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PubMed1992

Neural regulation of acetylcholine receptors in rat neonatal muscle.

1. The neuronal regulation of the developmental decline in skeletal muscle acetylcholine (ACh) receptors was studied by comparing the effects of sciatic nerve section or of neuromuscular blockade with botulinum toxin (BoTX) on this decline in neonatal and adult rats, using 125I-alpha-bungarotoxin (125I-BTX) as a ligand for the receptor alpha-subunit. 2. The decline in 125I-BTX binding site concentration in neonatal rat triceps surae muscle homogenates towards low, adult levels followed a simple exponential with a time constant of 8 days. This decline occurred while the muscle is still rapidly growing, before the postnatal increase in numbers of sodium channels. It also preceded the decline in muscle ACh receptor alpha-subunit mRNA, reported in other studies, suggesting that subunit levels are not regulated only by mRNA availability. 3. Muscle denervation in the first two weeks of life prevented this developmental decline. Denervation increased the concentration of 125I-BTX binding sites but the magnitude of this increase became progressively smaller as the muscle matured, showing that removal of innervation during adult life does not revert the muscle, in toto, to its pre-innervation state. 4. Blockade of neuromuscular activity with BoTX increased 125I-BTX binding sites to a lesser extent than muscle denervation during neonatal life. This lesser effect of BoTX blockade contrasts with the equal effects of BoTX blockade and denervation in the adult.

Aging↗
PubMed1988

Acetylcholine receptor alpha-, beta-, gamma-, and delta-subunit mRNA levels are regulated by muscle activity.

Denervation of adult skeletal muscle results in increased sensitivity to acetylcholine in extrajunctional regions of the muscle fiber. This increase in acetylcholine sensitivity is accompanied by a large increase in the level of mRNAs coding for the alpha-, beta-, gamma-, and delta-subunits of the acetylcholine receptor. To determine whether muscle activity is sufficient to regulate expression of extrajunctional acetylcholine receptor mRNA levels, denervated muscles were stimulated with extracellular electrodes. Direct stimulation of denervated muscle suppresses both the increase in extrajunctional acetylcholine sensitivity and the expression of mRNA encoding the alpha-, beta-, gamma-, and delta-subunits of the acetylcholine receptor. These results show that muscle activity regulates the level of extrajunctional acetylcholine receptors by regulating the expression of their mRNAs.

Animals↗
PubMed1998

Regulation of prothrombin, thrombin receptor, and protease nexin-1 expression during development and after denervation in muscle.

Prothrombin, thrombin receptor (ThR), and protease nexin-1 (PN-1) mRNA levels in mouse muscle were quantified using competitive reverse transcriptase-polymerase chain reaction during development and after denervation to examine the possible role of thrombin in activity-dependent synapse elimination at the neuromuscular junction. The results showed that the levels of prothrombin and ThR were maximal at birth and decreased by two orders of magnitude by postnatal day 20 (P20). The level of PN-1 mRNA was fairly constant during development except for a 4-fold to 5-fold downregulation at P10 and P15, the periods of maximal synapse elimination at the rodent neuromuscular junction. The expression of prothrombin mRNA in muscle at birth was 41-fold and 22-fold lower than those of ThR and PN-1, respectively, and the level of difference between prothrombin and PN-1 reached almost three orders of magnitude at adulthood. Denervation of adult muscle resulted in a reversal of the relative expression levels of the three genes. There were rapid 8-fold and 10-fold increases in prothrombin and ThR mRNA, respectively, and a 2-fold decrease in PN-1 mRNA. The changes in mRNA levels of the three genes after denervation indicated that these genes were regulated in a innervation-dependent manner and that nerve activity may play an important regulatory role in the expression of prothrombin, ThR, and PN-1. The concurrent regulation of prothrombin and ThR suggests that thrombin-mediated cellular activities in muscle may be affected via the activation of ThR. An elevated level of local thrombin or thrombin-like activity might result from the decreased inhibitory activity of PN-1 during the period of peak synapse elimination in muscle development.

Amyloid beta-Protein Precursor↗
PubMed1985

The all-or-none role of innervation in expression of apamin receptor and of apamin-sensitive Ca2+-activated K+ channel in mammalian skeletal muscle.

