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PubMed1989

Regeneration, neural crest derivatives and retinoids: a new synthesis.

Consideration of recent data from diverse fields of biology permits the presentation of a general theory to explain the underlying mechanism and phylogenetic distribution of vertebrate regenerative capacity. It is suggested that dermal xanthophores, which are neural crest derivatives that contain carotenoid pigments, serve as storage reservoirs for proretinoids. At trauma, carotenoids are released and are converted to retinoids. The spatial distribution of xanthophores at the amputation site determines the amount of carotenoids released, which in turn determines the number of cells which will participate in regeneration and their degree of dedifferentiation. It also influences the proliferative and morphogenetic potential of the blastema. The theory is based on several factors. (1) The pluripotency of neural crest derivatives in general and that of chromatophores in particular; (2) The storage metabolism of carotenoids, especially their convertability to retinoids; (3) The known roles of retinoids in regeneration; (4) Evidence suggesting a relationship between carotenoids and regeneration in invertebrates; and (5) Dynamic characteristics of regenerating systems. The theory is experimentally testable with currently available technology. Specific review of data concerning urodele lens regeneration illustrates the theory. Evidence from amphibian limb regeneration is also presented. Methods of evaluation of other regeneration systems are outlined.

Amphibians↗
PubMed1995

Platelet attachment stimulates endothelial cell regeneration after arterial injury.

BACKGROUND: Arterial injury is associated with endothelial disruption and attachment of platelets to an exposed subintimal layer. A variety of factors released by platelets may affect the ability of endothelial cells bordering an injury to regenerate. In this study an organ culture model of arterial injury was used to investigate the relationship between attachment of platelets to a superficial arterial injury and endothelial regeneration. METHODS: A defined superficial endothelial injury was made in whole vessel wall explants of rabbit thoracic aorta. Injured explants were treated with either fresh whole platelets, the supernatant of platelets aggregated by collagen, or basic fibroblast growth factor. Four days after injury and treatment, the average distance of endothelial regeneration was determined. RESULTS: A dramatic increase in the rate of endothelial cell regeneration was observed when injured vessels were exposed to fresh whole platelets (p = 0.003). This increase in regeneration was comparable to that observed with fibroblast growth factor. No increase in the regenerative rate was found after exposure of explants to the supernatant of aggregated platelets (p = 0.69). CONCLUSIONS: Platelets stimulate endothelial regeneration at a rate equal to that observed with the potent endothelial mitogen basic fibroblast growth factor. Because this effect was not demonstrated with the supernatant of aggregated platelets, endothelial regeneration may be dependent on attachment of the platelets to the area of injury.

Animals↗
PubMed2005

Deer antlers as a model of Mammalian regeneration.

Deer antlers are cranial appendages that develop after birth as extensions of a permanent protuberance (pedicle) on the frontal bone. Pedicles and antlers originate from a specialized region of the frontal bone; the 'antlerogeneic periosteum' and the systemic cue which triggers their development in the fawn is an increase in circulating androgen. These primary antlers are then shed and regenerated the following year in a larger, more complex form. Antler growth is extremely rapid-an adult red deer can produce a pair of antlers weighing approximately 30kg in three months, and involves both endochondral and intramembranous ossification. Since antlers are sexual secondary characteristics, their annual cycles of growth have evolved to be closely coordinated to the reproductive cycle which, in temperate species, is linked to the photoperiod. Cessation of antler growth and death of the overlying skin (velvet) coincides with a rise in circulating testosterone as the autumn breeding season approaches. The 'dead' antlers remain attached to the pedicle until they are shed (cast) the following spring when circulating testosterone levels fall. In red deer, the species that we study, casting of the old set of antlers is followed immediately by growth of the new set. Although the anatomy of antler growth and the endocrine changes associated with it have been well documented, the molecular mechanisms involved remain poorly understood. The case for continuing to decipher them remains compelling, despite the obvious limitations of using deer as an experimental model, because this research will help provide insight into why humans and other mammals have lost the ability to regenerate organs. From the information so far available, it would appear that the signaling pathways that control the development of skeletal elements are recapitulated in regenerating antlers. This apparent lack of any specific 'antlerogenic molecular machinery' suggests that the secret of deers' ability to regenerate antlers lies in the particular cues to which multipotential progenitor/stem cells in an antler's 'regeneration territory' are exposed. This in turn suggests that with appropriate manipulation of the environment, pluripotential cells in other adult mammalian tissues could be stimulated to increase the healing capacity of organs, even if not to regenerate them completely. The need for replacement organs in humans is substantial. The benefits of increasing individuals' own capacity for regeneration and repair are self evident.

