the muscle differentiation program. Signaling systems that regulate the growth and differentiation of muscle cells act, at least in part, by regulating the intracellular localization and associations of these chromatin remodeling enzymes with myogenic transcription factors. We describe the molecules and mechanisms involved in chromatin remodeling during skeletal muscle development.

Acetyltransferases↗
PubMed2000

Evidence for differential post-translational modifications of slow myosin heavy chain during murine skeletal muscle development.

The contractile properties of muscle fibres are, in part, determined by the myosin heavy chain (MyHC) isoforms they express. Using monoclonal antibodies, we show that at least three forms of slow twitch MyHC accumulate sequentially during mouse fetal development and that slow MyHC maturation in slow fibres occurs before expression of the adult fast MyHCs in fast fibres. Expression of deletion derivatives of beta-cardiac MyHC cDNA shows that the slow MyHC epitopes that are detected in adult but not in young animals are located near the N-terminus. The same N-terminal region of various fast MyHC molecules contains a conserved epitope that can, on occasions, be observed when slow MyHC cDNA is expressed in non-muscle cells. The results raise the possibility that the N-terminal epitopes result from post-translational modification of the MyHC and that a sequence of slow and fast MyHC isoform post-translational modifications plays a significant role during development of murine muscle fibres.

Animals↗
PubMed1997

Presence of laminin alpha5 chain and lack of laminin alpha1 chain during human muscle development and in muscular dystrophies.

There is currently a great interest in identifying laminin isoforms expressed in developing and regenerating skeletal muscle. Laminin alpha1 has been reported to localize to human fetal muscle and to be induced in muscular dystrophies based on immunohistochemistry with the monoclonal antibody 4C7, suggested to recognize the human laminin alpha1 chain. Nevertheless, there seems to be no expression of laminin alpha1 protein or mRNA in developing or dystrophic mouse skeletal muscle fibers. To address the discrepancy between the results obtained in developing and dystrophic human and mouse muscle we expressed the E3 domain of human laminin alpha1 chain as a recombinant protein and made antibodies specific for human laminin alpha1 chain (anti-hLN-alpha1G4/G5). We also made antibodies to the human laminin alpha5 chain purified from placenta. In the present report we show that hLN-alpha1G4/G5 antibodies react with a 400-kDa laminin alpha1 chain and that 4C7 reacts with a 380-kDa laminin alpha5 chain. Immunohistochemistry with the hLN-alpha1G4/G5 antibody and 4C7 revealed that the two antibodies stained human kidney, developing and dystrophic muscle in distinct patterns. Our data indicate that the previously reported expression patterns in developing, adult, and dystrophic human muscle tissues with 4C7 should be re-interpreted as an expression of laminin alpha5 chain. Our data are also consistent with earlier work in mouse, indicating that laminin alpha1 is largely an epithelial laminin chain not present in developing or dystrophic muscle fibers.

Adult↗
PubMed1991

Insulin-like growth factors and their receptors in muscle development.

Several proteins involved in IGF action are expressed in C2 cells and their abundance was found to vary as a function of development. IGF-I and II mRNA levels rose 10 and 25-fold, respectively, during differentiation, and were accompanied by an increase in growth factor secretion. The accumulation of IGF-II in conditioned culture medium was much greater than that of IGF-I. There was also an increase in the number of IGF-I receptors and IGF-II/CIMPR on the cell surface during differentiation. The sustained rise in IGF-II/CIMPR expression appeared to be a consequence of a similar increase in its mRNA abundance. The mechanisms responsible for the transient increment in IGF-I receptor number were not assessed, although it is likely that the decline in IGF-I receptor content after 72 hours in differentiation medium was a consequence of down-regulation by the IGF-II that accumulated in the medium (35). In contrast to the 13-fold rise in IGF-II/CIMPR mRNA levels, transcript levels for the CDMPR remained constant during C2 cell development, enzymatic activities of two lysosomal enzymes did not change, and only a small increment was detected at a single time point in the expression of several lysosomal enzyme mRNAs. In addition, during C2 muscle differentiation, a novel IGF binding protein was induced. These results demonstrate modulation of several components of IGF signaling pathways in differentiating myoblasts, and argue for a local role for IGFs in muscle development.

Animals↗
PubMed2006

Regulation of troponin T expression during muscle development in sea bream Sparus auratus Linnaeus: the potential role of thyroid hormones.