The long-lasting after-hyperpolarization(s) (AHP) that follows the action potential in rat myotubes differentiated in culture is due to Ca2+-activated K+ channels. These channels have the property to be specifically blocked by the bee venom toxin apamin at low concentrations. Apamin has been used in this work to analyze, by electrophysiological and biochemical techniques, the role of innervation in expression of these important channels. The main results are as follows: (i) Long-lasting AHP that follows the action potential in rat myotubes in culture disappears when myotubes are cocultured with nerve cells from the spinal cord under the conditions of in vitro innervation. (ii) Extensor digitorum longus muscles from adult rats have action potentials that are not followed by AHP but AHP are systematically recorded after muscle denervation and they are blocked by apamin. (iii) Specific 125I-labeled apamin binding is undetectable in innervated muscle fibers but it becomes detectable 2-4 days after muscle denervation to be maximal 10 days after denervation. (iv) Apamin receptors detected with 125I-labeled apamin are present at fetal stages with biochemical characteristics identical to those found in myotubes in culture. The receptor number decreases as maturation proceeds and 125I-labeled apamin receptors completely disappear after the first week of postnatal life, in parallel with the disappearance of multi-innervation. All these results taken together strongly suggest an all-or-none effect of innervation on the expression of apamin-sensitive Ca2+-activated K+ channels.

Animals↗
PubMed1986

Action of thyrotropin-releasing hormone (TRH) on the occurrence of fibrillation potentials and miniature end-plate potentials (MEPPs). An experimental study.

The effect of TRH on fibrillation potentials and MEPPs were studied to determine the sites of action of TRH on muscle weakness. Intravenous administration of 10(-4) U thyroid-stimulating hormone (TSH) did not change the fibrillation-frequency of the denervated muscles of rats, but subsequent intravenous administration of 1 mg TRH did. Drip application of 0.6 mg TRH directly onto the denuded denervated muscles of rats did not cause an increase in fibrillation. Application of 1 mg TRH to the rat diaphragm increased the frequency of MEPPs. Both the increase in frequency of fibrillation potentials and the increase in frequency of MEPPs by application of TRH suggest that TRH influences nerve terminals, and that TRH seems suitable for treatment of muscle weakness in patients with ALS.

Animals↗
PubMed1988

Characterization of acetylcholine receptor subunits in developing and in denervated mammalian muscle.

We have used subunit-specific antibodies to identify and to characterize partially the alpha, beta, gamma, and delta subunits of rat skeletal muscle acetylcholine receptor (AChR) on immunoblots. The alpha subunit of rat muscle is a single band of 42 kDa, whereas the beta subunit has an apparent molecular mass of 48 kDa. Both alpha and beta subunits are glycosylated and contain one or more N-linked oligosaccharide chains that are sensitive to endoglycosidase H digestion. The gamma and delta subunits, on the other hand, each appear as doublets on immunoblots, with apparent molecular masses of 52 kDa (gamma), 48 kDa (gamma') and 58 kDa (delta), 53 kDa (delta'), respectively. In each case, the two bands are structurally related and the lower band is probably the partial degradation product of the corresponding upper band. Each of the four gamma and delta polypeptides is N-glycosylated and contains both endoglycosidase H-sensitive and endoglycosidase H-resistant oligosaccharides. When the AChRs purified from embryonic, neonatal, adult, and denervated adult rat muscles were compared, no differences in the mobilities of alpha, beta, or delta subunits on sodium dodecyl sulfate gels were detected among them, either with or without endoglycosidase treatment. The gamma subunits, which were present in AChRs purified from neonatal, embryonic, or denervated rat muscles, were also identical; no gamma subunit was detected, however, in AChRs of normal adult rat muscle.

Affinity Labels↗
PubMed1990

Effects of long-impulse electrical stimulation on atrophy and fibre type composition of chronically denervated fast rabbit muscle.

