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PubMed2000

Proteomic analysis of the atrophying rat soleus muscle following denervation.

A proteomic analysis was performed comparing normal rat soleus muscle to denervated soleus muscle at 0.5, 1, 2, 4, 6, 8 and 10 days post denervation. Muscle mass measurements demonstrated that the times of major mass changes occurred between 2 and 4 days post denervation. Proteomic analysis of the denervated soleus muscle during the atrophy process demonstrated statistically significant (at the p < 0.01 level) changes in 73 soleus proteins, including coordinated changes in select groups of proteins. Sequence analysis of ten differentially regulated proteins identified metabolic proteins, chaperone and contractile apparatus proteins. Together these data indicate that coordinated temporally regulated changes in the proteome occur during denervation-induced soleus muscle atrophy, including changes in muscle metabolism and contractile apparatus proteins.

Animals↗
PubMed1996

Increased expression of dystrophin, beta-dystroglycan and adhalin in denervated rat muscles.

To evaluate a potential regulatory role of the nerve, the distribution and expression of dystrophin, of beta-dystroglycan (43DAG) and adhalin (50DAG), two of the dystrophin-associated proteins and utrophin (dystrophin related protein or DRP) were studied in rat muscles after 2 weeks of denervation. We found that dystrophin, beta-dystroglycan and adhalin were overexpressed in denervated muscle, whereas utrophin did not increase and was found only in the post-synaptic membrane. The study of the distribution of dystrophin in the sarcolemma of single muscle fibres indicates that the molecular organization of dystrophin was maintained after denervation. Dystrophin in addition of forming a scaffold around the fibre was found around the clusters of AChR that reappeared in the extra-synaptic membrane after denervation. Also beta-dystroglycan colocalises at these clusters. These results suggest that the increase in dystrophin, beta-dystroglycan and adhalin is correlated with the reappearance of AChRs in the extra synaptic membrane.

Animals↗
PubMed1997

Na+ channel and acetylcholine receptor changes in muscle at sites distant from burns do not simulate denervation.

Muscle weakness and aberrant responses to neuromuscular relaxants after burn injury are associated with upregulation of acetylcholine receptors (AChRs). Typically, these functional, pharmacological, and biochemical changes occur after denervation, in which transcriptionally mediated qualitative changes in AChRs and Na+ channels and of myogenic regulatory proteins MyoD and myogenin also occur. This study in rats, by an examination of changes in the above-enumerated proteins or their transcripts in the gastrocnemius muscle distant from the burn, verifies whether a denervation-like state exists after burns. Scatchard analysis of [3H]saxitoxin binding revealed no changes in the affinity (K(d)) and total number (B(max)) of Na+ channels between control and burn-injured animals at both 7 and 14 days after injury. The mRNA levels of the immature proteins, SkM2 of the Na+ channels and the gamma-subunits of AChRs, the increase of which is pathognomic of denervation, were assessed by Northern analysis and were unchanged. The transcripts of mature Na+ channels, SkM1, were significantly increased at day 14 after the burn (1.24 +/- 0.10 in burn-injured vs. 1.06 +/- 0.12 in sham animals, arbitrary units, P = 0.006). Although MyoD levels were increased in burn-injured animals at 14 days (0.21 +/- 0.02 vs. 0.15 +/- 0.07 arbitrary units, P = 0.05), myogenin levels were unaltered. The absence of changes in AChR transcripts, including alpha-, delta-, and gamma-subunits, indicates that the upregulation of AChR in burns is not transcriptionally mediated. The unaltered levels of transcripts of myogenin, SkM2 of Na+ channels and gamma-subunit of AChR, confirm that there is no denervation-like prejunctional (nerve-related) component to explain the muscle weakness or the upregulation of AChRs at sites distant from burns.

Animals↗
PubMed2000

Analysis for transcript expression of meltrin alpha in normal, regenerating, and denervated rat muscle.

