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PubMed1989

Denervated single myofibers: neurite interactions and synaptic molecules.

As a first step in defining the molecular cues that may be important for reinnervation of long-term denervated muscle, single adult rat muscle fibers that had been denervated from 2 to 24 months in vivo were maintained in culture for 5 days. Embryonic ventral spinal cord explants were added to some of these cultures. Interactions of neurites with individual short-term (up to 5 months) and long-term (17-24 months) denervated muscle fibers were compared with neurite interactions in cultures of young adult muscle fibers (from 3 to 5-month-old rats) or aged muscle fibers (from 17 to 26-month-old rats). We found the following. (1) Three molecules that are found at the neuromuscular junction (NMJ)--acetylcholinesterase (AChE), acetylcholine receptors (AChRs), and gelasmin (an acetylcholine receptor clustering factor that is found enriched at NMJ of adult muscle)--were reduced with increasing periods of denervation but not with aging. (2) The number of neurite contacts at junctional regions of muscle fibers that were formed and maintained on cultured muscle fibers depended on denervation time of the muscle in vivo; very few contacts were made or maintained on long-term denervated fibers. (3) Gelasmin, but not AChE or AChRs, was found at points of neurite contact on all muscle fibers examined, raising the possibility that it may serve as a cue for reinnervation and that its loss from long-term denervated muscle may be, at least in part, involved in the failure of neurite contacts to be made or maintained in culture and possibly in vivo.

Acetylcholine↗
PubMed1983

Reinnervation is followed by necrosis in previously denervated skeletal muscles of dystrophic hamsters.

Hind leg muscles of dystrophic hamsters were continually denervated by multiple crushes of the sciatic nerve to as long as 93 days of age. In these muscles, the prevalence of centronucleated fibers which is a cumulative index of prior necrosis, remained very low. In control dystrophic muscles the prevalence of centronucleated fibers increased steadily to approximately 80% where it leveled off. By omitting further crushes in other groups of animals, previously denervated muscles became adequately reinnervated. In the reinnervated muscles the prevalence of centronucleated fibers steadily increased throughout the necrotic phase of dystrophy at a rate that was comparable to corresponding stages of the natural history of the disease. These experiments indicated that continued denervation was effective in negating skeletal muscle fiber necrosis throughout the necrotic phase and that the electromechanical activity of muscle fibers which allows muscle fiber necrosis was not a time-locked factor.

Animals↗
PubMed1987

Neural determination of muscle fibre numbers in embryonic rat lumbrical muscles.

The generation and development of muscle cells in the IVth hindlimb lumbrical muscle of the rat was studied following total or partial denervation. Denervation was carried out by injection of beta-bungarotoxin (beta-BTX), a neurotoxin which binds to and destroys peripheral nerves. Primary myotubes were generated in denervated muscles and reached their normal stable number on embryonic day 17 (E17). This number was not maintained and denervated muscles examined on E19 or E21 contained many degenerating primary myotubes. Embryos injected with beta-bungarotoxin (beta-BTX) on E12 or E13 suffered a partial loss of motoneurones, resulting in a reduced number of axons in the L4 ventral root (the IVth lumbrical muscle is supplied by axons in L4, L5 and L6 ventral roots) and reduced numbers of nerve terminals in the intrinsic muscles of the hindfoot. Twitch tension measurements showed that all myotubes in partly innervated muscles examined on E21 contracted in response to nerve stimulation. Primary myotubes were formed and maintained at normal numbers in muscles with innervation reduced throughout development, but a diminished number of secondary myotubes formed by E21. The latter was correlated with a reduction in number of mononucleate cells within the muscles. If beta-BTX was injected on E18 to denervate muscles after primary myotube formation was complete, E21 embryo muscles contained degenerating primary myotubes. After injection to denervate muscles on E19, the day secondary myotubes begin to form, E21 muscles possessed normal numbers of primary myotubes. In both cases, secondary myotube formation had stopped about 1 day after the injection and the number of mononucleate cells was greatly reduced, indicating that cessation of secondary myotube generation was most probably due to exhaustion of the supply of competent myoblasts. We conclude that nerve terminals regulate the number of secondary myotubes by stimulating mitosis in a nerve-dependent population of myoblasts and that activation of these myoblasts requires the physical presence of nerve terminals as well as activation of contraction in primary myotubes.

