Inhibition of muscle cell development in culture by cells from spinal cord due to production of low molecular weight factor.
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Progressive predominance of 'skeletal' versus 'cardiac' types of excitation-contraction coupling during in vitro skeletal myogenesis.
Simultaneous recordings, in the presence or absence of cadmium, of current and contraction of skeletal muscle cells in primary culture (myoballs) showed that the relative part of contraction depending on calcium current progressively decreases with the age of cells whereas the cadmium-insensitive component becomes predominant. The coexistence of "cardiac" and "skeletal" excitation-contraction coupling mechanisms in developing muscle and its developmental regulation are consistent with recent molecular data showing the expression, in newborn animals, of an abbreviated isoform of the alpha 1 subunit of the DHP-receptor of muscle cells.
Animals↗
Resolving the structural basis for developmental changes in muscle ACh receptor function: it takes nerve.
The nicotinic acetylcholine (ACh) receptor undergoes extensive alterations in functional properties during muscle development. One such alteration, the developmental acquisition of the 'junctional' form of the channel, has been attributed to post-translational modification of pre-existing 'non-junctional' receptor channels. However, the discovery that a switch between the epsilon- and gamma-subunits of the muscle ACh receptor results in the 'junctional' form of the channel suggests a transcriptional mechanism of control. Although this issue is by no means settled, recent molecular biological and electrophysiological studies offer new ideas as to how innervation regulates the expression of functionally distinct forms of this receptor/channel.
Animals↗
Developmentally regulated troponin C mRNAs of chicken skeletal muscle.
Fast and slow/cardiac troponin C (TnC) are the two different isoforms of TnC. Expression of these isoforms is developmentally regulated in vertebrate skeletal muscle. Therefore, in our studies, the pattern of their expression was analyzed by determining the steady-state levels of both TnC mRNAs. It was also examined if mRNAs for both isoforms of TnC were efficiently translated during chicken skeletal muscle development. We have used different methods to determine the steady-state levels of TnC mRNAs. First, probes specific for the fast and slow TnC mRNAs were developed using a 390 base pair (bp) and a 255 bp long fragment, of the full-length chicken fast and slow TnC cDNA clones, respectively. Our analyses using RNA-blot technique showed that fast TnC mRNA was the predominant isoform in embryonic chicken skeletal muscle. Following hatching, a significant amount of slow TnC mRNA began to accumulate in the skeletal (pectoralis) muscle. At 43 weeks posthatching, the slow TnC mRNA was nearly as abundant as the fast isoform. Furthermore, a majority of both slow and fast TnC mRNAs was found to be translationally active. A second method allowed a more reliable measure of the relative abundance of slow and fast TnC mRNAs in chicken skeletal muscle. We used a common highly conserved 18-nucleotide-long sequence towards the 5'-end of these mRNAs to perform primer extension analysis of both mRNAs in a single reaction. The result of these analyses confirmed the predominance of fast TnC mRNA in the embryonic skeletal muscle, while significant accumulation of slow TnC mRNA was observed in chicken breast (pectoralis) muscle following hatching. In addition to primer extension analysis, polymerase chain reaction was used to amplify the fast and slow TnC mRNAs from cardiac and skeletal muscle. Analysis of the amplified products demonstrated the presence of significant amounts of slow TnC mRNA in the adult skeletal muscle.
Animals↗
Effects of bovine growth hormone analogs on mouse skeletal muscle structure.
Skeletal muscles of transgenic mice expressing altered bovine growth hormones (bGH) have been compared with those of nontransgenic mice to determine whether muscle fiber type-specific responses or histopathologies are associated with the altered gene. The slow soleus and predominantly fast gastrocnemius muscles were prepared for myofibrillar ATPase activity (to determine muscle fiber type) and histological examination from mice that were either giant (M4 line), larger than normal (M11 line), dwarf (G119K line), or nontransgenic (NTC). No histopathology was observed in any of the muscles. Although body weights were significantly different between all four lines of mice, only the giant M4 mice had significantly larger muscle fibers than the other lines of mice, while neither the G119K nor M11 lines were significantly different from the NTC for either muscle. No fiber type-specific differences were noted. These results suggest that the different muscles are the product of differences in numbers of muscle fibers expressed in the G119K and M11 lines of mice; the increase in body mass matched the fiber size growth only in the giant M4 line. Therefore, the altered bGH genes may be acting on fetal liver and myoblast/myotube GH receptors to change the GH and IGF-I regulated pattern of muscle development, and eventually, to determine the adult muscle fiber numbers.
