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PubMed2002

Change of chloride ion channel conductance is an early event of slow-to-fast fibre type transition during unloading-induced muscle disuse.

Disuse of postural slow-twitch muscles, as it occurs in hypogravity, induces a slow-to-fast myofibre type transition. Nothing is known about the effects of weightlessness on the resting membrane chloride conductance (gCl), which controls sarcolemma excitability and influences fibre type transition during development and adult life. Using the current-clamp method, we observed that rat hindlimb unloading (HU) for 1-3 weeks increased gCl in fibres of the slow-twitch soleus (Sol) muscle toward values found in fast muscle. Northern blot analysis suggested that this effect resulted from an increased ClC-1 chloride channel mRNA level. In the meantime, a 4-fold increase in fibres expressing fast isoforms of the myosin heavy chain (MHC) was observed by immunostaining of muscle sections. Also, Sol muscle function evolved toward a fast phenotype during HU, as demonstrated by the positive shift of the threshold potential for contraction. After 3-days HU, Sol muscle immunostaining and RT-PCR experiments revealed no change in MHC protein and mRNA expression, whereas the gCl was already maximally increased, due to a pharmacologically probed, increased activity of ClC-1 channels. Thus the increase in gCl is an early event in Sol muscle experiencing unloading, suggesting that gCl may play a role in muscle adaptation to modified use. Pharmacological modulation of ClC-1 channels may help to prevent disuse-induced muscle impairment.

Animals↗
PubMed2001

Transgenic mice with an expanded CAG repeat controlled by the human AR promoter show polyglutamine nuclear inclusions and neuronal dysfunction without neuronal cell death.

We generated transgenic mice that expressed a highly expanded 239 polyglutamine (polyQ) repeat under the control of the human androgen receptor promoter. These transgenic mice developed progressive neurological phenotypes of muscular weakness and ataxia, small body size and short life-span. PolyQ nuclear inclusions (NIs) were remarkable and widespread but found in selective regions of the central nervous system (CNS) such as the spinal cord, cerebrum and cerebellum as well as in selective peripheral visceral organs. This distribution pattern resembled that of spinal and bulbar muscular atrophy somewhat, but was more widespread. In neuronal tissues, NIs were present in astrocytes as well as neurons. Cytoplasmic and axonal inclusions were not observed. In the CNS regions with abundant NIs, neuronal populations were well-preserved, and neither neuronal cell death, reactive astrogliosis nor microglial invasions were detected. These findings suggest that polyQ alone can induce the neuronal dysfunction that precedes gross neuronal degeneration and provides a clue for investigating molecular mechanisms that underly the pathway to neuronal dysfunction from polyQ expansion.

Animals↗
PubMed2001

Expression of expanded repeat androgen receptor produces neurologic disease in transgenic mice.

Spinal and bulbar muscular atrophy (SBMA) is a motor neuron disease caused by the expansion of a polyglutamine tract within the androgen receptor. This disease is unusual among the polyglutamine diseases in that it involves lower motor and sensory neurons, with relative sparing of other brain structures. We describe the development of transgenic mice, created with a truncated, highly expanded androgen receptor driven by the neurofilament light chain promoter, which develop many of the motor symptoms of SBMA. In addition, transgenic mice created with the prion protein promoter develop widespread neurologic disease, reminiscent of juvenile forms of other polyglutamine diseases. Thus, in these experiments, the distribution of neurologic symptoms depends on the expression level and pattern of the promoter used, rather than on specific characteristics of androgen receptor metabolism or function. The transgenic mice described here develop neuronal intranuclear inclusions (NIIs), a hallmark of SBMA and the other polyglutamine diseases. We have shown these inclusions to be ubiquitinated and to sequester molecular chaperones, components of the 26S proteasome and the transcriptional activator CREB-binding protein. Apart from the presence of NIIs, evidence of neuropathology or neurogenic muscle atrophy was absent, suggesting that the neurologic phenotypes observed in these mice were the result of neuronal dysfunction rather than neuronal degeneration. These mice will provide a useful resource for characterizing specific aspects of motor neuron dysfunction, and for testing therapeutic strategies for this and other polyglutamine diseases.

Animals↗
PubMed2002

Rescue of polyglutamine-mediated cytotoxicity by double-stranded RNA-mediated RNA interference.

