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At least 37 records · Page 2Linked to original sources
PubMed2007

Is spinal cord isolation a good model of muscle disuse?

The patterns of normal daily activity that are required to maintain normal skeletal muscle properties remain unknown. The present study was designed to determine whether spinal cord isolation can be used as a reliable experimental model of neuromuscular inactivity, that is, as a baseline for the absence of activity. Electromyograms (EMGs) were recorded from selected hindlimb muscles of unanesthetized rats over 24-hour periods before and 7, 30, 60, and 90 days after surgical isolation of the lumbar spinal cord. Our data indicate that some rat slow muscle fibers pre-surgery were activated for less than 3 hours per day. Spinal cord isolation (SI) reduced the mean daily integrated EMG (IEMG) and daily EMG duration in the primary slow extensor muscle (soleus) to <1% of control, and in the primary fast extensor muscles [medial gastrocnemius (MG) and vastus lateralis (VL)] to <2% of control. These parameters were decreased to <8% and 3% of control, respectively, in a primary fast flexor muscle, the tibialis anterior (TA). From 30 to 90 days post-SI, the mean amplitudes of the spontaneous EMG bursts were relatively normal in the soleus, increased approximately 2-fold in the MG and VL, and increased approximately 4-fold in the TA. Some evidence of the normal antagonistic flexor-extensor relationship was apparent in the brief periods of recorded activity post-SI. These results indicate that SI eliminates nearly all of the normal EMG activity in the hindlimb muscles in the presence of relatively normal muscle innervation and functional intraspinal neural circuitry.

Action Potentials↗
PubMed2005

Progress in Spinobulbar muscular atrophy research: insights into neuronal dysfunction caused by the polyglutamine-expanded androgen receptor.

Spinobulbar muscular atrophy (SBMA, Kennedy's disease) results from the dysfunction and degeneration of specific motor and sensory neurons. The underlying cause of this ligand-dependent neurodegenerative disease is expansion of the CAG trinucleotide repeat in the androgen receptor (AR) gene which leads to lengthening of the polyglutamine tract in the AR protein. Recently, the effects of the polyglutamine-expanded AR have been explored in a number of cellular and animal models. Common themes include research on polyglutamine-containing nuclear inclusions and the effect of molecular chaperone overexpression on their formation. In addition, investigations have highlighted the role that abnormal transcriptional regulation, proteasome dysfunction and altered axonal transport may play in disease pathogenesis. These studies suggest a number of potential treatments for restoring neuronal function. One of the most interesting advances in SBMA research has been the creation of mouse models that recapitulate the key features of SBMA progression in men. Lowering testosterone levels in affected transgenic male mice rescued, and even reversed the polyglutamine-induced neuromuscular phenotype, indicating that manipulating androgen levels in men could be of therapeutic benefit. Although the question of why only a distinct subset of neurons is affected by polyglutamine expansion of the AR remains unsolved, future research will provide further insights into the mechanisms contributing to disease progression in SBMA.

Animals↗
PubMed2005

Real-time PCR analysis of trinucleotide repeat allele expansions in the androgen receptor gene.

INTRODUCTION: The expansion of specific trinucleotide repeats results in certain genetic disorders. METHOD: Real-time PCR analysis was used to rapidly discriminate between normal and expanded (CAG)(n) alleles in the androgen receptor gene. RESULT: The difference in melting temperature (T(m)) between the most common normal and expanded alleles was approximately 1 degrees C. CONCLUSION: Real-time PCR analysis seems to be a highly reliable and rapid method, which may facilitate the first molecular approach to human trinucleotide repeat disorders.

Alleles↗
PubMed2006

Modulation of Hsp90 function in neurodegenerative disorders: a molecular-targeted therapy against disease-causing protein.