Animals↗
PubMed2003

Promoting nerve regeneration through long gaps using a small nerve tissue graft.

BACKGROUND: If nerve tissue is capable of inducing regeneration, as suggested by the neurotropism theory, then even small pieces of nerve tissue should have the potential to induce nerve regeneration. Therefore, long gaps might presumably be bridged via the neurotrophic potential of small pieces of nerve tissue grafted into the middle of the nerve gap. It is necessary to confirm the validity of the neurotropism theory and to also explore the potential usefulness of small nerve grafting through long gaps. METHODS: A small piece of nerve tissue was grafted into a silicone tube bridging a relatively long nerve gap in an attempt to promote nerve regeneration. A 15-mm gap was created in the left sciatic nerve of 31 Wistar rats (8 weeks of age). The experimental groups included one with nonvascularized nerve tissue grafted into a silicone tube with no distal nerve suturing (NV-A), another with vascularized nerve tissue grafted into a silicone tube with no distal nerve suturing (V-A), a third group with nonvascularized nerve tissue grafted into a silicone tube with distal nerve suturing (NV-P), a fourth group with vascularized nerve tissue grafted into a silicone tube with distal nerve suturing (V-P), and a group with no nerve segment grafted into the silicone tube (control). Electrophysiologic and histologic examinations were performed 10 weeks after the operation. RESULTS: No regeneration was obtained in the control group. Nerve regeneration was evident at the proximal end of the tube in the NV-A, V-A, NV-P, and V-P groups, and at the distal end in the NV-P and V-P groups. The degree of distal regeneration was extremely slight in the NV-A and V-A groups. An electrophysiologic examination performed in the NV-P and V-P groups revealed better results in the latter group. CONCLUSION: Small nerve grafts are capable of inducing nerve regeneration even over a long nerve gap, by grafting nerve tissue into the middle of the lesion using a silicone tube.

Animals↗
PubMed1993

A mathematical model for regeneration rate and initial delay following surgical repair of peripheral nerves.

A mathematical model is presented by which the regeneration rate and initial delay for peripheral nerve regeneration can be calculated from sensory pinch test data following surgical repair of peripheral nerves. The model is based on the assumption that experimental variations in regeneration distances between animals is due to the initial delay period--the time period before the regenerating fibers cross the suture line whereas the rate of regeneration is constant. This model which accounts for all observed data including 'regenerating failures' showed that nerve fibers in the rat sciatic nerve repaired with a fresh nerve graft regenerated at a rate of 1.5 mm/day after an initial delay of 3.6 days.

Animals↗
PubMed2001

Expression pattern of a newt Notch homologue in regenerating newt retina.

We isolated part of a newt Notch homologue, N-Notch, from regenerating newt retina. The spatio-temporal pattern of N-Notch expression was studied by in situ hybridization at different stages of newt retinal regeneration. Proliferating cells were confirmed by the injection of bromodeoxyuridine (BrdU). In the early stage of regeneration, when the retina was one to two cells thick, all proliferating retinal progenitors expressed N-Notch. As the thickness of the retina increased with regeneration, N-Notch expression decreased in BrdU-positive cells on the vitreal side of the retina. Subsequently, presumptive retinal ganglion cells that were BrdU-negative cells appeared at the vitreal edge of the regenerating retina. These differentiating cells did not express N-Notch. Later, N-Notch expression decreased in the BrdU-positive cells on the scleral surface of the retina. Subsequently, presumptive photoreceptor cells that were BrdU-negative cells appeared in this region. These differentiating cells also did not express N-Notch. The proliferating retinal progenitors ceased expressing N-Notch and then stopped dividing during the differentiation of ganglion cells and photoreceptor cells. It was found that retinal regeneration involves the expression of an important developmental signaling molecule, Notch, in retinal progenitors and the expression of Notch ceased as cell differentiation proceeded during retinal regeneration.