Meltrin alpha (a disintegrin and metalloprotease (ADAM) 12) is a recently discovered molecule of the metalloprotease-disintegrin family which has been shown to participate in myotube formation in vitro and in myogenesis in vivo. In this study we investigated meltrin alpha in regenerating rat muscle, which is a condition where satellite cells (SC) contribute to myofiber growth by fusing with one another and with myotubes or muscle fibers. We studied meltrin alpha mRNA expression by RT-PCR and in situ-hybridization in normal adult muscle, in soleus muscle regenerating for 2, 5, or 10 days, and in muscle which had been denervated 1 week, 4 weeks, or 6 months previously. SC do not fuse after denervation. They detach from the principal muscle fiber. Immunohistochemistry using an antibody against M-cadherin was performed in parallel in order to identify SC. Messenger RNA as revealed by RT-PCR was absent in normal adult muscle, but present in regenerating and also in denervated muscle. Meltrin alpha transcript detected by in situ-hybridization was present in regenerating muscle only, not in normal or denervated muscle. It was localized to SC. Taken together, meltrin alpha is absent in normal muscle, and localized to SC in fusing conditions. After denervation, the transcript is upregulated. However, it is so lowly abundant that it fails to be detected by in situ-hybridization. This expression profile suggests a role for meltrin alpha in the fusion of SC with myotubes or muscle fibers, but not in SC adhesion to the adjacent myofiber in normal adult muscle.

ADAM Proteins↗
PubMed2004

Number of contractions to maintain mass and force of a denervated rat muscle.

Within 5 weeks, denervated extensor digitorum longus (EDL) muscles of rats lose 66% of mass, 91% of force, and 76% of fiber cross-sectional area (CSA). We previously determined the parameters of electrical stimulation for denervated rat EDL muscles to generate tetanic contractions sufficient to maintain mass and force close to control values. Using these parameters, we tested the hypothesis that a range exists for number of contractions per day, below and above which values for mass, maximum force, and fiber CSA are lower than values for innervated control muscles. For 5 weeks, denervated EDL muscles were stimulated to generate between 25 and 5000 contractions daily with contractions separated by constant intervals of rest, repeated 24 h per day. Force was not maintained with fewer than 200 or more than 800 contractions daily, whereas mass and fiber CSA were not maintained with fewer than 50 contractions daily. Protocols of stimulation that maintain muscle mass and force during prolonged periods of denervation may minimize problems clinically associated with denervation atrophy.

Animals↗
PubMed1993

The cell adhesion molecule M-cadherin is specifically expressed in developing and regenerating, but not denervated skeletal muscle.

The spatiotemporal distribution of M-cadherin mRNA has been determined by in situ hybridization in the mouse embryo and in adult skeletal muscle following experimental regeneration and denervation. M-cadherin mRNA is highly tissue specific and is found only in developing skeletal muscle. In contrast, N-cadherin mRNA has a broader tissue distribution in the embryo, being found on both neural elements and skeletal and cardiac muscle. M-cadherin is expressed in the myotomes shortly after they form, along with the myogenic regulatory factor myogenin. M-cadherin is expressed in muscles derived from the myotomes and is detected in forelimb bud precursor cells at embryonic day 11.5. In the latter case M-cadherin expression appears co-ordinately with that of myogenin and cardiac alpha-actin. Shortly before birth, M-cadherin expression is down regulated. M-cadherin can, however, be re-expressed following experimental regeneration of skeletal muscle. Here M-cadherin is transiently expressed on regenerating myoblasts but not myotubes. Following muscle denervation no evidence was found for re-expression of M-cadherin under conditions where there was strong expression of the nicotinic acetylcholine receptor on myofibres. The highly specific tissue distribution and unique developmental profile distinguishes M-cadherin from other cadherins and suggests a role in cell surface events during early myogenesis.

Actins↗
PubMed1989

Antibodies against fetal muscle proteins in serum from patients with amyotrophic lateral sclerosis.

The serum from 30 patients with amyotrophic lateral sclerosis and 30 controls was tested by immunoblot with protein extracts obtained from fetal muscle, adult muscle, and denervated muscle. Results with adult and denervated muscle confirm previous reports that show a lack of particular reactivity of ALS serum when compared with control serum. However, we found reacting bands 5 times more frequently with ALS than with controls in the immunoblot with protein extract from rat fetal muscle; we confirmed reactivity by immunoperoxidase staining in frozen sections of fetal muscle. Our results point to the possibility of an immune reaction in ALS patients against ephemeral proteins of muscle that are present in large quantities at early stages of muscle differentiation and innervation.

Amyotrophic Lateral Sclerosis↗
PubMed1997

Accumulation of muscle ankyrin repeat protein transcript reveals local activation of primary myotube endcompartments during muscle morphogenesis.