Animals↗
PubMed1991

Reinnervation of denervated skeletal muscle by central neurons regenerating via ventral roots implanted into the spinal cord.

The reinnervation of denervated skeletal muscle by central axons regenerating via a ventral root implanted into the spinal cord was examined in rats. The 8th thoracic ventral root was severed and its distal end implanted into the ventro-lateral column of the spinal cord via a stab incision. In control animals the root was severed, but was not implanted into the stab incision. After 12-14 months the animals were examined electrophysiologically to determine the presence or absence of motor units in the 8th intercostal muscle which were reinnervated by centrally derived axons regenerating via the implant. Such units were found in implanted animals, but in none of the controls. Evidence that the motor units were reinnervated by central axons included the facts that the units could be activated either, (1) reflexly (i.e. trans-synaptically) by electrical stimulation of the dorsal roots or spinal cord, or (2) pharmacologically by either the intraspinal injection of glutamate or acetycholine, or by the systemic administration of strychnine. Great care was taken to ensure that the only feasible connection between the spinal cord and the 8th intercostal muscle was via the site of implantation. The EMG signals from the motor units were of large amplitude, typical of reinnervated muscle, and their individual activation resulted in discernible contractions of regions of the T8 intercostal muscle. We conclude that regenerating CNS neurons can be guided to innervate denervated skeletal muscle by the implantation of severed ventral roots into the spinal cord. The neuromuscular synapses formed are functional and persistent. The findings may be relevant to the restoration of function after nervous injuries, such as the avulsion of ventral roots.

Animals↗
PubMed2002

Reversal of denervation-induced insulin resistance by SHIP2 protein synthesis blockade.

Short-term muscle denervation is a reproducible model of tissue-specific insulin resistance. To investigate the molecular basis of insulin resistance in denervated muscle, the downstream signaling molecules of the insulin-signaling pathway were examined in intact and denervated soleus muscle of rats. Short-term denervation induced a significant fall in glucose clearance rates (62% of control, P < 0.05) as detected by euglycemic hyperinsulinemic clamp and was associated with a significant decrease in insulin-stimulated tyrosine phosphorylation of the insulin receptor (IR; 73% of control, P < 0.05), IR substrate 1 (IRS1; 69% of control, P < 0.05), and IRS2 (82% of control, P < 0.05) and serine phosphorylation of Akt (39% of control, P < 0.05). Moreover, denervation reduced insulin-induced association between IRS1/IRS2 and p85/phosphatidylinositol (PI) 3-kinase. Nevertheless, denervation caused an increase in PI 3-kinase activity associated with IRS1 (275%, P < 0.05) and IRS2 (180%, P < 0.05), but the contents of phosphorylated PI detected by HPLC were significantly reduced in lipid fractions. In the face of the apparent discrepancy, we evaluated the expression and activity of the 5-inositol, lipid phosphatase SH2 domain-containing inositol phosphatase (SHIP2), and the serine phosphorylation of p85/PI 3-kinase. No major differences in SHIP2 expression were detected between intact and denervated muscle. However, serine phosphorylation of p85/PI 3-kinase was reduced in denervated muscle, whereas the blockade of SHIP2 expression by antisense oligonucleotide treatment led to partial restoration of phosphorylated PI contents and to improved glucose uptake. Thus modulation of the functional status of SHIP2 may be a major mechanism of insulin resistance induced by denervation.

Animals↗
PubMed1992

Changes in myosin and actin filaments in fast skeletal muscle after denervation and self-reinnervation.