Animals↗
Hedgehog signalling is required for maintenance of myf5 and myoD expression and timely terminal differentiation in zebrafish adaxial myogenesis.
Hedgehog proteins have been implicated in the control of myogenesis in the medial vertebrate somite. In the mouse, normal epaxial expression of the myogenic transcription factor gene myf5 is dependent on Sonic hedgehog. Here we examine in zebrafish the interaction between Hedgehog signals, the expression of myoD family genes, including the newly cloned zebrafish myf5, and slow myogenesis. We show that Sonic hedgehog is necessary for normal expression of both myf5 and myoD in adaxial slow muscle precursors, but not in lateral paraxial mesoderm. Expression of both genes is initiated normally in rostral presomitic mesoderm in sonic you mutants, which lack all Sonic hedgehog. Similar initiation continues during tailbud outgrowth when the cells forming caudal somites are generated. However, adaxial cells in sonic you embryos are delayed in terminal differentiation and caudal adaxial cells fail to maintain myogenic regulatory factor expression. Despite these defects, other signals are able to maintain, or reinitiate, some slow muscle development in sonic you mutants. In the cyclops mutant, the absence of floorplate-derived Tiggywinkle hedgehog and Sonic hedgehog has no discernible effect on slow adaxial myogenesis. Similarly, the absence of notochord-derived Sonic hedgehog and Echidna hedgehog in mutants lacking notochord delays, but does not prevent, adaxial slow muscle development. In contrast, removal of both Sonic hedgehog and a floorplate signal, probably Tiggywinkle hedgehog, from the embryonic midline in cyclops;sonic you double mutants essentially abolishes slow myogenesis. We conclude that several midline signals, likely to be various Hedgehogs, collaborate to maintain adaxial slow myogenesis in the zebrafish embryo. Moreover, the data demonstrate that, in the absence of this required Hedgehog signalling, expression of myf5 and myoD is insufficient to commit cells to adaxial myogenesis.
Amino Acid Sequence↗
Control of the murine phosphofructokinase-A gene during muscle differentiation.
The muscle-specific isoform of phosphofructokinase (PFK-A) is induced during muscle development. To understand expression of PFK at the molecular level, transcription of the mouse PFK-A gene was examined during C2 myoblast differentiation to myotubes. PFK-A gene transcription increased 5-7-fold during differentiation in vitro. To identify cis-acting elements which direct muscle-specific transcription of the PFK-A gene, its 5'-flanking region and first exon were cloned and characterized. S1 nuclease protection and primer extension assays showed four sites of transcription initiation at 106, 105, 88, and 87 bp upstream of the translation initiation codon. Stable transfection of fusion genes linking -1900 to +99 of PFK-A 5'-flanking sequence to chloramphenicol acetyltransferase coding sequences into myogenic C2 cells did not confer muscle-specific expression. However, larger fragments of PFK-A 5'-flanking region (-5800 to +99) showed muscle-specific expression by transient transfection assay. The sequences directing muscle-specific transcription were further defined by linking various PFK-A upstream fragments to the luciferase gene under the control of the PFK-A proximal promoter, -335 to +99 bp. We found DNA sequence responsible for muscle-specific expression of the PFK-A gene between -4800 and -3900 bp.
Animals↗
Influence of early postnatal cold exposure on myofiber maturation in pig skeletal muscle.
