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At least 19 recordsLinked to original sources
PubMed1995

Adaptation of nicotinic acetylcholine receptor, myogenin, and MRF4 gene expression to long-term muscle denervation.

Muscle activity alters the expression of functionally distinct nicotinic acetylcholine receptors (nAChR) via regulation of subunit gene expression. Denervation increases the expression of all subunit genes and promotes the expression of embryonic-type (alpha 2 beta delta gamma) nAChRs, while electrical stimulation of denervated muscle prevents this induction. We have discovered that the denervation-induced increases in alpha, beta, gamma, and delta subunit gene expression do not persist in muscles that have been denervated for periods extending beyond a couple of months. However, expression of RNA encoding the epsilon-subunit remains elevated suggesting a return to expression of predominantly adult-type (alpha 2 beta delta epsilon) nAChR in long-term denervated muscles; a finding confirmed by single channel patch-clamp analysis. Since the nAChR subunit genes are regulated by the MyoD family of muscle regulatory factors, and the genes encoding these factors are also induced following short-term muscle denervation, we determined their level of expression in long-term denervated muscle. Although MyoD and myf-5 RNA levels remained elevated, myogenin and MRF4 RNAs were induced only transiently by muscle denervation. Surprisingly, Id-1, a negative regulator of transcription, was gradually induced in denervated muscle with RNA levels peaking about two months after denervation. It is likely that this maintained level of increased Id expression, in conjunction with the returning levels of myogenin and MRF4 expression, account for the reduced level of embryonic receptors in long-term denervated muscle. These changing patterns of gene expression may have important consequences for the ability of muscle to recover function after denervation.

Adaptation, Physiological↗
PubMedDate not supplied

Magnetic resonance imaging examination of denervated muscle.

Denervated muscles due to lumbar radiculopathy, peroneal axonal neuropathy and hypoglossal neuropathy were studied with magnetic resonance imaging (MRI). Denervated muscle was clearly distinguished from normal muscle by its higher intensity signal. Comparison of the resulting signal intensity of the muscle using various imaging parameters suggests an alteration in water macromolecular binding. These preliminary findings indicate that MRI may be useful in the noninvasive in vivo diagnosis and study of the effects of denervation on muscle.

Humans↗
PubMed2000

Identification and characterization of differentially expressed genes in denervated muscle.

Denervation results in a series of changes in skeletal muscle. To elucidate the molecular basis underlying these changes, it is important to identify the profile of altered gene expression in skeletal muscle following nerve injury. In the present study, we have examined the differentially expressed genes in denervated gastrocnemius muscle using RNA fingerprinting by arbitrarily primed PCR. Eight differentially expressed mRNA transcripts have been identified. A bilateral regulatory profile can be observed for the up-regulated genes in both denervated and contralateral control muscle following unilateral sciatic nerve injury. The temporal expression profiles of the denervation-regulated genes in muscle during development, together with their dependency on nerve activity, suggest potential functional roles following nerve injury in vivo. In particular, the identification of two apoptosis-related genes in denervated muscle provides molecular evidence that the apoptotic process is likely to be involved in the intricate changes that lead to muscle atrophy. Our findings not only allow the identification of novel genes, but also suggest possible functions for some known genes in muscle following nerve injury. Taken together, these findings provide important insights into our understanding of the molecular events in denervated muscle and suggest that the differentially expressed genes may play potential roles during muscle denervation and regeneration.

Animals↗
PubMed1987

Clenbuterol, a beta 2-agonist, retards atrophy in denervated muscles.

Denervated soleus, anterior tibialis, and gastrocnemius muscles, but not the extensor digitorum longus, contained 95-110% more protein after 2-3 wk of treatment with the adrenergic beta 2-receptor agonist, clenbuterol, than denervated controls. In addition, the twofold difference in the protein content of denervated solei was paralleled by similar changes in contractile strength and muscle fiber cross-sectional area. In contrast, when the innervated contralateral muscles were examined, the extensor digitorum longus and anterior tibialis showed relatively small increases in protein of 32 and 19%, respectively, whereas the soleus and gastrocnemius were unaffected. The magnitude of the effects of clenbuterol in sparing the mass and functional capacity of denervated muscle suggests that this agent may be important in studies of neuromuscular diseases and disuse atrophy.

Animals↗
PubMed2006

Upregulation of gene encoding adipogenic transcriptional factors C/EBPalpha and PPARgamma2 in denervated muscle.