Abnormal accumulation of disease-causing protein is a commonly observed characteristic in chronic neurodegenerative disorders such as Alzheimer's disease, Parkinson's disease, and polyglutamine (polyQ) diseases. A therapeutic approach that could selectively eliminate would be a promising remedy for neurodegenerative disorders. Spinal and bulbar muscular atrophy (SBMA), one of the polyQ diseases, is a late-onset motor neuron disease characterized by proximal muscle atrophy, weakness, contraction fasciculations, and bulbar involvement. The pathogenic gene product is polyQ-expanded androgen receptor (AR), which belongs to the heat shock protein (Hsp) 90 client protein family. 17-Allylamino-17-demethoxygeldanamycin (17-AAG), a novel Hsp90 inhibitor, is a new derivative of geldanamycin that shares its important biological activities but shows less toxicity. 17-AAG is now in phase II clinical trials as a potential anti-cancer agent because of its ability to selectively degrade several oncoproteins. We have recently demonstrated the efficacy and safety of 17-AAG in a mouse model of SBMA. The administration of 17-AAG significantly ameliorated polyQ-mediated motor neuron degeneration by reducing the total amount of mutant AR. 17-AAG accomplished the preferential reduction of mutant AR mainly through Hsp90 chaperone complex formation and subsequent proteasome-dependent degradation. 17-AAG induced Hsp70 and Hsp40 in vivo as previously reported; however, its ability to induce HSPs was limited, suggesting that the HSP induction might support the degradation of mutant protein. The ability of 17-AAG to preferentially degrade mutant protein would be directly applicable to SBMA and other neurodegenerative diseases in which the disease-causing proteins also belong to the Hsp90 client protein family. Our proposed therapeutic approach, modulation of Hsp90 function by 17-AAG treatment, has emerged as a candidate for molecular-targeted therapies for neurodegenerative diseases. This review will consider our research findings and discuss the possibility of a clinical application of 17-AAG to SBMA and other neurodegenerative diseases.

Age Factors↗
PubMed2004

Resistance to disuse atrophy in a turtle hindlimb muscle.

The purpose of this study was to characterize the changes in a turtle hindlimb muscle (external gastrocnemius) after exposure to three conditions of disuse: immobilization, tenotomy, and spinalization. Histochemical analysis and measurement of muscle fiber cross-sectional area and weighted cross-sectional area were used to assess the potential conversion of muscle fiber types and changes in fiber size. It was found that unlike its counterpart in mammalian endotherms, the external gastrocnemius muscle of the adult turtle, Trachemys scripta elegans, was remarkably resistant to each model of reduced muscle function. It is suggested that such resistance to disuse is due to intrinsic mechanisms that enable heterothermic mammals and ectothermic vertebrates to tolerate an unfavorable climate and food and water shortages by using hypometabolic states.

Adenosine Triphosphatases↗
PubMed2003

Effects of 17-day spaceflight on electrically evoked torque and cross-sectional area of the human triceps surae.

The effects of spaceflight on triceps surae muscle torque and cross-sectional area (CSA) were investigated on four astronauts using electrically evoked contractions to by-pass neural control. Muscle twitch characteristics, ankle joint angle-twitch torque relation, frequency-torque relation, tetanic torque and fatigability were assessed before, during and after a 17-day Space Shuttle flight (STS-78). Muscle plus bone cross-sectional area (CSAm+b) was evaluated before and after the flight. Whereas no changes in muscle function were observed during the flight, marked alterations were found during the recovery period. Peak twitch (PTw) and tetanic torques at 50 Hz (PT50) continued to fall up to the 8th recovery day (R+8) on which losses in PTw and PT50 were 24.4% (P<0.01) and 22.0% (P<0.01), respectively. The decline in PTw was not joint-angle-specific. Post-flight, especially on R+8, torque decreased at all stimulation frequencies (1, 20, 30 and 50 Hz); however the shape of the frequency-torque curve, normalised for PT50, was not modified. Similarly, no changes in twitch kinetics were observed. Post- flight, an 8% (P<0.01) reduction in CSAm+b was found on R+2. Normalisation of PT50 values for CSAm+b showed a progressive loss in specific torque (PT50/CSAm+b), which was maximal on R+2 (19.5%, P<0.05). Also, fatigability during 2-min intermittent stimulation at 20 Hz increased throughout recovery, reaching a nadir of 16.4% (P<0.01) on R+15. In conclusion, 17 days of spaceflight resulted in significant changes in muscle function during the recovery phase, but not in microgravity. The disproportionate loss of torque compared with that of muscle size suggests the presence of muscle damage due to reloading in 1 g.