Early after birth, piglets rely almost exclusively on muscular shivering thermogenesis to produce heat in the cold and this can possibly modulate skeletal muscle development. An experiment involving 10 individually housed piglets was conducted to determine the influence of cold (24-15 degrees C, D5C group) vs. thermoneutrality (34-30 degrees C, D5TN group) between birth and 5 days on myosin heavy chain (MyHC) polymorphism and metabolic characteristics of longissimus lumborum (LL) and rhomboideus (RH) muscles. Five additional piglets were sacrificed at birth. Piglets exposed to cold received 43% more artificial milk on a liveweight basis in order to achieve similar growth rates. D5C piglets produced 93% more heat and exhibited intense shivering during the whole experiment. Contractile and metabolic characteristics of muscles were determined by immunocytochemistry, electrophoresis and enzyme activities. At least eight MyHC isoforms were detected, including atypical expressions of the alpha-cardiac and extraocular isoforms. Dramatic changes in MyHC composition, myofiber cross-sectional area (CSA) and energy metabolism occurred between birth and 5 days. Cold exposure did not affect either the total number of fibers or the CSA, but it did influence muscle maturation. In particular, it increased the expression of alpha-cardiac and type I MyHC, and decreased that of fetal MyHC, confirming an acceleration in the rate of postnatal maturation. An increase in oxidative enzyme activities was observed in both muscles in the cold, whereas the activity of a glycolytic enzyme, lactate dehydrogenase, remained unchanged. Cold exposure also induced an increase in T3 plasma levels. The extent to which these changes are the result of sustained shivering or are due to the action of hormonal factors, such as thyroid hormones, are discussed.
Age Factors↗
Synaptic acetylcholinesterase of chicken muscle changes during development from a hybrid to a homogeneous enzyme.
The asymmetric (20S) form of acetylcholinesterase (AChE) in 1-day-old chick muscle is a hybrid enzyme containing both AChE (110 kd) and butyrylcholinesterase (BuChE, 72 kd) catalytic subunits. However, we now report that the asymmetric AChE extracted or immunopurified from older adult chicken muscles, where it is the endplate form, shows a progressive developmental loss of the BuChE subunit and its activities, centred around 4 weeks of age, while the AChE and collagenous subunits remain. In confirmation, using differential labelling and co-sedimentation it was shown that the hybrid 20S AChE/BuChE form of 1-day chick muscle is gradually and completely replaced during muscle maturation by a 21.3S form, also collagen-tailed but otherwise homogeneous in AChE catalytic subunits. Two other changes occur concomitantly. Firstly, the AChE catalytic subunit of the adult form has a lower apparent mol. wt in gel electrophoresis, by 5 kd, than the same subunit in the 1-day hybrid enzyme; this difference does not reside in the carbohydrate attachments. Secondly, the collagen tail changes, in that some conformation-dependent epitopes on it disappear in the same period. Hence, a major reorganization of the asymmetric AChE, involving all three types of subunit, occurs in the course of muscle development.
Acetylcholinesterase↗
Formation of primary and secondary myotubes in aneural muscles in the mouse mutant peroneal muscular atrophy.
The role of motor innervation in supporting and regulating muscle development was studied using aneural muscles in the hindlimb of the mouse mutant peroneal muscular atrophy (pma). This is a single-locus autosomal mutation where homozygous animals lack the common peroneal nerve, so that muscles in the anterolateral compartment of the lower leg develop entirely without innervation. In adults, these muscles are extremely atrophied, and the mice display a clubfoot deformity. The mutant animals provide a preparation in which aspects of muscle formation can be studied in muscles that have never been exposed to direct contact with somatic motor or sensory axons, without pharmacological or surgical intervention. Using quantitative electron microscopy, we found that normal numbers of primary myotubes formed in aneural pma EDL muscles, but a greater than normal proportion degenerated during the first 2 days after their formation. Secondary myotubes appeared at their normal time and position within the muscle, initially in normal numbers, so that the ratio of secondary to primary myotubes initially was greater in pma than in CF1 control strain mice. No abnormalities in ultrastructure were seen until the time of birth, when retardation in development was obvious, together with invading macrophages and degenerating myofibres. The results show that secondary myotube formation in the mouse, as in the chick (B. J. Fredette and L. T. Landmesser, Dev. Biol. 143, 19-35, 1991) is not directly dependent on innervation. In control muscles, secondary myotubes first form in the vicinity of endplates on primary myotubes. No aggregations of ACh receptors or acetylcholinesterase were present in the aneural muscles, showing that these are neurally induced in the mouse, but secondary myotubes formed in their normal position indicating that positional information related to endplate formation is present in aneural muscles.