In the sea bream Sparus auratus three stage-specific fast troponin T (fTnT) isoforms have been cloned and correspond to embryonic-, larval- and adult-specific isoforms. Characterisation, using database searches, of the putative genomic organisation of Fugu rubripes and Tetraodon nigroviridis fTnT indicates that alternative exon splicing in the 5 region of the gene generates the different isoforms. Moreover, comparison of teleost fTnTs suggests that alternative splicing of fTnT appears to be common in teleosts. A different temporal expression pattern for each fTnT splice varotnt is found during sea bream development and probably relates to differing functional demands, as a highly acidic embryonic form (pI 5.16) is substituted by a basic larval form (pI 9.57). Thyroid hormones (THs), which play an important regulatory role in muscle development in flatfish and tetrapods, appear also to influence TnT gene expression in the sea bream. However, THs have a divergent action on different sea bream TnT genes and although the slow isoform (sTnT1) is TH-responsive, fTnT, sTnT2 and the itronless isoform (iTnT) are unaffected. The present results taken together with those published for flatfish seem to suggest differences may exist in the regulation of larval muscle development in teleosts.

Aging↗
PubMed1998

Tissue-specific effects of hypothyroidism on postnatal muscle development in the barnacle goose.

The hypothesis that tissue-specific levels of thyroid hormones may be required for normal locomotor muscle development was investigated in the barnacle goose Branta leucopsis. Hypothyroidism was induced in goslings by treatment with methimazole from either 3 days or 2 weeks of age, and birds were killed at 7 weeks of age. The masses of the pectoralis, iliofibularis, semimembranosus and cardiac ventricle muscles were measured, and samples from these tissues were analysed for the mass-specific activity of the mitochondrial enzyme citrate synthase (CS). An ultrastructural electron micrograph analysis of the pectoralis was also carried out. No significant differences were found between the two hypothyroid groups except for the effect on the relative mass of the iliofibularis muscle. Developmental responses to hypothyroidism were found to be tissue-specific. Hypothyroidism resulted in a significantly lower relative cardiac ventricle mass (by 17 %) and CS activity of the leg muscles (by 34 %), while absolute leg muscle mass was not affected. The relative mass of the pectoralis was significantly lower (by 57 %) in hypothyroid birds and showed a significant, uniformly lower CS activity (by 60-83 %) as a result of a lower mitochondrial fractional volume. Haematocrit and capillary-to-fibre ratio in the pectoralis were also significantly lower in hypothyroid birds, and skeletal growth and plumage development were affected.

Animals↗
PubMed1998

MyoD and MEF2A mediate activation and repression of the p75NGFR gene during muscle development.

In an effort to clarify transient expression of the NGF low-affinity receptor p75NGFR during muscle development we have focused on the molecular mechanisms involved in the initiation and cessation of p75NGFR gene expression. Using quiescent C3H10T1/2 fibroblast as a tool, we observed that induction of differentiation competence in MyoD-transfected 10T1/2 fibroblasts was accompanied by the initiation of p75NGFR expression. Moreover, we could show that the bHLH transcription factor MyoD itself is a powerful candidate for transcriptional activation of the p75NGFR gene in muscle precursor cells. By means of MyoD-mutants we have found that both the amino terminus of the MyoD molecule as well as the bHLH-region are essential for transcriptional activity on the p75NGFR promoter. The fact that myocyte enhancer factor MEF2A inactivated MyoD-induced p75NGFR promoter activity strongly suggests that cell-specific regulation of the p75NGFR gene might be strictly dependent on the intracellular composition and balance of the appropriate bHLH-transcription factors and their modulators.

Cell Differentiation↗
PubMed2004

Divergent functions of murine Pax3 and Pax7 in limb muscle development.

Pax genes encode evolutionarily conserved transcription factors that play critical roles in development. Pax3 and Pax7 constitute one of the four Pax subfamilies. Despite partially overlapping expression domains, mouse mutations for Pax3 and Pax7 have very different consequences. To investigate the mechanism of these contrasting phenotypes, we replaced Pax3 by Pax7 by using gene targeting in the mouse. Pax7 can substitute for Pax3 function in dorsal neural tube, neural crest cell, and somite development, but not in the formation of muscles involving long-range migration of muscle progenitor cells. In limbs in which Pax3 is replaced by Pax7, the severity of the muscle phenotype increases as the number of Pax7 replacement alleles is reduced, with the forelimb more affected than the hindlimb. We show that this hypomorphic activity of Pax7 is due to defects in delamination, migration, and proliferation of muscle precursor cells with inefficient activation of c-met in the hypaxial domain of the somite. Despite this, overall muscle patterning is retained. We conclude that functions already prefigured by the single Pax3/7 gene present before vertebrate radiation are fulfilled by Pax7 as well as Pax3, whereas the role of Pax3 in appendicular muscle formation has diverged, reflecting the more recent origin of this mode of myogenesis.

Animals↗
PubMed2004

Positive autoregulation of the Myocyte enhancer factor-2 myogenic control gene during somatic muscle development in Drosophila.