1. Myosin and actin filaments of the contractile apparatus of the denervated and self-reinnervated rat leg fast muscle were examined in ultrastructure. In parallel, the total contents of actin and of myosin heavy chains (MHC) were investigated. The results were compared with the corresponding ones in the slow muscle. 2. In the denervated-atrophying fast muscle the myosin filaments disappeared before the actin filaments. However, in contrast to the slow muscle, the local disproportion between the filaments was soon compensated, and their hexagonal arrangement was maintained for about one month after denervation. The contents of MHC and actin decreased, but their ratio remained similar to that in the controls. 3. In the later stage of atrophy the proportion of myosin to actin filaments and the ratio of the corresponding proteins decreased, and the hexagonal arrangement of filaments was disturbed. The denervated fast and slow muscles became similar (in the latter, such changes occurred during the initial weeks after denervation). 4. In the fast muscle recovering after reinnervation (on the third week after denervation) the numbers of myosin and actin filaments, and the contents of the corresponding proteins increased in parallel and the hexagonal arrangement of filaments was maintained (differently than those observed in the slow muscle).

Actins↗
PubMed1989

Evidence that the hypertrophic action of clenbuterol on denervated rat muscle is not propranolol-sensitive.

1. The effect of propranolol on the clenbuterol-induced protein anabolism in innervated and denervated soleus and plantaris muscles of the rat was studied. 2. The response to the beta-agonist, clenbuterol, in both innervated and denervated muscles, was not significantly inhibited by the beta-antagonist, propranolol. 3. The results provide further evidence to suggest that the action of clenbuterol on skeletal muscle protein accretion may not be directly mediated by beta-adrenoceptors.

Animals↗
PubMed1987

The role of frequency in the effects of long-term intermittent stimulation of denervated slow-twitch muscle in the rat.

1. Rat soleus muscle was denervated by sciatic transection and electrically stimulated for periods of between 3 and 9 weeks with intermittent 1 s bursts of pulses. Most of the bursts were either repeated every 90 s and pulses within them had frequencies between 10 and 100 Hz, or had a frequency of 50 Hz and were repeated at intervals between 60 and 600 s. Comparisons were made with continuous stimulation at 10 Hz. 2. At the end of the period of stimulation, isometric twitches and tetani were measured and, in a proportion, also isotonic shortening velocity. 3. Isometric twitch duration (contraction and relaxation) decreased with time of stimulation. Very similar effects were seen in all animals in which intermittent stimulation had been used. There was a significant relationship between the change in twitch duration and the frequency used within the bursts of chronic stimulation, with slightly larger effects at frequencies of 40 and 60 Hz. The lowest burst repetition rate produced the largest effects. 4. It was confirmed that similar changes were found in denervated muscles that were not stimulated, although these changes were smaller and developed more slowly. 5. The extreme loss of tetanic tension induced in the muscle by denervation was reduced by chronic stimulation, with no significant difference between different regimes, although there were small differences which showed the same patterns of effectiveness described for twitch durations. 6. Continuous stimulation at 10 Hz maintained the twitch contraction and relaxation phases at the values found 3 weeks after denervation, that is it prevented secondary shortening of the twitch. Continuous stimulation reduced tension loss but was, perhaps, less effective than intermittent stimulation. 7. Twitch-tetanus ratio increased with denervation with little spontaneous reversal later. Stimulation at all frequencies reduced the ratio, but it did not reach normal values. 8. Isotonic shortening velocity was measured in many of the muscles. Maximum velocity was estimated and normalized by muscle length.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Slow-like electrostimulation switches on slow myosin in denervated fast muscle.

