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PubMed2002

Reinnervation of denervated muscle in a split-nerve transfer model.

This study was performed to quantify the reinnervation of denervated muscle in a split-nerve transfer model and to determine any possible downgrading effects on the donor nerve and its end organ. Fifty-four adult Wistar rats weighing 200 to 250 g were used. The experimental design consisted of two groups. The motor nerve branch to the anterior tibial muscle and gastrocnemius muscle of the right hind limb were dissected in all rats. In the experimental group (N = 36), the motor nerve branch of the tibial nerve to the gastrocnemius muscle was exposed, cut, and ligated. The motor nerve branch to the anterior tibial muscle was split and transected longitudinally, and the medial half was routed posteriorly. End-to-end neural anastomosis was performed between this medial half of the split nerve and the distal stump of the gastrocnemius nerve. In the control group (N = 18), while the same surgical preparation was performed, the motor nerve branch to the anterior tibial muscle and gastrocnemius nerve were exposed and transected, and the nerve endings were ligated, but neural anastomosis was not performed between these nerves. The left hind limb of all rats served as a normal comparison side without any surgical intervention. Both of the groups were divided into three subgroups (12 rats each for the experimental groups and 6 rats each for the control group) to evaluate the results after periods of 1, 3, and 6 months. Electromyography, light microscopic and morphometric examination, and muscle weight measurements were used to document the results. Although stimulation of the peroneal and tibial nerves did not produce any compound muscle action potential (CMAP) recordings from either the anterior tibial or the gastrocnemius muscle in the control group, the normalized CMAP areas of the tibial nerve were (mean +/- standard deviation) 16.2 +/- 30.8% in the 1-month group, 63.4 +/- 34.7% in the 3-month group, and 72.4 +/- 16.3% in the 6-month group. For the peroneal nerve, the normalized CMAP areas were 17.0 +/- 32.2%, 53.4 +/- 29.4%, and 54.4 +/- 14.5% for the 1-, 3-, and 6-month groups in the experimental groups respectively. A high number of regenerating myelinated nerve fibers was identified in the distal part of the coapted motor nerve branch to the gastrocnemius muscle. The average number of myelinated fibers in the lateral half of the split nerve in the experimental group was 15,108 fibers per square millimeter, 14,167 fibers per square millimeter, and 19,830 fibers per square millimeter at months 1, 3, and 6 respectively. The average number of fibers proximal to the nerve anastomotic site was 15,423 fibers per square millimeter, 19,200 fibers per square millimeter, and 20,774 fibers per square millimeter. Distal to the nerve anastomotic site, the number of myelinated fibers was 17,941 fibers per square millimeter, 18,885 fibers per square millimeter, and 18,895 fibers per square millimeter at 1, 3, and 6 months respectively. There were no myelinated fibers in the control group sections. There were significant differences in muscle weight between the experimental and control groups at the end of month 6. The difference between the experimental side and the untouched normal healthy side was not significant in the weight measurements of both muscles. The results show acceptable reinnervation by split-nerve transfer with minimal functional impairment of the donor muscle. This study confirms that split-nerve transfer is a reliable method of reconstruction for paralyzed muscle with minimal donor area morbidity.

Animals↗
PubMed1988

Terminal sprouting in partially denervated muscle of the mouse: a scanning electron microscopic study.

Terminal sprouting in the mouse gastrocnemius muscle was examined by scanning electron microscopy after partial denervation. After one of the two muscle nerves in the medial head was cut, terminal sprouts arose from the outer edge of the intact motor endplates and grew out onto a connective tissue layer on the muscle fibres. The sprouts were very slender along their length, although some had a varicose appearance. The terminal tip of the sprouts was swollen in an amoeba-shaped configuration, forming a growth cone. Several shorter projections surrounded the initial part of a long terminal sprout, whilst in the centre the varicosity had a spindle shape like a diamond: the former most likely indicated the processes of a Schwann cell, and the latter may be a Schwann cell soma. Such swelling patterns suggested that the sprout initially grew out from a growth cone and then the Schwann cells migrated into the growing sprout. The sprouts had no synaptic connections with their muscle fibres at least during the growth cone-forming stage. No structural changes to guide the growing terminal sprouts could be recognized on the flat surface of the muscle fibres.