RNA interference (RNAi) is a mechanism that appears to control unwanted gene expression in a wide range of species. In Drosophila, RNAi is most effectively induced by double-stranded RNAs (dsRNAs) of over approximately 80 nucleotides (nt) and in mammalian cells an RNAi-like inhibition of gene expression has been shown to be mediated by dsRNAs of approximately 21-23 nt. To test if RNAi can be used to specifically down-regulate a human disease-related transcript we have used Drosophila and human tissue culture models of the dominant genetic disorder spinobulbar muscular atrophy (SBMA). A variety of different dsRNAs were assessed for the ability to inhibit expression of transcripts that included a truncated human androgen receptor (ar) gene containing different CAG repeat lengths (16-112 repeats). In Drosophila cells, dsRNAs corresponding to non-repetitive sequences mediated a high degree of sequence-specific inhibition, whereas RNA duplexes containing CAG repeat tracts only induced gene-specific inhibition when flanking ar sequences were included; dsRNAs containing various lengths of CAG repeats plus ar sequences were unable to induce allele-specific interference. In mammalian cells we tested sequence-specific small dsRNAs of 22 nt; these rescued the toxicity and caspase-3 activation induced by plasmids expressing a transcript encoding an expanded polyglutamine tract. This study demonstrates the feasibility of targeting a transcript associated with an important group of genetic diseases by RNAi.

Animals↗
PubMed2002

Genetic modulation of polyglutamine toxicity by protein conjugation pathways in Drosophila.

Spinal and bulbar muscular atrophy (SBMA) is a heritable neurodegenerative disease caused by the expansion of a polyglutamine [poly(Q)] repeat within the androgen receptor (AR) protein. We studied SBMA in Drosophila using an N-terminal fragment of the human AR protein. Expression of a pathogenic AR protein with an expanded poly(Q) repeat in Drosophila results in nuclear and cytoplasmic inclusion formation, and cellular degeneration, preferentially in neuronal tissues. We have studied the influence of ubiquitin-dependent modification and the proteasome pathway on neural degeneration and AR protein fragment solubility. Compromising the ubiquitin/proteasome pathway enhances degeneration and decreases poly(Q) protein solubility. Our data further suggest that Hsp70 and the proteasome act in an additive manner to modulate neurodegeneration. Through the over-expression of a mutant of the SUMO-1 activating enzyme Uba2, we further show that poly(Q)-induced degeneration is intensified when the cellular SUMO-1 protein conjugation pathway is altered. These data suggest that post-translational protein modification, including the ubiquitin/proteasome and the SUMO-1 pathways, modulate poly(Q) pathogenesis.

Animals↗
PubMed2004

A screen for drugs that protect against the cytotoxicity of polyglutamine-expanded androgen receptor.

Spinobulbar muscular atrophy is a neurodegenerative disorder caused by expansion of a CAG triplet repeat sequence encoding a polyglutamine tract in the androgen receptor. It has been shown that the mutant protein is toxic in cell culture and triggers an apoptotic cascade resulting in activation of caspase-3. We developed an assay of caspase-3 activation in cells expressing the mutant androgen receptor. This assay was used to screen 1040 drugs, most of which are approved for clinical use. Drugs that inhibit polyglutamine-dependent activation of caspase-3 were subjected to follow-up screens to identify compounds that reproducibly prevent polyglutamine-induced cytotoxicity. Four drugs satisfied these criteria. Three of these (digitoxin, nerifolin and peruvoside) are structurally and functionally related compounds of the cardiac glycoside class and known inhibitors of Na(+)K(+)-ATPase. The fourth compound, suloctidil, is a calcium channel blocker.

Apoptosis↗
PubMed2004

Sodium butyrate ameliorates phenotypic expression in a transgenic mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an inherited motor neuron disease caused by the expansion of a polyglutamine (polyQ) tract within the androgen receptor. Unifying mechanisms have been implicated in the pathogenesis of polyQ-dependent neurodegenerative diseases including SBMA, Huntington disease and spinocerebellar ataxias. It has been suggested that mutant protein containing polyQ inhibits histone acetyltransferase activity, resulting in transcriptional dysfunction and subsequent neuronal dysfunction. Histone deacetylase (HDAC) inhibitors alleviate neurological phenotypes in fly and mouse models of polyQ disease, although the therapeutic effect is limited by the toxicity of these compounds. We studied the therapeutic effects of sodium butyrate (SB), an HDAC inhibitor, in a transgenic mouse model of SBMA. Oral administration of SB ameliorated neurological phenotypes as well as increased acetylation of nuclear histone in neural tissues. These therapeutic effects, however, were seen only within a narrow range of SB dosage. Our results indicate that SB is a possible therapeutic agent for SBMA and other polyQ diseases, although an appropriate dose should be determined for clinical application.

Acetylation↗
PubMed2005

Metabolic consequences of muscle disuse atrophy.