The myocyte enhancer factor-2 (MEF2) transcription factor plays a central role in the activation and maintenance of muscle gene expression in fruit flies and vertebrates. The mechanism of action and downstream target genes of MEF2 have been defined in considerable detail, but relatively little is known about the mechanisms that regulate MEF2 expression during muscle development. Here we demonstrate that MEF2 maintains its own expression in all differentiated muscle cell types during late embryonic and larval development in Drosophila by binding a conserved MEF2 site in a muscle-specific regulatory enhancer. Ectopic expression of Mef2 is sufficient to directly activate this enhancer in some, but not all, non-muscle cells. Furthermore, activation of the Mef2 enhancer normally in muscle cells and ectopically in non-muscle cells is dependent upon the integrity of the MEF2 binding site. These findings suggest an evolutionarily conserved mechanism whereby MEF2 can stabilize the muscle phenotype by sustaining its own expression through a myogenic autoregulatory loop.

Animals↗
PubMed2006

MIR-206 regulates connexin43 expression during skeletal muscle development.

Skeletal myoblast fusion in vitro requires the expression of connexin43 (Cx43) gap junction channels. However, gap junctions are rapidly downregulated after the initiation of myoblast fusion in vitro and in vivo. In this study we show that this downregulation is accomplished by two related microRNAs, miR-206 and miR-1, that inhibit the expression of Cx43 protein during myoblast differentiation without altering Cx43 mRNA levels. Cx43 mRNA contains two binding sites for miR-206/miR-1 in its 3'-untranslated region, both of which are required for efficient downregulation. While it has been demonstrated before that miR-1 is involved in myogenesis, in this work we show that miR-206 is also upregulated during perinatal skeletal muscle development in mice in vivo and that both miR-1 and miR-206 downregulate Cx43 expression during myoblast fusion in vitro. Proper development of singly innervated muscle fibers requires muscle contraction and NMJ terminal selection and it is hypothesized that prolonged electrical coupling via gap junctions may be detrimental to this process. This work details the mechanism by which initial downregulation of Cx43 occurs during myogenesis and highlights the tight control mechanisms that are utilized for the regulation of gap junctions during differentiation and development.

3' Untranslated Regions↗
PubMed1987

Developing muscle spindles in the mouse masseter muscle studied by electron microscopy.

The morphogenesis of the muscle spindles of the masseter muscle was investigated by electron microscopy. The mice used in this study were those from the 16-day-old fetuses to the four-day-old young, and the three-month-old adult ICR mice. At the time of observation the formation of the masseter muscle spindle had already started in the 16-day-old fetus. In the 17-day-old fetus, the sensory nerve terminated not only in the myotube but also in the myoblast in which no myofilaments were yet formed. From the observations on the 16-day-old and 17-day-old fetuses, it is suggested that the myotubes of the intrafusal muscle fibers are formed by the fusion of the myocytes already containing the myofilaments. The gamma motor end-plate appeared two days later than the sensory nerve terminal formation in the muscle spindle. The initial inner capsule of the spindle was observed in the four-day-old young. The cell without the myofilaments appeared amidst the cluster of the intrafusal muscle fibers in the three-day-old young. It is considered that this cell may be the origin of the inner capsule cell. The periaxial space formation and the myelination of the masseteric nerve fiber occurred in the four-day-old young. The formation of the postsynaptic folds was observed in the extrafusal muscle fiber at the same stage. Thus, the muscle spindles, nerve fibers and the extrafusal muscle fibers showed a remarkable development at the same time in this early postnatal stage.

Animals↗
PubMed1988

Quantitative relationships between motoneuron and muscle development in Xenopus laevis: implications for motoneuron cell death and motor unit formation.

A common approach to the study of neural regression has been to correlate the timing of cell loss with other events such as target development. Most of these studies have areas of uncertainty. First, the analysis is normally carried out on groups of neurons that innervate a variety of targets. Second, there are some doubts about the reliability of light microscopic quantitation of muscle development. In this study, the period of cell death in the semimembranosus motor pool of Xenopus laevis has been estimated and correlated with an electron microscopic study of the development of the semimembranosus. The period of cell death of semimembranosus motoneurons was estimated on the basis of their position in the spinal cord and from the number of myelinated axons in the semimembranosus motor nerve. The semimembranosus motor pool contained approximately 70 motoneurons and was located 17-37% along the rostrocaudal axis of the lumbar cord. Cell loss from this motor pool occurred between stages 53-54 and 56, whereas cell death in the entire lumbar cord extended beyond stage 58. Primary myogenesis occurred between stages 53 and 54 in the semimembranosus. There was then a hiatus in myotube production until secondary myogenesis began around stage 56. It is concluded that secondary myotubes are not involved in regulating motoneuron cell death and that the number of primary myotube clusters is similar in magnitude to the number of motoneurons that will ultimately survive the period of cell death. The implications of these observations for theories of cell death and motor unit formation are discussed.

Aging↗