Animals↗
PubMed2003

Inhibition of caspases promotes long-term survival and reinnervation by axotomized spinal motoneurons of denervated muscle in newborn rats.

We examined whether (1) a pan-caspase inhibitor, Boc-D-FMK, exerts long-term neuroprotective effects on spinal motoneurons (MNs) after root avulsion in neonatal rats and (2) whether the rescued spinal MNs regenerate their axons into a peripheral nerve (PN) graft and reinnervate a previously denervated target muscle. Eight weeks after root avulsion, 67% of spinal MNs remained in the Boc-D-FMK-treated group, whereas all MNs died in the sham control group. By 12 weeks postinjury, however, all Boc-D-FMK treated MNs died. In the regeneration experiment, a PN graft was implanted at different times after injury. The animals were allowed to survive for 4 weeks following the operation. Without caspase inhibition, MNs did not regenerate at any time point. In animals treated with Ac-DEVD-CHO, a caspase-3-specific inhibitor, and Boc-D-FMK, 44 and 62% of MNs, respectively, were found to regenerate their axons into a PN graft implanted immediately after root avulsion. When the PN graft was implanted 2 weeks after injury, however, MNs failed to regenerate following Ac-DEVD-CHO treatment, whereas 53% of MNs regenerated their axons into the graft after treatment with Boc-D-FMK. No regeneration was observed when a PN graft was implanted later than 2 weeks after injury. In the reinnervation study, injured MNs and the target biceps muscle were reconnected by a PN bridge implanted 2 weeks after root avulsion with administration of Boc-D-FMK. Eight weeks following the operation, 39% of MNs reinnervated the biceps muscle. Morphologically normal synapses and motor endplates were reformed in the muscle fibers. Collectively, these data provide evidence that injured neonatal motoneurons can survive and reinnervate peripheral muscle targets following inhibition of caspases.

Animals↗
PubMed2006

Muscle denervation promotes opening of the permeability transition pore and increases the expression of cyclophilin D.

Loss of neural input to skeletal muscle fibres induces atrophy and degeneration with evidence of mitochondria-mediated cell death. However, the effect of denervation on the permeability transition pore (PTP), a mitochondrial protein complex implicated in cell death, is uncertain. In the present study, the impact of 21 days of denervation on the sensitivity of the PTP to Ca2+-induced opening was studied in isolated muscle mitochondria. Muscle denervation increased the sensitivity to Ca2+-induced opening of the PTP, as indicated by a significant decrease in calcium retention capacity (CRC: 111 +/- 12 versus 475 +/- 33 nmol (mg protein)(-1) for denervated and sham, respectively). This phenomenon was partly attributable to in vivo mitochondrial and whole muscle Ca2+ overload. Cyclosporin A, which inhibits PTP opening by binding to cyclophilin D (CypD), was significantly more potent in mitochondria from denervated muscle and restored CRC to the level observed in mitochondria from sham-operated muscles. In contrast, the CypD independent inhibitor trifluoperazine was equally effective at inhibiting PTP opening in sham and denervated animals and did not correct the difference in CRC between groups. This phenomenon was associated with a significant increase in the content of the PTP regulating protein CypD relative to several mitochondrial marker proteins. Together, these results indicate that Ca2+ overload in vivo and an altered expression of CypD could predispose mitochondria to permeability transition in denervated muscles.

Animals↗
PubMed1978

Increased cyclic GMP in the end-plate region of denervated frog muscle.