In response to decreased usage, skeletal muscle undergoes an adaptive reductive remodeling. This adaptive response has been found with disuse during human spaceflight, rat spaceflight, rat hind-limb unloading, bed rest, and aging. The reductive remodeling of skeletal muscle with disuse is largely independent of the reason for the disuse. The process involves more than a transition from slow to fast myosin fiber types. There are associated metabolic changes including a fuel shift toward glycolysis, decreased capacity for fat oxidation, and energy substrate accumulation in the atrophied muscles. Glycolysis is very effective for high-intensity short-duration acute activities, but if sustained output is needed, an energy profile where fat use is favored rather than compromised is desirable. For astronauts, there is a need to maintain as much functional capacity as possible during spaceflight for extravehicular activities. The shift toward increased activity of the glycolytic enzymes in atrophied muscle is accommodated by an increase in gluconeogenic capacity in the liver.

Animals↗
PubMed2004

Disuse atrophy and exercise rehabilitation in humans profoundly affects the expression of genes associated with the regulation of skeletal muscle mass.

Skeletal muscle atrophy occurs as a consequence of injury, illness, surgery, and muscle disuse, impacting appreciably on health care costs and patient quality of life, particularly in the absence of appropriate rehabilitation. The molecular mechanisms that regulate muscle mass during atrophy and rehabilitation in humans have not been elucidated, despite several robust candidate pathways being identified. Here, we induced skeletal muscle atrophy in healthy volunteers using two weeks of limb immobilization, and then stimulated the restoration of muscle mass with six weeks of supervised exercise rehabilitation. We determined muscle mass and function and performed targeted gene expression analysis at prescribed time points during immobilization and rehabilitation. For the first time, we have identified novel changes in gene expression following immobilization-induced atrophy and during a program of rehabilitative exercise that restored muscle mass and function. Furthermore, we have shown that exercise performed immediately following immobilization induces profound changes in the expression of a number of genes in favor of the restoration of muscle mass, within 24 h. This information will be of considerable importance to our understanding of how immobilization and contraction stimulate muscle atrophy and hypertrophy, respectively, and to the development of novel therapeutic strategies aimed at maintaining or restoring muscle mass.

Adolescent↗
PubMed2004

Continuous muscle stretch prevents disuse muscle atrophy and deterioration of its oxidative capacity in rat tail-suspension models.

OBJECTIVE: The purpose of this study was to evaluate the effect of continuous muscle stretch on disuse-atrophied muscles. DESIGN: Sprague-Dawley rats were used and divided into five groups: control group, hind limb suspended for 3 and 7 days, and hind-limb suspension plus strenuous continuous muscle stretch for 3 and 7 days. In the hind-limb suspension plus strenuous continuous muscle stretch groups, the gastrocnemius-plantaris-soleus muscles were stretched using a plastic plate that immobilized the ankle joint at the maximum dorsal flexed position during the hind-limb suspension period. The intracellular energy metabolism of the working muscle during electric stimulation was evaluated by phosphorus-31 magnetic resonance spectroscopy in vivo. Changes in phosphocreatine, inorganic phosphate, and the intracellular pH were monitored to evaluate intramuscular oxidative capacity. Maximum tension and muscle wet mass were also measured. RESULTS: The oxidative capacity, muscle wet weight, and maximum tension decreased after hind-limb suspension. The muscle oxidative capacity at control levels was maintained during the first 3 days in muscles subjected to continuous strenuous stretch. It was also effective to prevent the decrease in muscle mass and maximum twitch tension during the initial 3 days. However, the effects did not persist. CONCLUSION: Continuous strenuous stretch was effective to prevent disuse muscle atrophy and its functional deterioration; however, its effects did not last long.

Animals↗
PubMed2003

Effects of muscle immobilization at different lengths on tetrodotoxin-induced disuse atrophy.

Previous studies have shown that immobilization causes muscle atrophy and that the rate of atrophy depends on the length at which the muscle is immobilized. However, most studies have been carried out in neurologically intact animals that were capable of generating at least some voluntary muscle activation. In this study, tetrodotoxin was applied chronically to the rat sciatic nerve to produce complete paralysis of distal muscles for seven days, and the ankle was immobilized to hold the muscles at long or short lengths. Paralysis without immobilization resulted in relative weight losses of 36% for soleus, 19% for tibialis anterior (TA), and 17% for lateral gastrocnemius (LG) muscles. Casting the ankle in plantarflexion stretched TA and reduced its weight loss to 10%. Soleus and LG were shortened by this intervention and had increased losses of 43% and 28%, respectively. Fixing the limb in dorsiflexion resulted in a posture similar to that adopted by the unrestrained rats and had no significant effect on the amount of muscle atrophy compared to that in unrestrained paralyzed animals.