Adult↗
PubMed2000

Cell death in polyglutamine diseases.

An increasing number of inherited neurodegenerative diseases are known to be caused by trinucleotide repeat expansions in the respective genes. At least nine disorders result from a CAG trinucleotide repeat expansion which is translated into a polyglutamine stretch in the respective proteins: Huntington's disease (HD), dentatorubral pallidolysian atrophy (DRPLA), spinal bulbar muscular atrophy (SBMA), and several of the spinocerebellar ataxias (SCA1, 2, 3, 6, 7 and 12). Although the molecular steps leading to the specific neuropathology of each disease are unknown and are still under intensive investigation, there is increasing evidence that some CAG repeat disorders involve the induction of apoptotic mechanisms. This review summarizes the clinical and genetic features of each CAG repeat disorder and focuses on the common mechanistic steps involved in the disease progression of these so-called polyglutamine diseases. Among the common molecular features the formation of intranuclear inclusions, the recruitment of interacting polyglutamine-containing proteins, the involvement of the proteasome and molecular chaperones, and the activation of caspases are discussed with regard to their potential implication for the induction of cell death.

Animals↗
PubMed2006

The fear-avoidance model of musculoskeletal pain: current state of scientific evidence.

Research studies focusing on the fear-avoidance model have expanded considerably since the review by Vlaeyen and Linton (Vlaeyen J. W. S. & Linton, S. J. (2000). Fear-avoidance and its consequences in chronic musculoskeletal pain: a state of the art. Pain, 85(3), 317--332). The fear-avoidance model is a cognitive-behavioral account that explains why a minority of acute low back pain sufferers develop a chronic pain problem. This paper reviews the current state of scientific evidence for the individual components of the model: pain severity, pain catastrophizing, attention to pain, escape/avoidance behavior, disability, disuse, and vulnerabilities. Furthermore, support for the contribution of pain-related fear in the inception of low back pain, the development of chronic low back pain from an acute episode, and the maintenance of enduring pain, will be highlighted. Finally, available evidence on recent clinical applications is provided, and unresolved issues that need further exploration are discussed.

Affect↗
PubMed2006

Neuromuscular disorders in critical illness.

Neuromuscular disorders in the background of critical illness are under diagnosed. Standardized screening for weakness in the intensive care unit (ICU) setting is uncommon and persistent weakness as a sequel of critical illness is usually not recognized by physicians in the ICU for whom survival from acute illness is the primary outcome. The spectrum of illness ranges from isolated nerve entrapment with focal pain or weakness, to disuse muscle atrophy with mild weakness, and to severe myopathy or neuropathy with associated severe, prolonged weakness. This update focuses on neuromuscular disorders occurring in the critical care set up associated with diffuse and severe weakness.

Critical Illness↗
PubMed2005

Low amplitude, high frequency strains imposed by electrically stimulated skeletal muscle retards the development of osteopenia in the tibiae of hindlimb suspended rats.