Adult fast and slow skeletal muscles are composed of a large number of fibers with different physiological and biochemical properties that under neuronal control can respond in a plastic manner to a variety of stimuli. Although muscle cells synthesize muscle-specific contractile proteins in the absence of motoneurons, after innervation the neuron controls the particular set of isoforms subsequently synthesized. However, agreement has not been reached on the mechanism, either chemotrophic or impulse-mediated, by which the nerve influences gene expression in the muscle. Here we report the effect on isomyosins of continuous, low-frequency (a protocol mimicking the discharge pattern of the slow motoneuron) direct electrical stimulation of a permanently denervated fast muscle, the extensor digitorum longus of adult rat. After several weeks, unlike sham-stimulated muscle, the stimulated muscle showed a dramatic increase of the slow myosin light and heavy chains. Myosin light chains were identified by two-dimensional gel electrophoresis. The slow myosin heavy chain was clearly distinguished from fast and embryonic types by one-dimensional sodium dodecyl sulfate-polyacrylamide gel electrophoresis and orthogonal peptide mapping. The myosin change could be restricted to a portion of the muscle by the position of the stimulating electrodes. Taking into account the morphologic appearance of the electrostimulated muscle and the large body of evidence demonstrating the absolute dependence of slow myosin on specific innervation, our observations indicate that at least the slow motoneuron influences the isomyosin genes' expression by the kind of activity it imposes on developing muscle fibers.

Animals↗
PubMed1988

Isomyosin changes after functional electrostimulation of denervated sheep muscle.

Isomyosin analyses by biochemical, immunochemical, and histochemical investigations have been carried out in five sheep following unilateral recurrent laryngeal nerve paralysis and direct functional electrostimulation of the denervated cricoarytenoid posterior muscle. Myosin light chains were identified by two-dimensional gel electrophoresis. Myosin heavy chains were analyzed by one-dimensional SDS-polyacrylamide gel electrophoresis. Slow myosin heavy chain was identified by orthogonal peptide mapping and immunochemistry. The stimulation effect at cellular level was determined using adenosine triphosphatase (ATPase) histochemistry. A dramatic increase of the type 1 fiber area (slow, fatigue-resistant fibers) could be seen after many weeks of an increasing regime of low-frequency direct electrical stimulation. Biochemically, the amount of slow myosin was always higher than in normal muscles. Some muscles were transformed almost completely to the slow type. At the time they were studied and with the methods employed, the expression of embryonic isomyosin was not observed. In conclusion, after numerous weeks of maintained functional activity, elicited by direct electrostimulation, the denervated muscle regionally showed areas of hypertrophy or at least lack of atrophy of slow myofibers without major signs of muscle damage.

Animals↗
PubMed1988

Diabetic state-induced modifications of succinylcholine binding mode in the microsomal fractions of mouse skeletal muscles.

The skeletal muscles of alloxan-induced diabetic mice and genetically diabetic KK-CAY mice are hypersensitive to a depolarizing blocker, succinylcholine (SuCh) but not to the competitive antagonist, d-tubocurarine (d-TC). The mechanism by which the action of the depolarizing blocker is modified in the diabetic state was investigated on the binding of 14C-SuCh to the microsomal fraction isolated from mouse skeletal muscles. The Scatchard plot of microsomal preparations from normal ddY mice showed positive cooperativity in SuCh binding, whereas that of the preparations from alloxan-induced diabetic mice as well as genetically diabetic KK-CAY mice lost the positive cooperative interactions. The dissociation constant (Kd) of high affinity site in diabetic muscles was significantly lower than that in non-diabetic ddY muscle. The microsomal fractions from denervated muscles of normal ddY mice maintained weakly positive cooperativity in SuCh binding, and the affinity of SuCh binding in denervated muscles was lower than that of non-denervated muscles. In conclusion, the diabetic state selectively altered the SuCh binding mode. This alteration seems to be closely correlated with the pharmacological hypersensitivity to SuCh.

Alloxan↗
PubMed1984

Improvement of continence by myoplasty of the pelvic floor.