Muscle denervation induces fatty degeneration in skeletal muscle. However, the possible mechanism(s) remains to be elucidated. To gain insight into the regulation of this process, this study was designed to characterize the expression pattern of genes encoding transcriptional factors that regulate adipogenesis and the terminal differentiation marker of adipocytes in denervated muscle. Female mice underwent surgery to transect the sciatic nerve, and then the gastrocnemius muscles were harvested 5, 10, 20 or 30 days after surgery. The extent of fatty degeneration was assessed as lipid accumulation by Oil Red O staining. The cellular localization of CCCAT/enhancer-binding protein alpha (C/EBPalpha) and peroxisome proliferator-activated receptor gamma2 (PPARgamma2), which play an important role in the regulation of adipocyte differentiation, was assessed by immunohistochemistry. The mRNA levels were analysed using a real-time polymerase chain reaction. After muscle denervation, most muscle fibres atrophied pathologically, and lipid accumulation was observed in the superficial region of the gastrocnemius muscle, suggesting that fatty degeneration occurs in this model. Both C/EBPalpha and PPARgamma2 proteins were observed in the interstitial space of denervated muscle but detected in small amounts in normal muscle. The expression levels of C/EBPalpha and PPARgamma2 were significantly upregulated 30 days after muscle denervation. The expression levels of fatty acid binding protein 4 (FABP4), which reflects fatty acid metabolism, were decreased slightly at 5 and 10 days and then returned to control levels 30 days after muscle denervation. These findings suggest that muscle denervation-induced fatty degeneration may be mediated through C/EBPalpha and PPARgamma2.

Adipogenesis↗
PubMed2000

Insulin-mediated translocation of GLUT-4-containing vesicles is preserved in denervated muscles.

Skeletal muscle denervation decreases insulin-sensitive glucose uptake into this tissue as a result of marked GLUT-4 protein downregulation ( approximately 20% of controls). The process of insulin-stimulated glucose transport in muscle requires the movement or translocation of intracellular GLUT-4-rich vesicles to the cell surface, and it is accompanied by the translocation of several additional vesicular cargo proteins. Thus examining GLUT-4 translocation in muscles from denervated animals allows us to determine whether the loss of a major cargo protein, GLUT-4, affects the insulin-dependent behavior of the remaining cargo proteins. We find no difference, control vs. denervated, in the insulin-dependent translocation of the insulin-responsive aminopeptidase (IRAP) and the receptors for transferrin and insulin-like growth factor II/mannose 6-phosphate, proteins that completely (IRAP) or partially co-localize with GLUT-4. We conclude that 1) denervation of skeletal muscle does not block the specific branch of insulin signaling pathway that connects receptor proximal events to intracellular GLUT-4-vesicles, and 2) normal levels of GLUT-4 protein are not necessary for the structural organization and insulin-sensitive translocation of its cognate intracellular compartment. Muscle denervation also causes a twofold increase in GLUT-1. In normal muscle, all GLUT-1 is present at the cell surface, but in denervated muscle a significant fraction (25.1 +/- 6.1%) of this transporter is found in intracellular vesicles that have the same sedimentation coefficient as GLUT-4-containing vesicles but can be separated from the latter by immunoadsorption. These GLUT-1-containing vesicles respond to insulin and translocate to the cell surface. Thus the formation of insulin-sensitive GLUT-1-containing vesicles in denervated muscle may be a compensatory mechanism for the decreased level of GLUT-4.

Animals↗
PubMed1996

Effect of muscle denervation on the expression of substance P in the ventral raphe-spinal pathway of the rat.

The medullary raphe nuclei, wherein serotonin (5-HT) coexists with substance P (SP) and thyrotropin-releasing hormone (TRH), innervate lower motor neurons in the spinal cord ventral horn by means of the ventral raphe-spinal pathway. Destruction of the ventral raphe-spinal pathway is associated with deficient recovery of denervated muscle, indicating that it may exert a trophic effect upon lower motor neurons. To determine whether SP could be a trophic factor for lower motor neurons within the ventral raphe-spinal pathway, the effect of muscle denervation with botulinum toxin type A on SP-encoding beta-preprotachykinin mRNA in the rat medullary raphe was examined by in situ hybridization histochemistry. Silver grain density over hybridized medullary raphe neurons was increased by up to 11%, although the number of hybridized neurons did not change in denervated as compared to control rats. Increased SP gene expression in the medullary raphe in response to motor unit lesioning suggests that raphe-spinal SP may be trophic to lower motor neurons.