The characteristic shapes and positions of each individual body muscle are established during the process of muscle morphogenesis in response to patterning information from the surrounding mesenchyme. Throughout muscle morphogenesis, primary myotubes are arranged in small parallel bundles, each myotube spanning the forming muscles from end to end. This unique arrangement potentially assigns a crucial role to primary myotube end regions for muscle morphogenesis. We have cloned muscle ankyrin repeat protein (MARP) as a gene induced in adult rat skeletal muscle by denervation. MARP is the rodent homologue of human C-193 (Chu, W., D.K. Burns, R.A. Swerick, and D.H. Presky. 1995. J. Biol. Chem. 270:10236-10245) and is identical to rat cardiac ankyrin repeat protein. (Zou, Y., S. Evans, J. Chen, H.-C. Kuo, R.P. Harvey, and K.R. Chien. 1997. Development. 124:793-804). In denervated muscle fibers, MARP transcript accumulated in a unique perisynaptic pattern. MARP was also expressed in large blood vessels and in cardiac muscle, where it was further induced by cardiac hypertrophy. During embryonic development, MARP was expressed in forming skeletal muscle. In situ hybridization analysis in mouse embryos revealed that MARP transcript exclusively accumulates at the end regions of primary myotubes during muscle morphogenesis. This closely coincided with the expression of thrombospondin-4 in adjacent prospective tendon mesenchyme, suggesting that these two compartments may constitute a functional unit involved in muscle morphogenesis. Transfection experiments established that MARP protein accumulates in the nucleus and that the levels of both MARP mRNA and protein are controlled by rapid degradation mechanisms characteristic of regulatory early response genes. The results establish the existence of novel regulatory muscle fiber subcompartments associated with muscle morphogenesis and denervation and suggest that MARP may be a crucial nuclear cofactor in local signaling pathways from prospective tendon mesenchyme to forming muscle and from activated muscle interstitial cells to denervated muscle fibers.

Amino Acid Sequence↗
PubMed2003

[Effect of electric stimulation on denervated skeletal muscle atrophy].

OBJECTIVE: To study the influence of the electric stimulation of denervated muscle atrophy. METHODS: Sixteen SD rats were made the model of denervated skeletal muscle in two lower limbs by cutting off the sciatic nerve and femoral nerve. The right gastrocnemius muscle was stimulated with JNR-II nerve & muscle recovery instrument by skin as the experimental side and the left was not treated as the control side. The muscle histology, ultrastructure, fibrillation potential amplitude, Na(+)-K(+)-ATPase and Ca(2+)-ATPase activities were observed 2 weeks and 4 weeks after operation. RESULTS: Electric stimulation could protect mitochondria and sarcoplasmic reticulum from the degeneration. The reduction rates of muscle cell diameter and cross section in the experimental side were slower significantly than those in control side. There was no influence on fibrillation potential amplitude in the both sides after electric stimulation. The reduction rates of Na(+)-K(+)-ATPase activity in the experimental side were slower 15.59% and 27.38% respectively than those in the control side. The reduction rates of Ca(2+)-ATPase activity in the experimental side were slower 4.83% and 21.64% respectively than those in the control side. CONCLUSION: The electric stimulation can protect muscle histology, electrophysiology and enzymic histochemistry of denervated skeletal muscle from the degeneration. The electric stimulation is an effective method to prevent and treat muscle atrophy.

Animals↗
PubMed2000

Differential adaptation of growth and differentiation factor 8/myostatin, fibroblast growth factor 6 and leukemia inhibitory factor in overloaded, regenerating and denervated rat muscles.

Mice genetically deficient in growth and differentiation factor 8 (GDF8/myostatin) had markedly increased muscle fiber numbers and fiber hypertrophy. In the regenerating muscle of mice possessing FGF6 mutation, fiber remodeling was delayed. Although myostatin and FGF6 may be important for the maintenance, regeneration and/or hypertrophy of muscle, little work has been done on the possible role of these proteins in adult muscle in vivo. Using Western blot and immunohistochemical analysis, we investigated, in rats, the distribution of myostatin, FGF6 and LIF proteins between slow- and fast-type muscles, and the adaptive response of these proteins in mechanically overloaded muscles, in regenerating muscles following bupivacaine injection and in denervated muscles after section of the sciatic nerve. The amounts of myostatin and LIF protein were markedly greater in normal slow-type muscles. In the soleus muscle, myostatin and LIF proteins were detected at the site of the myonucleus in both slow-twitch and fast-twitch fibers. In contrast, FGF6 protein was selectively expressed in normal fast-type muscles. Mechanical overloading rapidly enhanced the myostatin and LIF but not FGF6 protein level. In the regenerating muscles, marked diminution of myostatin and FGF6 was observed besides enhancement of LIF. Denervation of fast-type muscles rapidly increased the LIF, but decreased the FGF6 expression. Therefore, the increased expressions of myostatin and LIF play an important role in muscle hypertrophy following mechanical overloading. The marked reduction of FGF6 in the hypertrophied and regenerating muscle would imply that FGF6 regulates muscle differentiation but not proliferation of satellite cells and/or myoblasts.