Acetylcholinesterase↗
Angiotensin converting enzyme inhibition prevents development of muscle and nerve dysfunction and stimulates angiogenesis in streptozotocin-diabetic rats.
The effects of the angiotensin converting enzyme inhibitor lisinopril on slow and fast twitch muscle contractile properties, nerve conduction and hypoxic resistance, and muscle and nerve capillary density were examined in streptozotocin-diabetic rats. Prolongation of soleus contraction and relaxation were partially prevented by treatment (p less than 0.01). A 22% deficit in fast twitch extensor digitorum longus tetanic tension production was also ameliorated (p less than 0.01). Sciatic motor and sensory conduction velocity, 25% and 12% reduced by diabetes respectively, were 75% normalized by lisinopril (p less than 0.01). There was a 47% increase in resistance to hypoxic conduction block with diabetes (p less than 0.01). Lisinopril treatment resulted in normal hypoxic resistance. Capillarization of nerve and muscle was little affected by diabetes; however, there was a 17% increase in capillary density in sciatic nerve, and a 40% increase in extensor digitorum longus muscle with lisinopril (p less than 0.01). For soleus, a smaller treatment-induced increase in capillary density led to an elevated capillary/muscle fibre ratio (p less than 0.01). These results suggest that lisinopril promoted angiogenesis. It was concluded that the beneficial effect of preventive lisinopril treatment is likely to depend upon a reduction of peripheral vascular resistance and improvement of tissue blood flow, which implicates relative hypoxia as an important factor in the development of myopathy and neuropathy in experimental diabetes.
Action Potentials↗
Contractile activity regulates isoform expression and polysialylation of NCAM in cultured myotubes: involvement of Ca2+ and protein kinase C.
Muscle development involves a series of complex cell-cell interactions that are mediated, at least in part, by several different cell adhesion molecules. Previous work from this lab showed that the different isoforms of NCAM and its level of polysialylation are developmentally regulated during chick myogenesis in vivo and that this regulation is important for normal muscle development. Using developing chick secondary myotubes grown in culture, we show here that both the polysialylation of NCAM and the developmental switch in isoform expression are regulated by activity and that Ca2+ entry through voltage-gated channels and the subsequent activation of protein kinase C are required for the developmental changes in NCAM isoform synthesis. Specifically, PSA expression was shown to be developmentally regulated with high expression being temporally correlated with the onset of spontaneous contractile activity. Furthermore, blocking contractile activity caused a decrease in PSA expression, while increasing activity with electrical stimulation resulted in its up-regulation. Immunoblot and metabolic labeling studies indicated that dividing myoblasts synthesize primarily 145-kD NCAM, newly formed, spontaneously contracting myotubes synthesize 130-, 145-, and 155-kD NCAM isoforms, while older, more mature myotubes primarily synthesize the glycosylphosphatidylinositol-anchored 130-kD isoform which, in contrast to the other three isoforms, had a high rate of turnover. This developmental switch in NCAM isoform expression could be inhibited with Ca2+ channel blockers and inhibitors of protein kinase C. Taken together, these results suggest that Ca2+ ions and protein kinase C are involved in a second messenger cascade coupling membrane depolarization with transcriptional factors that regulate NCAM isoform synthesis and polysialylation.
Alternative Splicing↗
Alteration in myosatellite cell commitment with muscle maturation.