Amino Acid Sequence↗
PubMed1999

Choline acetyltransferase and acetylcholinesterase in the normal, developing and regenerating newt retinas.

The presence of the choline acetyltransferase (ChAT) and acetylcholinesterase (AChE) was demonstrated in the adult newt retina using immunocytochemical and histochemical techniques. Within the inner plexiform layer (IPL), two ChAT-positive bands were detected at relative depths of 0-15% and 45-60% of the total thickness (100%) of the IPL. AChE-positive band occupied approximately 0-60% of the IPL width with an intensive AChE-positive band at a depth of 20-40% within the IPL. Localizations of maximum ChAT and AChE activity were not exactly the same in the IPL of the mature retina. To elucidate whether retinal regeneration follows the same sequence of cellular differentiation steps that occur in retinal development, we examined the time course of appearance of the cholinergic neurons and AChE activity in both developing and regenerating retinas. The ChAT-positive cells were first detected in the retina just before or at the beginning of the morphological development of the IPL in both developing and regenerating retinas. AChE activity first became detectable in somata located at the most proximal layer of the retina before the ChAT-positive cells could be detected and well before the IPL developed in both developing and regenerating retinas. During subsequent development and regeneration, the outer plexiform layer, the IPL, and somata close to either side of the IPL became AChE-positive. The fact that the time course of the appearance of ChAT and AChE molecules during regeneration was similar to that observed during development suggests that common mechanisms may control both the development and the regeneration of the newt retina.

Acetylcholinesterase↗
PubMed1997

Impaired vision for binocular tasks after unilateral optic nerve regeneration in the frog Litoria moorei.

Behavioural responses to objects in the binocular field were examined in frogs with one regenerate and one intact optic nerve. Data were compared to those for normal controls and for frogs with vision via one intact optic nerve. During prey acquisition, frogs with regenerated optic nerves underestimated the distance to the prey on their first strike; as a consequence, the regenerate series made several attempts to achieve a successful prey capture. By contrast, normal frogs and those using only one eye struck accurately at the prey and usually captured it on the first attempt. However, frogs using only one eye struck from a closer distance than either the regenerate or normal series. Frogs with regenerated optic nerves also made more errors than either of the other series when leaping through a set of closely spaced horizontally aligned rods. Our results show that prey capture and the negotiation of horizontally aligned rods is impaired in animals using one regenerated and one intact optic nerve as compared to both normal frogs and those using only one eye. We suggest that the poor visual performance for frogs with one regenerated and one intact optic nerve for tasks presented in the binocular field is related to the integration of a degraded and a normal image within the visual centres.

Animals↗
PubMed1998

Axonal regeneration with functional restoration in the vestibulospinal tract in young rats.

The present study examined regeneration and restoration of function of the mammalian central vestibular system in the infant rat. The lateral vestibulospinal tract (LVST) of rats was completely transected unilaterally by a ventral approach. After a postoperative interval of one day to three months, the LVST was examined by anterograde transport of wheat-germ agglutinin-conjugated horseradish peroxidase (WGA-HRP) and retrograde transport of fluorescent dye. Twelve of the 22 LVST-transected rats showed successful regeneration. The regenerated fibers formed a compact fiber bundle, which sent terminals to their normal targets. The contribution of the regenerated fibers to functional recovery was estimated by analyzing the locomotor capacity of the transected rats. The locomotor movements were measured on the surface of a digitizer table by attaching a miniature resonance coil to the abdomen of the rats. Rats which shows normal locomotor movements represented a marked regeneration of LVST fibers. In contrast, rats with poorly-controlled locomotor movements showed unsuccessful regeneration. These results suggest that, contrary to previous thought, regeneration and functional restoration of the central vestibular system in young rats does occur.