Animals↗
PubMed2005

Differential gene expression profiling of short and long term denervated muscle.

Skeletal muscle function and viability are dependent upon intact innervation. Peripheral nerve injury and muscle denervation cause muscle atrophy. Time to re-innervation is one of the most important determinants of functional outcome. While short-term denervation can result in nearly fully reversible changes in muscle mass, prolonged denervation leads to irreversible muscle impairment from profound atrophy, myocyte death and fibrosis. We performed transcriptional profiling to identify genes that were altered in expression in short-term (1 month) and long-term (3 month) denervated muscle and validated the microarray data by RT-PCR and Western blotting. Genes controlling cell death, metabolism, proteolysis, stress responses and protein synthesis/translation were altered in expression in the denervated muscle. A differential pattern of expression of genes encoding cell cycle regulators and extracellular matrix components was identified that correlated with the development of irreversible post-denervation changes. Genes encoding mediators of protein degradation were differentially expressed between 1 and 3 month denervated muscle suggesting different signaling networks are recruited over time to induce and maintain muscle atrophy. Understanding of the timing and type of pathological processes that are triggered by denervation may allow the design of interventions that delay or protect muscle from loss of nerve function.

Animals↗
PubMed2006

Time course of changes in angiogenesis-related factors in denervated muscle.

AIM: Denervation leads to capillary regression in skeletal muscle. To gain insight into the regulation of this process, we investigated the time course of changes in capillary supply and gene expression of angiogenesis-related factors during muscle denervation. METHOD: Female mice underwent surgery to transect the sciatic nerve, and then the gastrocnemius muscles were isolated at 12 h, 1, 3, 5, 10, 20, or 30 days after surgery. The capillary supply was assessed by immunohistochemistry using anti-PECAM-1/CD31 antibody. The mRNA levels for angiogenesis-related factors were analysed using a real-time polymerase chain reaction. RESULTS: We found that the capillary-to-fibre ratio began to decrease 10 days after muscle denervation and decreased by 52% after 30 days. The levels of mRNA for vascular endothelial growth factor (VEGF), its receptors [fms-like tyrosine kinase (Flt-1) and a kinase insert domain-containing receptor/fetal liver kinase-1 (KDR/Flk-1)], angiopoietin-1 and angiopoietin-2 of denervated muscle were immediately down-regulated after 12 h and remained lower than control muscle until 30 days after muscle denervation. The levels of mRNA for the VEGF receptor, neuropilin-1, angiopoietin receptor and Tie-2 decreased within 12-24 h, but returned to near those of control muscle after 10-20 days, and again decreased after 30 days. CONCLUSIONS: These findings suggest that denervation-induced capillary regression may be associated with down-regulation of VEGF and angiopoietin signalling.

Angiogenesis Inducing Agents↗
PubMed2000

Fibrillation potential amplitude to quantitatively assess denervation muscle atrophy.

Denervated muscle fibers exhibit spontaneous, repetitive single muscle fiber discharges and display fibrillation potentials detectable by electromyography. To explore the changing pattern of fibrillation potential amplitude after peripheral nerve injury and its relationship to the degree of muscle atrophy, fibrillation potential amplitudes were recorded on completely denervated biceps brachii of 173 patients with brachial plexus injury. Biceps brachii biopsies were taken at the same sites as the electromyogram recordings in 63 patients. The biopsies were analyzed by ATPase staining and the cross-sectional areas of fast and slow-twitch fibers were calculated. We found that the fibrillation potential amplitude and the cross-sectional areas of denervated muscle decay over time (P < 0.05), and both correlate negatively with denervation time (P < 0.01-0.05) within the first 15 months. The fibrillation potential amplitude correlates positively with both type I and II fiber cross-sectional areas (P < 0.0005-0.01). Our results show that fibrillation potential amplitude is closely correlated with muscle fiber size during the first 15 months after nerve injury, and it may therefore serve as a convenient index to evaluate quantitatively the degree of atrophy of denervated muscles. Electromyographic studies thus may help in designing treatment strategies.

Adolescent↗
PubMed1985

Parvalbumin in cross-reinnervated and denervated muscles.