Denervated frog sartorius muscles showed an approximately 2--3 fold increase of cyclic GMP in their end-plate rich regions which did not appear up to 5 weeks after denervation in the normally end-plate-free pelvic region. No increase in cyclic AMP was seen in these preparations. The results suggest that the increase of cyclic GMP is related to processes specific to the region in which end plates are normally present.

Acetylcholine↗
PubMedDate not supplied

[Analysis of changes in the membrane potential of denervated muscle].

Quantitative analysis of the experimental data presented in the previous paper has shown that the electrogenic pump component of the membrane potential of muscle fibres on the third day after denervation is in the average 8.7 mV, and the diffusion component--12.9 mV lower than that in the normal fibres. It is due to a decrease of the stechiometric coefficient of Na+,K+-pump at denervation from 2.15 to 1.3 and to a change of the passive ionic permeability: at denervation permeability for Na+ increases from 0.52.10(-7) to 0.67.10(-7) cm.sec-1, and for K+ decreases from 0.75.10(-5) to 0.53.10(-5) cm.sec-1.

Animals↗
PubMed1975

Regneration in free grafts of normal and denervated muscles in the rat: morphology and histochemistry.

Intact soleus and extensor digitorum longus muscles in the rat were freely grafted to the contralateral leg after either no preliminary treatment or 14 days prior denervation. Normal muscle grafts during the first week were characterized by a central zone of degenerating original muscle fibers (disappearing by 7-9 days) and a peripheral zone, containing regenerating muscle as well as small numbers of surviving original muscle fibers. A radial gradient of regeneration was establihed, with more mature muscle at the periphery and less mature muscle toward the center. Denervated grafts were characterized by rapid degeneration (within 2-3 days) of original muscle fibers in the central area, rapid appearance of regenerating muscle fibers (e.g. cross striations by 5 days) with uniform levels of differentiation throughout the graft and larger numbers of surviving original muscle fibers at the periphery. During the first week, stages of muscle differentiation in denervated grafts were attained 1-2 days earlier than comparable stages in normal grafts. Later stages of muscle differentiation were similar in both types of grafts. Histochemical studies revealed a loss of enzyme activity (phosphorylase, ATPase and SDH) in the center of early (2-4-day) normal and denervated grafts. Denervated grafts, however, possessed a thicker peripheral rim of enzymatically active surviving muscle fibers than normal grafts. In both types of grafts the old muscle fibers in the center were replaced by enzymatically active regenerating muscle fibers which stained uniformaly (ATPase) until 30 days. By 60 days a mixed fiber pattern had developed. Muscle spindles were found within the grafts.

Adenosine Triphosphatases↗
PubMed1992

Experimental study of denervated muscle atrophy following severance of posterior rami of the lumbar spinal nerves.

The morphologic changes in denervation atrophy of paravertebral muscles after severance of the posterior rami in cats were investigated, using histochemical methods and electromyography. Using a paraspinal approach, three branches of the posterior rami on the left side were cut under microscopy at one, two, or three levels (L2 approximately L4). Muscle atrophy was evaluated, using the percent wet weight and the percent diameter of muscle fibers as parameters. Myosine ATPase stain was used to observe reinnervation. Four weeks after surgery, the range and severity of muscle atrophy increased proportionally to the number of posterior rami severed. Muscle atrophy was revealed at one or two levels caudal to the injured nerve level. At 12 and 24 weeks, muscle atrophy recovered gradually. In more than two-level injury groups, however, recovery of percent wet weight reached up to 80% even after 24 weeks, despite the fact of reinnervation demonstrated in some parts of the denervated muscles.

Animals↗
PubMed1993

Upstream sequences of the myogenin gene convey responsiveness to skeletal muscle denervation in transgenic mice.