The efficacy of electrical stimulation on a chronically denervated muscle depends on stimulus parameters, which have an important influence on the development of atrophy. Stimulus frequency and/or total activity are particularly responsible for the development of some histological, biochemical and contractile features. The present study in 18 rabbits deals with a recently developed electrical stimulus, which had proved effective in maintaining muscle force following denervation. This current has (1) unusual long bidirectional rectangular impulses (20 ms) and (2) a frequency of 25 Hz, which is between the frequencies of fast- and slow-firing motor units. Electrical stimulation began 28 (in one animal 53) days after total motor and sensory denervation of the right hindleg, and was continued until the end of the experiment, up to 205 days. To mimic a therapeutic regimen, which should be agreeable to patients, daily treatment times were kept to a minimum (2 x 6 min), and surface electrodes were used. Morphometric evaluation of the fast flexor digitorum sublimis muscle showed that such electrical stimulation was able to preserve fibre diameter at a level of 72-86% of the initial values for several months, while unstimulated fibres showed the usual atrophy with a decrease of diameters below 40% of normal. The stimulation induced a "hybrid" fibre type with properties of a slow muscle (rich in mitochondria in NADH-dependent tetrazolium reductase staining and electron microscopy) as well as of a fast-twitch muscle (fibre type IIb in myofibrillar ATPase stainings).

Animals↗
PubMed2001

Reinnervation of a denervated skeletal muscle by spinal axons regenerating through a collagen channel directly implanted into the rat spinal cord.

In the present study, the continuity between the central nervous system (CNS) and the peripheral nervous system (PNS) was restored by mean of a collagen channel in order to reinnervate a skeletal muscle. Three groups of animals were considered. In the first group, one end of the collagen channel was implanted in the cervical spinal cord of adult rats. The other end was connected to a 30-mm autologous peripheral nerve graft (PNG) implanted into the denervated biceps brachii muscle. The gap between the spinal cord and the proximal nerve stump varied from 3 to 7 mm. In the second group of animals, the distal end of the PNG graft was ligatured in order to compare the survival of the growing axons in the presence and in the absence of a muscular target. In the third group of animals, the extraspinal stump of the collagen channel was ligatured. Our study demonstrates that spinal neurons and dorsal root ganglion (DRG) neurons can grow long axons through the collagen channel over a 7-mm gap and reinnervate a denervated skeletal muscle. The results also indicate that the presence of a PNG at the extraspinal stump of the collagen channel is essential for axonal regrowth and that the muscle target contributes to the long-term maintenance of the regenerating axons. These data might be interesting for clinical application when the continuity between the CNS and PNS is interrupted such as in root avulsion.

Absorbable Implants↗
PubMed1972

Some quantitative observations upon the responses of neuroglial cells which follow axotomy of adjacent neurones.

1. The dry mass and nucleic acid content of freshly isolated neuroglial cells and of their nucleoli were measured by interference microscopy and ultraviolet absorption microspectrography. The incorporation of tritiated nucleosides and of an amino acid was followed autoradiographically.2. After hypoglossal axotomy in the adult rat hypertrophy of astrocytes of the hypoglossal nucleus occurred in a biphasic manner. The first phase lasted from days 1-10 and was accompanied by a small degree of astrocytic hyperplasia, and the second from days 20-80. Hypertrophy of oligodendrocytes accompanied the second phase of the astrocytic response.3. When severed axons failed to reinnervate denervated muscle, the second phase of the astrocytic response was markedly reduced and the hypertrophy of oligodendrocytes did not occur.4. If the severed axons re-innervated denervated muscle after a controlled delay, the second phase of the astrocytic response and the oligodendroglial hypertrophy was also delayed.5. Injection of botulinum toxin into the tongue caused changes in astrocytes and oligondendrocytes closely resembling those found after axotomy.6. Transient astrocytic hypertrophy occurred in the uninjured right hypoglossal nucleus, and had a different time course to the changes occurring on the injured side.7. The results are discussed in relation to changes in the metabolism and to alterations in the dendritic fields of injured neurones, previously measured in these circumstances.

Animals↗
PubMedDate not supplied

Denervation hypertrophy of muscle: MR features.