Myosatellite cells are myoblasts found between the basal lamina and sarcolemma of myofibers of postnatal mice. The extent to which these cells are programmed, upon differentiation, to express isoforms of contractile protein genes specific to the type of fiber with which they are associated has been evaluated in vitro using myosatellite cells derived from the soleus and the extensor digitorum longus muscles (EDL) of 4-day-old and adult transgenic mice, which express nuclear localizing beta-galactosidase (nlsbeta-gal) under the control of the promoter and 3' enhancer of the gene encoding fast myosin light chain 3F (MLC3F) (Kelly et al. [1995] J. Cell Biol. 129:383-396). Cultures were allowed to differentiate either as myocytes (mononucleated cells), to prevent possible modification of the myosatellite phenotype by other myonuclei in mosaic myotubes, or as myotubes. Transgene expression was age related, with 90% and 70% of the myocytes derived from the neonatal EDL and soleus muscles (muscles that had not yet achieved their mature phenotype), respectively, having nuclei encoding beta-gal; 61% and 32% of the myocyte nuclei derived from myosatellite cells of the adult EDL (a fast muscle) and the adult soleus muscle (a mixed muscle containing many slow myofibers), respectively, expressed this transgene. Because myosatellite cells found in adult muscles are the progeny of those found in the neonate, an alteration of myosatellite cell commitment to express this transgene occurs with muscle maturation. Because expression of the transgene in neonatal and adult muscle in vivo reflects the expression of the endogenous MLC3F gene (Kelly et al. [1995] J. Cell Biol. 129:383-396), it is likely that expression of the transgene by differentiated myosatellite cells reflects the extent of commitment of these cells to produce MLC3F. A hypothesis is presented that MLC3F is widely expressed in developing muscles but eliminated in myofibers that undergo maturation toward a slower phenotype.
Animals↗
Muscle LIM proteins are associated with muscle sarcomeres and require dMEF2 for their expression during Drosophila myogenesis.
A genetic hierarchy of interactions, involving myogenic regulatory factors of the MyoD and myocyte enhancer-binding 2 (MEF2) families, serves to elaborate and maintain the differentiated muscle phenotype through transcriptional regulation of muscle-specific target genes. Much work suggests that members of the cysteine-rich protein (CRP) family of LIM domain proteins also play a role in muscle differentiation; however, the specific functions of CRPs in this process remain undefined. Previously, we characterized two members of the Drosophila CRP family, the muscle LIM proteins Mlp60A and Mlp84B, which show restricted expression in differentiating muscle lineages. To extend our analysis of Drosophila Mlps, we characterized the expression of Mlps in mutant backgrounds that disrupt specific aspects of muscle development. We show a genetic requirement for the transcription factor dMEF2 in regulating Mlp expression and an ability of dMEF2 to bind, in vitro, to consensus MEF2 sites derived from those present in Mlp genomic sequences. These data suggest that the Mlp genes may be direct targets of dMEF2 within the genetic hierarchy controlling muscle differentiation. Mutations that disrupt myoblast fusion fail to affect Mlp expression. In later stages of myogenic differentiation, which are dedicated primarily to assembly of the contractile apparatus, we analyzed the subcellular distribution of Mlp84B in detail. Immunofluorescent studies revealed the localization of Mlp84B to muscle attachment sites and the periphery of Z-bands of striated muscle. Analysis of mutations that affect expression of integrins and alpha-actinin, key components of these structures, also failed to perturb Mlp84B distribution. In conclusion, we have used molecular epistasis analysis to position Mlp function downstream of events involving mesoderm specification and patterning and concomitant with terminal muscle differentiation. Furthermore, our results are consistent with a structural role for Mlps as components of muscle cytoarchitecture.
Actinin↗
Characterization of a developmentally regulated perinatal myosin heavy-chain gene expressed in skeletal muscle.
A cDNA clone, labeled pFOD5, isolated from a fetal-rat skeletal-muscle cDNA library, has been characterized and found to contain sequences corresponding to a perinatal-specific skeletal myosin heavy-chain (MHC) mRNA. This MHC cDNA demonstrates a high degree of nucleotide- and amino acid-sequence conservation with other MHC genes, but its carboxyl-terminal peptide and 3'-untranslated region are highly divergent and specific for this gene. S1 nuclease mapping experiments have shown that the perinatal MHC gene represented by this cDNA clone is only transiently expressed during skeletal-muscle development. Perinatal MHC mRNA is first detected late in fetal life, reaches maximal levels of expression at the end of the first postnatal week, and is de-induced thereafter. Its levels are almost undetectable at 28 days of postnatal life. During fetal and early postnatal life, the expression of this perinatal gene in skeletal muscle overlaps with the expression of the embryonic MHC gene. After the first week of extrauterine life, this gene is coexpressed with two adult MHC genes. The transient expression of this perinatal MHC gene raises interesting questions about the physiological significance of the MHC transitions and offers an interesting model for the study of MHC gene regulation.