Myogenin, as well as other MyoD-related skeletal muscle-specific transcription factors, regulate a large number of skeletal muscle genes during myogenic differentiation. During later development, innervation suppresses myogenin expression in the fetal hind limb musculature. Denervation of skeletal muscle reverses the effects of the nerve, and results in the reactivation of myogenin expression, as well as of other embryonic muscle proteins. Here we report that myogenin upstream sequences confer tissue- and developmental-specific expression in transgenic mice harboring a myogenin/chloramphenicol acetyltransferase (CAT) reporter construct. Using in situ hybridization to analyze serial sections of E12.5 embryos, we found colocalization of CAT and endogenous myogenin transcripts in the primordial muscle of the head and limbs, in the intercostal muscle masses, and in the most caudal somites. Later in development, we observed that the expression of the transgene and endogenous myogenin gene continued to be restricted to skeletal muscle but decreased shortly after birth; a period that coincides with the innervation of secondary myotubes. Furthermore, denervation of the mouse hind limbs induced a 10-fold accumulation of CAT and endogenous myogenin transcripts by 1 day after sciatic nerve resection; a 25-fold increase was observed by 4 days after denervation. Interestingly, we observed that the accumulation of CAT enzyme activity lagged considerably with respect to the increase in CAT transcripts. Our results indicate that the cis-acting elements that temporally and spatially confine transcription of the gene during embryonic development, and that mediate the responses to innervation and denervation of muscle, lie within the upstream sequences analyzed in these studies.

Animals↗
PubMed1987

[Effect of acetylcholine and carbamylcholine on the resting membrane potential of denervated muscle in the rat].

The decrease of resting MP after denervation in diaphragm muscle of the rat was studied in vitro. Transitory activation of Na+,K+-pump by carbamylcholine, acetylcholine or adrenaline hyperpolarized the muscle fiber membrane but did not compensate the postdenervation fall of the MP. Similarly, the permanent presence of carbamylcholine at culturing media did not prevent the development of changes in the MP after denervation. The decrease of MP was accompanied by spontaneous release of acetylcholine for 24 hrs. Synaptic acetylcholine seems to play no obvious role in neurotrophic control of the resting MP.

Acetylcholine↗
PubMed1978

Firing rates of human motor units in partially denervated muscle.

Single motor unit firing rates were measured from the first dorsal interosseous muscle (FDI) of normal subjects and patients with partial denervation of that muscle. Motor unit discharges were recorded at various levels of voluntary, stationary, isometric contraction of the FDI. The mean increase in firing rate associated with an increased muscle tension of 100 gm was significantly greater in severely weak muscle. However, when an "adjustment" was made for the degree of weakness, reduced firing rate responses were observed which correlated with the degree of muscle weakness.

Electromyography↗
PubMed1999

Adaptive changes in motor activity associated with functional recovery following muscle denervation in walking cats.

In this investigation we examined the changes in the pattern of activity in the medial gastrocnemius (MG) muscle in walking cats following transection of the nerves innervating synergist muscles (lateral gastrocnemius, soleus, and plantaris). Immediately following the nerve transections, there was a large increase in ankle flexion during early stance (from approximately 10 to approximately 30 degrees ) and a marked increase in the magnitude of the MG bursts during stance. We attribute this increase in the magnitude of the MG bursts to an increase in afferent feedback from the abnormally stretched MG muscle. During the week after the nerve transections, there was a progressive decrease in ankle yield. This improvement in ankle function was correlated with an increase in magnitude of two components of the MG bursts; the initial component starting during late swing and ending approximately 40 ms after ground contact, and a late component associated with stance. The time courses of the increases in the initial and late components of the MG bursts were different. Large and significant increases in the late component occurred the day after the nerve transections, whereas increases in the initial component occurred more gradually. This difference in time course was reflected in the kinematics of ankle movement. Over the first few days after the nerve transections, improvement in ankle movement occurred primarily late in the stance phase, and there was little change in ankle yield during early stance. At 1 wk, however, there was a significant reduction in ankle yield during early stance. This decreased yield was most likely due to an increase in stiffness of the MG muscle at the time of ground contact resulting from the increase in magnitude of the initial component of the MG bursts. The increases in the magnitude of the initial and late components of the MG bursts, as well as the improvement in ankle function, depended on use of the leg. All these changes were delayed by immobilizing the leg for 6 days in an extended position. We discuss possible mechanisms underlying the increase in the magnitude of the MG bursts and propose that proprioceptive signals from the stretched MG muscles provide an error signal for rescaling the magnitude of the centrally generated initial component. Our data support the concept that proprioceptive feedback functions to scale the magnitude of feed-forward motor commands to ensure they are appropriate for the biomechanical properties of the musculoskeletal system.