The authors report their experiences with sphincter reconstructions by free muscle transplant using a denervated muscle with its blood supply intact. The transplanted muscle is fixed to the remaining functioning sphincter musculature. New muscle fibres grow from this muscle into the transplanted muscle, allowing the reconstructed sphincter to contract voluntarily as well as reflexively. The operative technique depends on the existing sphincter defect. Free muscle transplantation is preferred if the external sphincter is still partially existing. Eight patients were examined 2 years after the reconstruction operation and the result was very satisfactory. Solid and semi-solid stool could be controlled by all patients. Large muscle transplantations carried out after the method reported by Thompson (1971) are followed by an increased intramuscular scar formation, as was shown by our experiments. A denervated muscle transposition with its own blood supply is therefore preferable. The change of innervation allows the transplanted muscle to perform its new function. In the treatment of congenital sphincter malformations, a larger muscle, i.e. transposition of the denervated gracilis muscle, should be used. This operation was performed in 7 cases of incontinence following operations for rectal atresia and in 1 case of extensive posttraumatic destruction of the sphincter apparatus. In only 1 case was continence for solid stool achieved. In 6 patients there was a temporary control of fluid stools, but under stress all patients with complex sphincter malformations soiled.

Adolescent↗
PubMed1978

Differential response to chick skeletal muscle to denervation. A histopathological study with reference to lipid and lipase distribution.

The effects of denervation on the three gastrocnemii muscle of chick have been studied with regard to the lipid and lipase distribution on the different fibre types, for a maximum period of 8 weeks after unilateral sciatectomy. The observations exhibit a loss of intrafibrillar lipids which is not on account of enhanced lipolytic activity within the muscle fibres. The lipases also exhibit lowered intrafibrillar activity during the corresponding period and may be one of the several lytic enzymes responsible for the degenerative changes in the muscle cells. The differential response of the three muscles, the muscle bundles in each of them and the different fibre types, to denervation, has been explained on the basis of the balance maintained between the trophic and the intrinsic regulatory mechanisms.

Animals↗
PubMed1992

Modulation of prostaglandin E2 synthesis in rat skeletal muscle.

The effect of muscle denervation, inhibitors of protein synthesis, G proteins, and sphingolipids on prostaglandin E2 (PGE2) release by rat soleus muscle in vitro was investigated. To assess the effect of muscle denervation, the sciatic nerve in one hindlimb of rats was interrupted, and soleus muscles from the denervated hindlimb and the contralateral sham (control) hindlimb were excised 1-5 days after surgery. Compared with corresponding sham muscles, PGE2 release by denervated muscles was increased 56, 230, and 435% at 1, 3, and 5 days after denervation, respectively. Protein synthesis inhibitors cycloheximide (10 microM) and puromycin (10 microM) lowered PGE2 release by sham and denervated muscles 62-80%. The release of PGE2 by sham and denervated muscles was not altered by pertussis toxin (1 microgram/ml) but was inhibited 30-51% by AlF4-. Addition of 100 microM guanosine 5'-O-(3-thiotriphosphate) to saponin-permeabilized sham and denervated muscles had only a moderate, if any, stimulatory effect on PGE2 release. This effect was not counteracted by 1 mM guanosine 5'-O-(2-thiodiphosphate). Increasing muscle ceramide concentration by incubation with sphingomyelinase (100 mU/ml) increased PGE2 release by sham and denervated muscles 43 and 157%, respectively. Because degradation of ceramides yields sphingosine, the effect of sphingosine was also tested. Sphingosine (25 microM) increased PGE2 release by sham and denervated muscles 139 and 187%, respectively, without affecting muscle viability, as assessed by the release of lactate dehydrogenase. The data indicate that muscle denervation, treatment with sphingomyelinase, and sphingosine stimulate, whereas inhibitors of protein synthesis inhibit PGE2 synthesis by muscle.

Aluminum↗
PubMed1989

[An ultrastructural study of the neuromuscular junctions of the cat intrinsic laryngeal muscles. I. Denervation and reinnervation].