Amidines↗
PubMed1997

Liver regeneration: methods for monitoring and their applications.

Liver regeneration is an essential component of the reparative process following liver injury and surgical resection. It can be assessed by different tissue-based tests such as liver weights, mitotic counts, DNA contents and synthesis rates, immunohistochemical staining of nuclear antigens, gene expressions and certain protein levels or various serum-based tests that largely consist of specific enzyme determinations or documentation of certain proliferation markers. Although the simplest tissue-based test of liver regeneration is measurement of liver weights, these determinations are influenced by the extent of deposition of various materials not directly related to regeneration, such as lipids, glycogen and blood volumes. Because mitosis constitutes a very short segment of the cell cycle, mitotic counts are infrequently observed by light microscopy. Thymidine and BrdU incorporation into DNA are the reference tools for studying DNA synthesis, but their use requires pre-injection with radioactive isotopes or nucleotides which render them impractical for human studies. Flow cytometry is an accurate and objective method of monitoring hepatic regenerative activity but requires sophisticated equipment that is not generally available in many laboratories. Immunohistochemical staining for nuclear antigens (Ki-67, proliferating cell nuclear antigen [PCNA], DNA polymerase alpha and nucleolar organizer region [NOR] proteins) are acceptable and commonly used methods of monitoring regenerative activity but are subject to inter- and intra-observer variability. Gene expression rates such as Histone-3 mRNA abundance are hampered by the relatively low rates of gene transcription and the need for recombinant DNA technology. Protein and enzyme levels in liver tissues, such as putrescine, ornithine decarboxylase and thymidine kinase, are not precise and are confounded by the nutritional status of the host. While PCNA protein levels measured by immunoblot hold promise as a simple, accurate and reproducible marker of liver regeneration, additional studies are required to determine if this is a valid marker of regenerative activity in various models of hepatic injury and in humans. Of the serum-based determinations: thymidine kinase, ornithine decarboxylase, fibronectin, alpha fetoprotein, and early pregnancy factor offer practical and non-invasive tools to monitor liver regeneration, but the sensitivity and specificity of these tests have yet to be determined. In conclusion, many tissue and serum-based methods have been employed in clinical and experimental studies to assess liver regeneration; however, a gold standard has yet to be identified. Because of the disadvantages inherent in each method, and until a new, more accurate marker is identified, clinicians and scientists should incorporate a minimum of two independent markers in studies of liver regeneration.

Animals↗
PubMed1997

Regeneration in the developing optic nerve: correlating observations in the opossum to other mammalian systems.

Regeneration of severed axons within the central nervous system of adult mammals does not normally occur with any degree of success. During development, however, newly forming projections must send axons to distant sites and form appropriate connections with their targets: successful regeneration has been observed during this critical period. The opossum central nervous system develops during early postnatal life and has provided a useful experimental model to investigate this specialized mode of axonal regeneration in mammals. The presence of a clear decision point at the optic chiasm has also provided a useful site at which to investigate the navigational capacity of retinal ganglion cells regenerating along the optic nerve during this critical period. Regeneration failure occurs as the central nervous system progresses from this permissive, developing state to a mature, non-permissive adult state. Studies into the behaviour of glial and neuronal elements around this transition period can help elucidate some of the factors that need to be overcome if regeneration is ever to become successful in adult mammals. The regeneration characteristics of a lesioned projection are dependent upon its developmental stage and are also related to the proximity of axotomy along its pathway. A system of staging is proposed to correlate observations in the opossum optic nerve to other mammalian systems.

Animals↗
PubMed1998

Use of explant cultures of peripheral nerves of adult vertebrates to study axonal regeneration in vitro.