Adaptation, Physiological↗
PubMed1996

Type-specific changes in fibre size and satellite cell activation following muscle denervation in two strains of turkey (Meleagris gallopavo).

Morphological features and the chronology of muscle changes after denervation were studied over a 21 d period in 2 heavy (HW) and light-weight (LW) strains of 6-wk-old male turkeys. The atrophy of tibialis cranialis, gastrocnemius lateralis and plantaris muscles was apparent at d 3 after denervation. By d 21 the weight of these muscles had reached 45-60% of that of nondenervated contralateral muscle. Cellular lesions, such as irregularities in mitochondrial distribution or coagulative necrosis with fragmentation and lysis associated with moderate infiltration of inflammatory cells, were similar in both strains. Ten days after denervation, immunolabelling of a proliferating cell nuclear antigen (PCNA) expressed during the G1 and S phase of the cell cycle revealed satellite cell activation in denervated muscles. The number of satellite cells activated at d 21 was markedly greater in the HW than LW strain. Morphometric analysis revealed that fast twitch (type II) fibres were atrophied after denervation, whereas slow-twitch (type I) and slow tonic (type III) fibres were hypertrophied from d 10. Hypertrophy occurred more rapidly in the LW than HW strain.

Animals↗
PubMed1976

Experimental myasthenia in Balb/c mice immunized with rat acetylcholine receptor from rat denervated muscle.

A new model of an autoimmune disease of the neuromuscular junction was obtained by injection of acetylcholine receptor purified from rat denervated muscles into Balb/c mice. Anti-rat, then anti-mouse acetylcholine receptor antibodies, appear in mouse serum during the immunization procedure. Electrophysiological investigations performed on immunized mice reveal a neuromuscular block similar to that found in myasthenia gravis. Not a single mouse with objective signs of muscular weakness was lacking anti-mouse acetylcholine receptor antibodies but no correlation was found between their level and the severity of the disease.

Action Potentials↗
PubMed1975

Studies on the mechanism of fibrillation potentials in denervated muscle.

1. Intracellular electrodes were used to study the origin of fibrillation potentials in chronically denervated rat muscle. 2. Fibrillation potentials were observed to start from spontaneous biphasic membrane potential oscillations. Each action potential was followed by an after-hyperpolarization which in turn served as a pre-potential for the next spike. The critical level (threshold) for the initiation of the first spike in a train was lower than that of the next and subsequent spikes. 3. A correlation was found between the level of membrane potential and the critical level for action potential generation. This relation was most marked around the resting membrane potential (minus 60 to minus 80 mV) where 10 mV hyperpolarization caused a 9 m V increase in the critical potential level. At higher membrane potentials the correlation was less pronounced. In innervated muscles a similar correlation existed but it was less marked and was present only at membrane polarizations below the resting potential. 4. Increasing the external calcium concentration from 2 to 8 mM reduced the membrane potential-critical level relationship in denervated fibres towards that of innervated ones. 5. As critical level changes with membrane hyperpolarization, the rate of rise of the action potential increased, suggesting a progressive removal of sodium inactivation. 6. It is suggested that a mechanism similar to anode break excitation is important for the induction and maintenance of fibrillation potentials.

Action Potentials↗