Animals↗
PubMed1994

Trophic effect of ciliary neurotrophic factor on denervated skeletal muscle.

The actions and receptor for ciliary neurotrophic factor (CNTF) are largely restricted to cells of the nervous system, although one of the CNTF receptor components, CNTFR alpha, is expressed by skeletal muscle. Here we show that the other CNTF receptor components, LIFR beta and gp130, are also expressed by skeletal muscle and that expression of all three CNTF receptor components is greatly increased in denervated muscle. In vivo, administration of CNTF activates these receptors on skeletal muscle by inducing receptor phosphorylation and immediate-early gene responses. Furthermore, CNTF reduces the denervation-induced atrophy of muscle and attenuates the reduced twitch and tetanic tensions that result from muscle denervation. Our findings reveal that, in addition to its known neurotrophic actions, CNTF exerts myotrophic effects by attenuating the morphological and functional changes associated with denervation of rat skeletal muscle.

Animals↗
PubMedDate not supplied

Satellite cells and myonuclei in neonatally denervated rat muscle.

While it is well know that the percentage of stellite cells in relation to myonuclei rapidly decreases in aneurally regenerating adult muscle, the fate of satellite cells in neonatally denervated muscles has received little attention so far. In the present study, rat tibialis anterior muscles were denervated at birth and analysed after 5, 7 and 10 weeks. At least 400 myonuclei in each muscle were assessed by electron microscopy and the percentage of satellite cell nuclei in relation to the number of myonuclei was calculated. The results indicated that the percentage of satellite cells steeply declines after neonatal denervation and, after 10 weeks, satellite cells were practically lacking in the muscles under analysis. This process of exhaustion of the satellite cell pool appears to be more rapid in developing than in adult muscles.

Animals↗
PubMed1978

Electrical and mechanical activities in the denervated semitendinosus muscle of the frog.

Denervated frog's semitendinosus muscles were studied. No differences in resting potential were found between denervated and control fibres. Spontaneous discharges of fibrillation potentials were recorded from random points along the length of denervated fibres. The frequency of the potentials varied between 2 and 30/sec; the duration of the discharges varied between 5 and 120 sec. Each potential originated from a prepotential, reversed the sign of the membrane potential between 10--20 mV, and was followed by a transient hyperpolarization. The time course of the spontaneous potential produced by a fibre was slower than that of a spike elicited by an electrical pulse applied to the same fibre. After the cessation of a train the fibrillation potentials were replaced by small rhythmic potentials 10--15 mV in amplitude; this activity lasted for periods as long as 7 min. Some reduction of the resting potential was usually observed during the discharge of a train of fibrillation potentials, however, repolarization occurred after the end of electrical activity and a second discharge of full size fibrillation potentials could be observed in most of the fibres. Mechanical activity was not always present. When observed, it was reduced to light movements unable to eject the microelectrode. In general, no one-to-one correlation could be observed between fibrillation potentials and mechanical activity. In those fibres in which the correlation was present, the tension developed by a single fibrillation was less than 0.2/kg/cm2. Some denervated fibres developed tetanus-like contractions, the maximal tension developed by these fibres was less than 1.0 kg/cm2. The data are discussed according to the current ideas on generation of fibrillation potentials.

Action Potentials↗
PubMed1984

Repression of inactive motor nerve terminals in partially denervated rat muscle after regeneration of active motor axons.