Explanted preparations of peripheral nerves with attached dorsal root ganglia of adult mammals and amphibia survive for several days in serum-free medium and can be used to study axonal regeneration in vitro. This review outlines the methods which we routinely use and how they may be applied to study different aspects of axonal regeneration. When the peripheral nerves are crushed in vitro, axons regenerate through the crush site into the distal stump within 1 day (mouse) or 3 days (frog). The outgrowth distance of the leading sensory axons can be determined with the use of a simple method based on axonal transport of labelled proteins. A compartmentalised system permits selective application of drugs and other agents to either ganglia or peripheral nerve containing the regenerating axons and has been used to study selected aspects of regeneration including influence of non-neuronal cells, retrograde signalling, axonal release of proteins during regeneration and the role of phospholipase A2 activity. Explanted preparations may also be cultured in a layer of extracellular matrix material (matrigel), in which spontaneous outgrowth of a large number of naked axons from the cut ends of nerves starts within 1 day and continues for several days. This provides an opportunity to study the direct effects of different agents on axonal elongation. Preparations cultured in collagen gels show sparse spontaneous axonal growth, but this can be increased by addition of certain growth factors. The phenotype of the regenerating axons can be studied using immunohistochemical methods.

Animals↗
PubMed2000

Regulation of the expression and phosphorylation of microtubule-associated protein 1B during regeneration of adult dorsal root ganglion neurons.

Microtubule-associated protein 1B is a major constituent of the neuronal cytoskeleton during the early stages of development. This protein and its phosphorylated isoform, microtubule-associated protein 1B-P, defined by the monoclonal antibody 1B-P [Boyne L. J. et al. (1995) J. Neurosci. Res. 40, 439-450], are present in growing axons and concentrated in the distal end near the growth cone. In most regions of the central nervous system, microtubule-associated protein 1B and microtubule-associated protein 1B-P are developmentally down-regulated. They remain, however, at relatively high levels in the adult peripheral nervous system, where microtubule-associated protein 1B-P is localized exclusively in axons. The aim of this study was to examine the levels of microtubule-associated protein 1B and its phosphorylated isoform during regenerative growth of peripheral axons. Following transection and re-apposition of the sciatic nerve at midthigh, the levels of total microtubule-associated protein 1B, microtubule-associated protein 1B-P and microtubule-associated protein 1B messenger RNA were analysed in dorsal root ganglion neurons and sciatic nerve axons using western blots and RNase protection assays. After the lesion, there was a small decrease in the levels of microtubule-associated protein 1B and its messenger RNA in dorsal root ganglion neurons. The proximal axonal stump showed a similar decrease in the levels of microtubule-associated protein 1B 30days after lesion and returned to normal 60-90days post-lesion. In the distal stump of the sciatic nerve, the levels of microtubule-associated protein 1B increased dramatically and rapidly between three and 14days, but the protein was localized mainly in activated Schwann cells and myelin-like structures, and not in axons [Ma D. et al. (1999) Brain Res. 823, 141-153]. With the regeneration of axons into the distal stump, an intense expression of microtubule-associated protein 1B was observed in these axons. Microtubule-associated protein 1B-P, however, disappeared from the degenerated distal axonal stump as early as three days post-operation, and was absent in the regenerating axons and in Schwann cells between three and 14days. The levels of microtubule-associated protein 1B-P recovered slowly and did not reach the normal levels even after 90days post-operation. In contrast to the response following transection, the levels of microtubule-associated protein 1B and microtubule-associated protein 1B-P were much less affected after nerve crush. We propose that the relatively high levels of microtubule-associated protein 1B and its messenger RNA in adult dorsal root ganglions support peripheral neuron regeneration. The presence of microtubule-associated protein 1B in the regenerating axons suggests that microtubule-associated protein 1B is involved in axonal growth during peripheral nerve regeneration. However, the phosphorylated microtubule-associated protein 1B-P isoform, associated with growing axons during development, is not present in the regenerating axons after transection, presumably because of changes in the activities of kinases and phosphatases associated with the injury. These observations underscore the difference between axonal development and regeneration and the importance of injury-related effects that occur locally.

Animals↗
PubMed2003

Intravitreal injections of neurotrophic factors and forskolin enhance survival and axonal regeneration of axotomized beta ganglion cells in cat retina.