Adaptation, Physiological↗
PubMed2004

Morphological changes in rat hindlimb muscle fibres during recovery from disuse atrophy.

AIM: The present study attempted to use HE staining to clarify morphological changes in muscle fibres during recovery from disuse muscle atrophy. METHODS: Disuse muscle atrophy was induced by suspending 7-week-old male Wistar rats by their tails for 5 weeks (hindlimb unloading or HU group). Histological changes in the soleus muscle (SOL) during the recovery process were examined and compared with those in control rats who were raised freely without unloading (C group). RESULTS: Wet muscle mass and muscle cross-sectional area per fibre of SOL in the HU group were 52 +/- 5 and 22 +/- 5% of those in the C group, respectively. Muscle atrophy was largely attributable to decreases in the size of muscle fibres, rather than to muscle fibre damage or loss. Muscle mass in the HU group increased quickly after reloading, but recovery of cross-sectional area per fibre was slow, with mean area in the HU group measuring 69 +/- 10% of that in the C group even after 5 weeks of reloading. After 1, 2 and 5 weeks of reloading, incidences of muscle fibres displaying central nuclei (regenerated muscle fibres) were 7.4 +/- 2.4, 7.2 +/- 6.3 and 19.2 +/- 14.5%, respectively. CONCLUSION: These findings suggest that recovery of muscle fibres atrophied by disuse involves not only growth of atrophied muscle fibres, but also regeneration of muscle fibres. Cross-sectional areas recovery of atrophied muscle fibres thus continues after increases of muscle mass.

Animals↗
PubMed2003

Degenerative neurological and neuromuscular disease in young rottweilers.

A number of idiopathic degenerative diseases affecting the central nervous system, peripheral nerves and muscles of immature and young adult rottweilers are reported. Tetraparesis or ataxia causing abnormalities in gait and posture are clinical findings common to these conditions. The current knowledge about these syndromes is presented in this review, with an emphasis on the clinical characteristics. Knowledge of these syndromes and a methodical approach to neurological diagnosis can help the veterinarian to identify the underlying disease and establish a prognosis when presented with a tetraparetic or ataxic young rottweiler.

Animals↗
PubMed2005

Human expanded polyglutamine androgen receptor mutants in neurodegeneration as a novel ligand target.

Androgen receptor (AR) plays key roles in various biological events, including pathological processes such as prostate cancer, androgen-insensitive syndrome, and spinal and bulbar muscular atrophy (SBMA). SBMA is caused by mutation of the expanded polyglutamine (polyQ) stretches in the AR gene. Recently, we established a Drosophila SBMA model that expresses the expanded polyQ hAR mutant in eyes, which monitors neurodegeneration as a rough eye phenotype. In addition, we showed that androgen binding to the mutant hAR causes structural alterations, leading to the onset of neurodegeneration in the fly eyes. In the present study, we examined whether the ligand-induced neurodegeneration via the hAR mutant is coupled with the known ligand-induced transactivation function of hAR. By testing several known AR antagonists and several of their structure-related compounds, we unexpectedly found that none of the AR ligands antagonized the hAR mutant neurodegeneration function, and surprisingly, compound 4-(4,4-dimethyl-2,5-dioxo-1-imidazolidinyl)-2-trifluoromethylbenzonitrile (RU56279) was more potent in inducing neurodegeneration. However, in vitro and in vivo mammalian assays showed that RU56279 exhibited the expected antagonistic activity with the same potency as those of the other compounds. Thus, these findings suggest the presence of a novel ligand-induced function of the polyQ hAR mutant in neurodegeneration that could not be prevented by known antagonists for the hAR transactivation function.

Androgen Antagonists↗
PubMed2000

Trinucleotide repeats: mechanisms and pathophysiology.

Within the closing decade of the twentieth century, 14 neurological disorders were shown to result from the expansion of unstable trinucleotide repeats, establishing this once unique mutational mechanism as the basis of an expanding class of diseases. Trinucleotide repeat diseases can be categorized into two subclasses based on the location of the trinucleotide repeats: diseases involving noncoding repeats (untranslated sequences) and diseases involving repeats within coding sequences (exonic). The large body of knowledge accumulating in this fast moving field has provided exciting clues and inspired many unresolved questions about the pathogenesis of diseases caused by expanded trinucleotide repeats. This review summarizes the current understanding of the molecular pathology of each of these diseases, starting with a clinical picture followed by a focused description of the disease genes, the proteins involved, and the studies that have lent insight into their pathophysiology.

Female↗