The purpose of this study was to determine the extent to which high frequency, low amplitude skeletal muscle contractions, induced using electrical stimulation, could prevent or retard disuse osteopenia. Ten minutes of 30 Hz electrical stimulation was delivered, 5 days a week, during a 4 week rat-hindlimb suspension protocol. Each pulse generated a peak compressive dynamic strain on the tibia of approximately 200 microepsilon. We hypothesized that the electrical stimulation protocol would significantly reduce the loss of tibial bone mineral density compared to the contralateral control tibia that did not receive electrical stimulation. Compared to the contralateral control limb, the tibia of the stimulated limb had significantly higher bone mineral density and enhanced newly formed bone in the tibial diaphysis. The diaphysis, specifically the posterior bone cortex, of the tibia of the limb receiving the stimulation also demonstrated substantially larger mineral-binding fluorochrome biomarker within the osteocyte lacunae and canalicular volumes. Although the protocol did not prevent disuse osteopenia the evidence suggests that it was effective at reducing the extent of the osteopenia. One possibility for this outcome may be the insensitivity of bone to static, compared to dynamic compressive loads. In the present study there was a considerable static component to the compressive loads that accounted for a large component of the peak load generated by the stimulated skeletal muscle. Nevertheless, the results provide impetus for further development of the methods by which muscle contraction-induced loading of bone can be clinically exploited.

Animals↗
PubMed2001

Effects of short- and long-term rat hind limb immobilization on spinal cord insulin-like growth factor-I and its receptor.

In this study we investigated changes in the spinal cord insulin-like growth factor-I peptide (IGF-I) and its receptors (IGF-IR) after hind limb immobilization for 5 days, 2, 4, and 8 weeks. Moreover, effects on IGF-I and nicotinic cholinergic receptors (nAChRs) in two types of skeletal muscle were also investigated. IGF-I levels were measured by radioimmunoassay (RIA) whereas IGF-IR and nAChRs were measured by quantitative receptor autoradiography. Spinal cord IGF-I levels decreased significantly after 5 days, 2 and 4 weeks of immobilization, whereas IGF-IR increased significantly after 4 and 8 weeks compared to controls. In skeletal muscles, nAChRs increased significantly after 5 days and 2 weeks in the soleus (SOL) and tibialis anterior (TIB) muscles, respectively, and continued up to 8 weeks in both muscles. IGF-I concentration decrease significantly after 4 and 8 weeks in the SOL and TIB muscles, respectively. Despite the normal levels of IGF-I in both muscles at the early time points (5 days and 2 weeks), low levels of IGF-I were observed concurrently in the spinal cord ipsilateral to the immobilized limb. Our findings suggest that the early decrease in the IGF-I level and the late upregulation in the IGF-IR in the spinal cord might represent a nervous system response to disuse.

Animals↗
PubMed2000

Analytical and diagnostic performance of troponin assays in patients suspicious for acute coronary syndromes.

BACKGROUND: The controversy whether there is a clinically significant difference between troponin T (cTnT) and troponin I (cTnI) in regard to predictive value and cardiac specificity is still ongoing. METHODS: We evaluated enzyme-linked immunosorbent assay systems for cTnI and cTnT in patients with acute coronary syndromes and multiple control groups to define threshold values for risk stratification and compare their predictive value. RESULTS: In 312 patients with noncardiac chest pain, cTnI levels were below the detection limit of 0.2 microg/L and cTnT levels were 0.011 [0.010-0. 013] microg/L. In patients with end-stage renal failure (n = 26) and acute (n = 38) or chronic (n = 16) skeletal muscle damage, median concentrations were 0.20 [0.20-0.35], below the detection limit, and 0.20 [0.20-0.25] for cTnI, and 0.04 [0.01-0.10], 0.011 [0.005-0.025], and 0.032 [0.009-0.054] microg/L for cTnT. In patients with acute coronary syndromes (n = 1130), maximized prognostic value for 30-day outcome (death, infarction) was observed at a threshold level of 1.0 microg/L for cTnI (29.0% positive) and at 0.06 microg/L for cTnT (35. 0% positive). Significant differences in the area-under-the-curve values were observed between cTnI and cTnT (0.685 vs. 0.802; p = 0. 005). For both markers, the area-under-the-curve values did not increase with the second (within 24 h after enrollment) or third (48 h) blood draw. CTnI showed a less strong association with 30-day outcome than cTnT. When cTnI was put in a logistic multiple-regression model first, cTnT did add significant information. CONCLUSION: By using the defined threshold values and the employed test systems, single testing for cTnI and cTnT within 12 h after symptom onset was appropriate for risk stratification. Despite the lower cardiac specificity for cTnT, it appears to have a stronger association with the patients' outcome, whereas, as previously shown, the ability to identify patients who benefit from treatment with a GP IIb/IIIa receptor antagonist is similar.