Some retinal ganglion cells in adult cats survive axotomy for two months and regenerate their axons when a peripheral nerve is transplanted to the transected optic nerve. However, regenerated retinal ganglion cells were fewer than 4% of the total retinal ganglion cell population in the intact retina. The present study examined the effects of intravitreal injections of neurotrophic factors (brain-derived neurotrophic factor, ciliary neurotrophic factor, basic fibroblast growth factor, glial cell-derived neurotrophic factor, neurotrophin 4), first on the survival of axotomized cat retinal ganglion cells within 2 weeks, and then on axonal regeneration of the retinal ganglion cells for 2 months after peripheral nerve transplantation. We tested first enhancement of the survival by one of the factors, and then one or two of them supplemented with forskolin, which increases intracellular cAMP. Single injections of 0.5 microg or 1 microg brain-derived neurotrophic factor, 1 microg ciliary neurotrophic factor, or 1 microg glial cell-derived neurotrophic factor significantly increased total numbers of surviving retinal ganglion cells; 1.6-1.8 times those in control retinas. Identification of retinal ganglion cell types with Lucifer Yellow injections revealed that the increase of surviving beta cells was most conspicuous: 2.5-fold (brain-derived neurotrophic factor) to 3.6-fold (ciliary neurotrophic factor). A combined injection of 1 microg brain-derived neurotrophic factor, 1 microg ciliary neurotrophic factor, and 0.1 mg forskolin resulted in a 4.7-fold increase of surviving beta cells, i.e. 50% survival on day 14. On the axonal regeneration by peripheral nerve transplantation, a combined injection of brain-derived neurotrophic factor, ciliary neurotrophic factor, and forskolin resulted in a 3.4-fold increase of beta cells with regenerated axons. The increase of regenerated beta cells was mainly due to the enhancing effect of neurotrophic factors on their survival, and possibly to a change of retinal ganglion cell properties by cAMP to facilitate their axonal regeneration.

Animals↗
PubMed1999

Glial cells in degenerating and regenerating optic nerve of the adult rat.

The glial cell reaction both in degenerating and regenerating adult rat optic nerve was studied by immunohistochemistry and electron microscopy. Degeneration in the optic nerve was achieved by complete transection, and the retinal stump was then analyzed. The regeneration was observed by autotransplantation of a sciatic nerve segment to the transected retinal stump. In both cases, optic nerve axons were labeled anterogradely with rhodamine, followed by immunohistochemical staining. Glial fibrillary acidic protein-positive astrocytes covered the transected end of degenerating optic nerve, whereas in the regenerating optic nerve they enwrapped axonal bundles emerging from the optic nerve stump and migrated together into the transitional zone intervening between the retinal stump and graft. In electron microscopy, direct attachment of astrocyte and Schwann cell was found within the transitional zone, whereby these cells were holding axons between them. Decrease of 04 immunoreactivity, which labels oligodendrocytes, was apparent in the transected end of retinal stump during the regeneration. The ED1 -positivity, which labels microglia/macrophages, was found in cells accumulated in the transitional zone of degenerating optic nerve, whereas during regeneration, ED1-immunoreactive cells were also distributed in the retinal stump. These results suggest that astrocytes, usually considered to interfere with optic nerve regeneration, change their characteristics in the presence of peripheral nerve graft and guide the regenerating axons in cooperation with Schwann cells. The response of oligodendrocytes and microglia/macrophages may also be modulated by peripheral nerve.

Animals↗
PubMed1993

Restoring lens capsule integrity enhances lens regeneration in New Zealand albino rabbits and cats.

In studies conducted by numerous investigators for 150 years, lenses regenerated following endocapsular lens extraction in New Zealand albino rabbits have been irregular in shape, appearing primarily doughnut-shaped as a result of lack of lens growth at the site of the anterior capsulotomy and its adhesion to the posterior capsule. In the present study, we restored the lens capsule integrity by inserting a collagen patch at the time of surgery to seal the anterior capsulotomy and to improve the shape and structure of the regenerated lenses. We then filled the capsule bag with air to prevent adhesions between the anterior and posterior capsule and maintain capsule tautness and shape. Lens regeneration was first noted as early as one to two weeks. Regenerated lens filled approximately 50% of the capsule bag at two weeks and 100% by five weeks. Subsequent growth was in the anterior-posterior direction and measured by A-scan biometry. Lens thickness increased by 0.3 mm per month. The regenerated lenses were spherical with normal cortical structure and a nuclear opacity. In conclusion, restoration of lens capsular integrity with a collagen patch following endocapsular lens extraction enhanced the shape, structure, and growth rate of the regenerated lenses. In addition, lens regeneration was shown to occur in two cats.