The extensor digitorum longus (EDL) muscle was cross-reinnervated by the soleus (SOL) nerve, leading to the well-known transformation toward a slow muscle. Nine weeks after the operation, the quantitative analysis of the Ca2+-binding protein, parvalbumin (PV), using high-performance liquid chromatography, showed a threefold reduction of PV in the cross-reinnervated EDL muscle. Denervation of the EDL muscle, which leads to an increase of the half-relaxation time, resulted in a 20% decrease of the PV concentration within 4 days. This significant lower PV level was detectable prior to any change of the myofibrillar adenosine triphosphatase (ATPase). Normal PV concentrations were reached after 9 weeks following self-reinnervation of the EDL muscle. The experiments support the view that PV is involved in the relaxation of rat fast skeletal muscles and that its expression is dependent on nerve-muscle interaction. Since PV changes preceded histochemical changes after denervation, this protein may be a sensitive marker for early stages of neuromuscular disturbances.

Adenosine Triphosphatases↗
PubMed1991

Real-time sonography of acute and chronic muscle denervation.

Presented are real-time ultrasound findings in partially and completely denervated muscles of 30 patients with focal neuropathy and various other disorders of the second motor neuron. Sonographic scans of affected muscles are analyzed in conjunction with unaffected muscles of the same individual, under identical examination conditions. Initial pathological ultrasound changes could be detected as soon as 2 weeks after an acute neurogenic lesion. In denervation, the echodensity of the muscle was high and the normal intramuscular pattern was decomposed. Findings were more intense in severe and longstanding denervation. Ultrasound-indicated pathology correlated highly (chi-square: P less than 0.001) with pathological spontaneous activity detected by electromyography. Focal and systemic neuropathies showed no differences in ultrasound pathology. Six cases with central motor palsy had normal sonograms. Poor spatial resolution of real-time ultrasonography--as compared with CT and MRI--is compensated by its bedside availability, frequent repeatability without patient risk and discomfort, and its in vivo correlation of muscle morphology with muscle function.

Adult↗
PubMed1995

New fiber formation in rat soleus muscle following administration of denervated muscle extract.

A study was made of Wistar rat soleus muscle following intraperitoneal administration of denervated muscle extract over 1 and 2 days. Light microscopy revealed the appearance on fiber surfaces of basophilic satellite structures whose histochemical behaviour differed from that of the parent fiber. Small fibers showing regenerative characteristics were also detected, mainly in the extrafascicular spaces. At ultrastructural examination, activated satellite cells were visible, and there was evidence of splitting in subsarcolemmal regions of apparently hypertrophic muscle fibers. Interstitial cells were occasionally observed, containing structures like myofilaments. The hypothesis is advanced that denervated muscle extract contains substances able to stimulate new fiber formation in adult skeletal muscle.

Animals↗
PubMed2003

Slowing growth and histology changes in Lewis lung carcinoma implanted in a partly denervated muscle.

The purpose of this study is to test the effect of partial muscle denervation on a tumor inocculated on the same muscle. Experiments were performed on male C57BL mice divided into two numerically equal A and B groups, each of which was subdivided into three subgroups AA, AB, Ac and BA, BB, BC, respectively. The right sciatic nerve of each mice of the A group was incised and partly dissected (day 0). Then Lewis lung carcinoma (LLC) cells were implanted on the right gastrocnemia of each mice of both groups on day 0 for subgroups AA and BA, on day 1 for subgroups AB and BB, and on day 4 for subgroups AC and BC. The incision and dissection of the sciatic nerve caused a significant reduction in the size of the tumor in all three A subgroups of mice. Fourteen days after implantation, the size of the primary tumors implanted on the right hind leg was 2.6 +/- 0.32 cm3, 3.5 +/- 0.21 cm3, and 4.7 +/- 0.31 cm3 for the three BA, BB, BC subgroups of the control group compared to 1.4 +/- 0.19 cm3, 2.0 +/- 0.28 cm3, and 3.0 +/- 0.27 cm3 for the three subgroups AA, AB, Ac, in which sciatic nerve was incised and dissected, indicating inhibition of the tumor growth of 46.2%, 43.0% and 36.2%, respectively. Although a smaller part of gastrocnemius is innervated by the anterior femoral nerve, which was left intact, denervation of the sciatic nerve caused inhibition of the tumor growth. This may be due to worse nutrition and/or blood supply of the LLC tumor. Mitochondria function and the degree of apoptosis of the tumor cells are further studied by us.

Animals↗