Aging↗
Relation between oxygen uptake and developed tension in dog skeletal muscle.
Isometric developed tension of in situ gastro-cnemius-plantaris and semitendinosus muscles of the dog was increased 30% with twitch contraction frequency over the range of 0.5--2.0 tw/sc. Developed tension was decreased 75% after 30--40 min of 11--14 tw/s contractions, fatigue. Recovery from fatigue was slow. Intravenously injected K+ after fatigue increased developed tension 50%. Infusions of epinephrine, norepinephrine, and ouabain did not change developed tension. When the oxygen uptake of gastrocnemius-plantaris muscle was measured during twitch contractions at 0.5, 1.0, and 2.0 tw/s before and after fatigue and after injection of K+, the oxygen uptake was found to be directly related to the developed tension.
Action Potentials↗
In-vivo analysis of serum-borne growth factors in developing co-twinned fetuses.
Double-muscled fetuses develop more muscle fibers than normal-muscled fetuses. To examine whether serum growth factors modulate muscle development in cattle, twin pregnancies were induced in eight Holstein heifers using embryos from Belgian Blue and Holstein genetics representing heavy (HM) and light (LM) muscled cattle, respectively. Twin combinations were 1) two pairs of Belgian Blue fetuses that were designated as HM (HM), 2) two pairs of Holstein fetuses that were designated as LM (LM), and 3) four pairs of mixed fetuses; the four Holstein fetuses were designated as LM (HM) and the four Belgian Blue fetuses were designated as HM (LM). Pregnancies were terminated at 175 +/- 5 d after conception and fetuses, with evidence of vascular anastomosis, were dissected. Carcass weights were greatest (P < .05) for HM fetuses. Total bone and individual femur weights were greatest (P < .05) for LM (LM) fetuses. Total skeletal muscle mass and mass of semitendinosus, quadriceps femoris, infraspinatus, and longissimus muscles were in the order of HM (HM) > HM (LM) > LM (HM) = LM (LM) (P < .05). Estimated apparent muscle fiber number determined from a cross-section of semitendinosus muscle was in the order of HM (LM) > HM (HM) > LM (HM) = LM (LM) (P < .05). These data show that the presence of a co-twinned fetus with a lower genetic propensity for muscle development reduces the capacity of heavily muscled fetuses to develop muscle mass by 175 d after conception and strongly support the idea that blood-borne factors regulate muscle hypertrophy in fetal cattle.
Animals↗
Hepatocyte growth factor/scatter factor stimulates migration of muscle precursors in developing mouse tongue.
Hepatocyte growth factor (HGF) stimulates the migration of myogenic cells during the development of skeletal muscles. The inactivation of HGF genes or that of its receptor, c-met, in mice causes hypoplasia of skeletal muscle organs, such as the tongue. Basic fibroblast growth factor (FGF-2) also induces migration of skeletal myoblasts. A comparison of the functions of HGF and FGF-2 in myogenesis revealed the crucial effect of HGF in the development of skeletal muscles. Unlike FGF-2, HGF induced migration of myoblasts from the developing mouse tongue. The differences between the activities of HGF and FGF-2 were determined by comparing their effects on the expression of matrix metalloproteinase-9 (MMP-9) in myoblasts, C2C12 cells, cultured in collagen-coated dishes. The results showed that HGF, but not FGF-2, stimulated MMP-9 expression, and that the stimulation was mediated through the activation of phosphoinositide 3-kinase (PI3K) which was not associated with FGF-2 signal transduction. Nevertheless, both growth factors exerted almost the same effect on the reduction of myogenin expression in, and on the proliferation of, C2C12 cells, suggesting that HGF, rather than FGF-2, plays a crucial role in the generation of skeletal muscles, including the tongue. Moreover, the specific role of HGF through the PI3K signal pathway is the induction of MMP-9 expression in, and the migration of, myoblasts.
Animals↗