Air↗
PubMed1998

Activation of the skeletal alpha-actin promoter during muscle regeneration.

Little is known concerning promoter regulation of genes in regenerating skeletal muscles. In young rats, recovery of muscle mass and protein content is complete within 21 days. During the initial 5-10 days of regeneration, mRNA abundance for IGF-I, myogenin and MyoD have been shown to be dramatically increased. The skeletal alpha-actin promoter contains E box and serum response element (SRE) regulatory regions which are directly or indirectly activated by myogenin (or MyoD) and IGF-I proteins, respectively. We hypothesized that the skeletal alpha-actin promoter activity would increase during muscle regeneration, and that this induction would occur before muscle protein content returned to normal. Total protein content and the percentage content of skeletal alpha-actin protein was diminished at 4 and 8 days and re-accumulation had largely occurred by 16 days post-bupivacaine injection. Skeletal alpha-actin mRNA per whole muscle was decreased at day 8, and thereafter returned to control values. During regeneration at day 8, luciferase activity (a reporter of promoter activity) directed by -424 skeletal alpha-actin and -99 skeletal alpha-actin promoter constructs was increased by 700% and 250% respectively; however, at day 16, skeletal alpha-actin promoter activities were similar to control values. Thus, initial activation of the skeletal alpha-actin promoter is associated with regeneration of skeletal muscle, despite not being sustained during the later stages of regrowth. The proximal SRE of the skeletal alpha-actin promoter was not sufficient to confer a regeneration-induced promoter activation, despite increased serum response factor protein binding to this regulatory element in electrophoretic mobility shift assays. Skeletal alpha-actin promoter induction during regeneration is due to a combination of regulatory elements, at least including the SRE and E box.

Actins↗
PubMed2001

The expression of dystrophin and alpha1-syntrophin during skeletal muscle regeneration.

The expression of dystrophin and alpha1-syntrophin in rat tibialis anterior muscles were evaluated during a cycle of regeneration after myonecrosis induced by the injection of cardiotoxin. Immunohistochemical studies were performed in cryosections of muscles on days 1, 3, 5, 7, 10, 14, 21 and 28 after injection of cardiotoxin. Western blot analysis was also examined in muscle on days 1, 3, 5, 7, 10, 14, 21 and 28. In immunohistochemical studies, dystrophin was stained weakly at the sarcolemma of some regenerating muscle fibers on day 3, and by day 10 it was stained strongly on almost all regenerating muscle fibers. Alpha1-syntrophin was stained weakly at the sarcolemma of some regenerating fibers on day 5, and by day 14 it was detected on all regenerating muscle fibers. In Western blot analysis, dystrophin (DYS1) and alpha1-syntrophin (alpha1S) were completely absent on day 1. Re-expression of DYS1 and alpha1S was visible by day 5 and accelerated thereafter. The Western blots of DYS1 and alpha1S were densitometrically analyzed on each day. The protein levels on each day were converted to the percentage of the protein level on day 28, which was taken as 100%. From the sequential line based on these data, the following results were obtained on the chronological course of DYS1 and alpha1S. DYS1: 25% of the protein level on day 28 was reached by 3.5 days, 50% was reached by 5.3 days, and 90% was reached by 6.9 days. Alpha1S: 25% of the protein level on day 28 was reached by 4.6 days, 50% was reached by 6.0 days, and 90% was reached by 12.5 days. In this study, DYS1 regenerated earlier than alpha1S at the sarcolemma of regenerating muscle fibers.

Animals↗