Morphological changes of the neuromuscular junctions induced by denervation and reinnervation have been investigated electronmicroscopically using cat intrinsic laryngeal muscles. Two experiments were performed: 1. simple transection of the unilateral recurrent laryngeal nerve at the level of the second tracheal ring; 2. neurorrhaphy immediately after the transection at the same level. 1. All the ipsilateral intrinsic laryngeal muscles except for the cricothyroid muscle were denervated 48 hours after the transection of the recurrent laryngeal nerve. In the denervated neuromuscular junctions some primary synaptic clefts were narrowed and others were flattened, while the secondary synaptic clefts were structurally preserved. 2. Some of the regenerating axons returned to the neuromuscular junctions 3 weeks after neurorrhaphy, and all the muscle fibres were reinnervated after 6 weeks. The structural features of the reinnervated neuromuscular junctions were as follows; 1) synaptic vesicles of the nerve terminals were more densely observed, 2) the original postsynaptic membranes were only partially in contact with the regenerated nerve terminals. These conditions persisted until 22 weeks after neurorrhaphy, when the appearance of remyelination was found in the vicinity of the neuromuscular junctions. Using an evoked electromyogram, the presence of neuromuscular transmission was observed 3 weeks after neurorrhaphy, indicating that the structural maturation of the neuromuscular junction was not necessary for neuromuscular transmission.

Animals↗
PubMed1985

Contractile properties of cat motor units enlarged by motoneurone sprouting.

The fast-twitch flexor digitorum longus (FDL) muscle was partially denervated by a unilateral section of the L7 ventral root. After approximately 100 days the isometric, force-velocity and histochemical properties of single motor units from the partially denervated muscle were determined. The diameter of the nerve axons supplying the muscle were also examined. The extrapolated maximum speed of sarcomere shortening (Vmax) of the enlarged motor units was significantly less than that of the control whole muscle Vmax. It is concluded that the motoneurone is capable of expanding its territory and therefore its tension generating capability without any apparent change in axonal diameter. In addition, the intrinsic properties of the muscle fibres are altered.

Animals↗
PubMed1998

Neuronal nitric oxide synthase inhibitor, 7-nitroindazole, delays motor dysfunction and spinal motoneuron degeneration in the wobbler mouse.

Gene mutations of superoxide dismutase (SOD) have been discovered in familial amyotrophic lateral sclerosis (ALS). Neuronal nitric oxide synthase (NOS), endothelial NOS and 3-nitrotyrosine immunoreactivities are selectively increased in the spinal motoneurons of sporadic ALS. Other study suggests that 3-nitrotyrosine immunoreactivity is enhanced in the spinal motoneurons of sporadic and familial ALS patients. The hypothesis is postulated that increased production of radical species, such as superoxide and peroxynitrite, may cause motoneuron degeneration in ALS. There are increased amounts of nitric oxide and SOD hypoactivities in the brain and spinal cord of wobbler mice. NOS is also induced in the vacuolated spinal motoneurons or axons in this animal. Free radicals might contribute to the pathogenesis of wobbler mouse motoneuron disease. Lecithinized SOD treatment has retarded the progression of this disease. This evidence allowed us to determine whether NOS inhibitors delay progression of wobbler mouse motoneuron disease. After clinical diagnosis at age 3-4 weeks, wobbler mice were injected with intraperitoneal non-selective NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME, 50 mg/kg), two doses of neuronal NOS inhibitor, 7-nitroindazole (5 or 50 mg/kg) or a vehicle solution, daily for 4 weeks in a blind fashion. In comparison with vehicle, 7-nitroindazole-treated mice potentiated grip strength and attenuated deformities in the forelimbs. 7-Nitroindazole treatment increased the biceps muscle weight, reduced denervation muscle atrophy, and suppressed degeneration of spinal motoneurons. To a lesser degree, L-NAME-treated mice displayed slowed progression of disease. The present studies indicate that neuronal NOS inhibitor may be a candidate for promising therapy in lower motoneuron disease or motor neuropathy.

Amyotrophic Lateral Sclerosis↗