Acute Disease↗
PubMed2000

Selective paraspinal muscle amyotrophy.

A 56-year-old female presented with mild low back pain. Examination revealed severe, selective atrophy of the thoracic and lumbar paraspinal muscles. Fibrillations were seen in the paraspinal muscles on EMG. Limb EMG was normal. Biopsy of the gluteus maximus was normal. Paraspinal muscle biopsy revealed neurogenic features. Atrophy of the thoracic and lumbar paraspinal muscles was noted on magnetic resonance imaging. This patient has selective amyotrophy of the thoracic and lumbar paraspinal muscles. This may be an addition to the spectrum of 'benign focal amyotrophy'. The differential diagnosis of paraspinal muscle weakness is discussed.

Biopsy↗
PubMed2005

[A clinical, neurophysiological and molecular study of 12 patients from 4 families with spinal and bulbar muscular atrophy].

INTRODUCTION: Spinal and bulbar muscular atrophy (SBMA) is an X-linked, late-onset neuro-endocrine disorder resulting from an expansion of a CAG repeat in the androgen receptor gene. Material and method. We report the detailed phenotypic study in a series of 12 SBMA patients evaluated in four kindreds. RESULTS: Clinical phenotypic spectrum varied considerably, ranging from childhood-onset weakness and atrophy mimicking limb-girdle myopathy in patients with 53 CAG repeats to isolated hyperCKemia in an adult with 42 CAG repeats. All male patients had gynecomastia. Two female carriers presented with paresthesias and hand action tremor. Homozygous deletions of SMN1 and SMN2 genes were not found in any patients. CONCLUSION: This report demonstrates that SBMA may present with a wider clinical spectrum than previously described and suggests that clinical phenotype severity in SBMA is partially linked to the number of CAG repeats. It also suggests that SMN1 and SMN2 genes do not act as modifying genes in SBMA.

Adolescent↗
PubMed2004

Consequences of forced disuse of the impaired forelimb after unilateral cortical injury.

Extreme over-reliance on the impaired forelimb following unilateral lesions of the forelimb representation area of the rat sensorimotor cortex (FL-SMC) leads to exaggeration of injury when overuse is begun during the first week, but not later periods, after injury. Behavioral impairment is partially worsened by the additional tissue loss. In the present study, we show that complete disuse of the impaired forelimb during the first post-operative week renders surviving tissue vulnerable to later overuse of the same limb, in effect extending the window of vulnerability in which use-dependent exaggeration of brain injury can occur. Behavioral recovery is disrupted by complete disuse, but the degree of impairment is variable depending on the nature of the behavioral test employed. Our results uphold the idea that mild rehabilitative training early after injury is beneficial, while either extreme overuse or complete disuse may disrupt functional recovery.

Animals↗
PubMed1999

Polyglutamine repeat length influences human androgen receptor/c-Jun mediated transcription.

The androgen receptor and c-Jun are known to interact to modulate each others transcriptional activities. The androgen receptor contains a polymorphic polyglutamine repeat and expansion of this repeat to beyond approximately 40 causes spinobulbar muscular atrophy (SBMA; also known as Kennedy's disease), a genetic form of motor neurone disease. Here we show that the size of this polyglutamine tract influences both c-Jun regulation of androgen receptor-mediated transcription and androgen receptor regulation of c-Jun activity. c-Jun is a key mediator of neuronal survival and death by apoptosis. Inappropriate interactions between c-Jun and androgen receptors containing pathological length glutamine repeats may therefore be part of the pathogenic process in SBMA.

Cells, Cultured↗