The fourth deep lumbrical muscle in the hind foot of adult rats was partially denervated by crushing the sural nerve (s.n.). The denervated muscle fibres became completely reinnervated by sprouts from lateral plantar nerve (l.p.n.) motor axons. By about 20 days after the nerve crush, s.n. motor axons started to reinnervate the muscle. In control muscles, a small proportion of the muscle fibres--about 2.5% of the muscle per motor unit--was reinnervated by s.n. motor axons over the following 20 days. Hence the regenerating terminals were able to re-establish functional synapses, despite the fact that all the muscle fibres were functionally innervated by l.p.n. terminals. When nerve impulse conduction in the l.p.n. was blocked with tetrodotoxin for up to 2 weeks, starting from the time when s.n. axons returned to the muscle, s.n. motor axons retrieved a much larger proportion of the muscle fibres--about 6.5% of the muscle per motor unit. There was a concomitant decrease in the tension produced by the sprouted l.p.n. motor axons. Intracellular recordings showed that many muscle fibres became innervated exclusively by regenerated s.n. motor nerve terminals. Measurements of end-plate potentials suggested that l.p.n. sprouts and the original nerve terminals were eliminated non-selectively. These results suggest that regenerating, active motor nerve terminals have an additional competitive advantage in reinnervating innervated muscles, if the intact terminals are inactive. When the l.p.n. was cut, rather than blocked, extensive reinnervation by the s.n. occurred-about 30% of the muscle per motor unit. This suggests that the absence of an intact nerve terminal in the motor end-plate provides a stronger stimulus than inactivity for synapse formation by regenerating motor axons.

Action Potentials↗
PubMed1996

The effect of succinylcholine on energy metabolism studied by 31P-NMR spectroscopy in rat denervated skeletal muscle.

BACKGROUND: The goals of this study were: (1) to demonstrate the differences of metabolic changes induced by succinylcholine (SCh) administration between normal and denervated muscle by 31P-NMR spectroscopy: (2) to determine whether three kinds of drugs (vecuronium, midazolam and magnesium sulfate) could prevent these metabolic changes. METHODS: Following unilateral sciatic nerve section, 20 male Wistar rats were studied at three-week intervals. After SCh 1 mg.kg-1 was administered intravenously, the changes of the inorganic phosphate/phosphocreatine (Pi/PCr) ratio, the beta ATP/(PCr+Pi) ratio, and intracellular pH were measured by 31P-NMR both in normal and denervated hind limb muscles of 5 rats. The other 15 rats were allocated to the pretreatment groups by the following drugs: vecuronium 0.02 mg.kg-1, midazolam 0.1 mg.kg-1 and magnesium sulfate 60 mg.kg-1. After pretreatment 3 min before SCh administration, we measured the same parameters by 31P-NMR. RESULTS: SCh administration did not change the Pi/PCr ratio in normal muscle, but significantly increased that in denervated muscle (P < 0.05). This increase of the Pi/PCr ratio was also observed in all pretreated groups but was minimal as compared with that in non-pretreatment denervated muscle. CONCLUSION: These data suggested that SCh administration decreased the level of "energy reserve" in denervated muscle, and that this metabolic change was not totally inhibited by vecuronium, midazolam, or magnesium sulfate.

Adenosine Triphosphate↗
PubMed1993

Partial denervation of the medial gastrocnemius muscle results in growth-associated protein-43 immunoreactivity in sprouting axons and Schwann cells.

Regeneration in the mammalian peripheral nervous system following nerve injury is associated with the upregulation of a developmentally regulated phosphoprotein, growth-associated protein-43 (GAP-43), in the injured neurons. We have examined whether uninjured adult neurons also express GAP-43 when they sprout. The model system investigated has been the sprouting induced in the terminal axons of intact motor neurons by a partial muscle denervation. Partial denervation of the medial gastrocnemius muscle in adult rats was produced by resecting the terminal nerve supply to the anterolateral quadrant of the muscle. Three zones could be identified in the motor endplate region of the muscle after such a denervation using protein gene product (PGP) 9.5, calcitonin gene-related peptide and silver staining as axonal markers and S-100 to identify Schwann cells: a normally innervated zone, a totally denervated zone and a border or intermediate zone between the two which contained axons at the endplates with nodal and terminal sprouts. The endplates in the normally innervated zone were GAP-43 negative. In the denervated zone, Schwann cells were GAP-43 positive and had a distinctive appearance with a lack of any normal endplate organization. Endplates in the intermediate zone were GAP-43 immunoreactive. In approximately half, the GAP-43 immunoreactivity was axonal-like, identical to PGP 9.5 in an adjacent section; in the remainder it was Schwann cell-like, identical to S-100 staining. Partial muscle denervation results, therefore, in the appearance of GAP-43 both in axons and Schwann cells in the endplates bordering the denervated zone. The presence of GAP-43 in these cells may contribute to their capacity to sprout.

Acetylcholinesterase↗