OBJECTIVE: Denervation hypertrophy is an entity well recognized in the neurology literature, but with little mention in the radiology literature. Denervation hypertrophy occurs when a muscle paradoxically enlarges rather than atrophies in response to loss of innervation. The purpose of this report is to describe the MR appearance of true hypertrophy and pseudohypertrophy of muscle following denervation. MATERIALS AND METHODS: The clinical data and MRI findings in three patients with muscle enlargement due to denervation hypertrophy are reviewed retrospectively. Two women and one man aged 19-80 years were included. Denervation resulted from spinal stenosis in one patient, a herniated thoracic disc in another, and spina bifida with a tethered cord in the third. RESULTS: True hypertrophy of a single muscle was seen in one patient and pseudohypertrophy of two muscles was present in one patient. One patient had one muscle with true hypertrophy and one muscle with pseudohypertrophy. Electromyographic examination was performed and was consistent with denervation in two patients. Biopsy confirmation of denervation was obtained in two patients. All five abnormal muscles exhibited increased volume, well defined margins, and normal contour. In true hypertrophy the enlarged muscle was isointense with normal muscle on all MRI sequences. In pseudohypertrophy the MRI appearance was consistent with an excessive amount of fat interspersed throughout normal muscle. CONCLUSION: Magnetic resonance in these cases established muscle hypertrophy rather than neoplasm as the cause of a palpable mass. If muscle hypertrophy or pseudohypertrophy is seen on an MR examination of an enlarged extremity, the possibility of an underlying neurologic process should be considered.

Adult↗
PubMed1999

A substituted dextran enhances muscle fiber survival and regeneration in ischemic and denervated rat EDL muscle.

Ischemia and denervation of EDL muscle of adult rat induce a large central zone of degeneration surrounded by a thin zone of peripheral surviving muscle fibers. Muscle regeneration is a complex phenomenon in which many agents interact, such as growth factors and heparan sulfate components of the extracellular matrix. We have shown that synthetic polymers, called RGTA (as regenerating agents), which imitate the heparan sulfates, are able to stimulate tissue repair when applied at the site of injury. In crushed muscles, RGTA were found to accelerate both regeneration and reinnervation. In vitro, RGTA act as protectors and potentiators of various heparin binding growth factors (HBGF). It was postulated that in vivo their tissue repair properties were due in part to an increase of bioavailability of endogenously released HBGF. In the present work, we show that ischemic and denervated EDL muscle treated by a unique injection of RGTA differs from the control after 1 wk in several aspects: 1) the epimysial postinflammatory reaction is inhibited and the area of fibrotic tissue among fibers is reduced; 2) the peripheral zone, as measured by the number of intact muscle fibers, was increased by more than twofold; and 3) In the central zone, RGTA enhances the regeneration of the muscle fibers as well as muscle revascularization. These results suggest that RGTA both protects muscle fibers from degeneration and preserves the differentiated state of the surviving fibers. For the first time it is demonstrated that a functionalized polymeric compound can prevent some of the damage resulting from muscle ischemia. RGTA may therefore open a new therapeutic approach for muscle fibrosis and other postischemic muscle pathologies.

Animals↗
PubMed1985

Changes in the ionic currents sensitivity to inhibitors in twitch rat skeletal muscles following denervation.

Under voltage clamp conditions, using the double mannitol gap technique, ionic currents developed by fast (e.d.l.) and slow (soleus) twitch muscle fibers of the rat were analysed at different times following denervation and the results compared with those obtained in normal cells. In slow fibers, denervation caused the appearance of a new population of TTX-resistant Na+ channels (dissociation constant K2 = 2,800 nM) compared with the normal TTX-sensitive Na+ channels (K1 = 9 nM). This new population of Na channels appeared in 5 days and contributed about 32% of the total Na conductance. Denervated fast fibres developed a slow component in the delayed outward current which was found to be typical of slow innervated muscles. This component appeared 5 to 20 days after nerve section. These changes are associated with modifications of potassium channels' sensitivity for specific inhibitors (TEA and 4-AP). After denervation, the delayed outward current in the two types of muscles becomes resistant to 4-AP whereas TEA, which blocks the total delayed outward current in innervated fibers (dissociation constant of 21.4 mM) becomes more effective in blocking the fast component (dissociation constant of 0.61 mM) and less effective in blocking the slow component in denervated cells. The analysis of the characteristics of the TEA sensitive and TEA insensitive components of the outward current leads to the proposal that these components were related to the fast and to the slow components previously described in fast and slow twitch mammalian skeletal muscles.

4-Aminopyridine↗