PubMed Health⌕ Search

SEARCH · PubMed Health

Results for “Muscular Disorders, Atrophic”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 55 records · Page 3Linked to original sources
PubMedDate not supplied

Cytochrome c oxidase subunit Vb interacts with human androgen receptor: a potential mechanism for neurotoxicity in spinobulbar muscular atrophy.

Spinobulbar muscular atrophy (SBMA) is a neurodegenerative disease caused by the expansion of the polyglutamine (polyGln) tract in the human androgen receptor (hAR). One mechanism by which polyGln-expanded proteins are believed to cause neuronotoxicity is through aberrant interaction(s) with, and possible sequestration of, critical cellular protein(s). Our goal was to confirm and further characterize the interaction between hAR and cytochrome c oxidase subunit Vb (COXVb), a nuclear-encoded mitochondrial protein. We initially isolated COXVb as an AR-interacting protein in a yeast two-hybrid screen to identify candidate proteins that interacted with normal and polyGln-expanded AR. Using the mammalian two-hybrid system, we confirm that COXVb interacts with normal and mutant AR and demonstrated that the COXVb-normal AR interaction is stimulated by heat shock protein 70. In addition, blue fluorescent protein-tagged AR specifically co-localized with cytoplasmic aggregates formed by green fluorescent protein-labeled polyGln-expanded AR in androgen-treated cells. Mitochondrial dysfunction may precede neuropathological findings in polyGln-expanded disorders and may thus represent an early event in neuronotoxicity. Interaction of COXVb and hAR, with subsequent sequestration of COXVb, may provide a mechanism for putative mitochondrial dysfunction in SBMA.

Animals↗
PubMed2003

Disuse and deconditioning in chronic low back pain: concepts and hypotheses on contributing mechanisms.

For years enhancement of a patient's level of physical fitness has been an important goal in rehabilitation treatment in chronic low back pain (CLBP), based on the hypothesis that physical deconditioning contributes to the chronicity of low back pain. However, whether this hypothesis in CLBP holds is not clear. In this paper, possible mechanisms that contribute to the development of physical deconditioning in CLBP, such as avoidance behaviour and suppressive behaviour, are discussed. The presence of both deconditioning-related physiological changes, such as muscle atrophy, changes in metabolism, osteoporosis and obesity as well as deconditioning related functional changes, such as a decrease in cardiovascular capacity, a decrease in muscle strength and impaired motor control in patients with CLBP are discussed. Results of studies on the level of physical activities in daily life (PAL) and the level of physical fitness in patients with CLBP compared to healthy controls were reviewed. In studies on PAL results that were either lower or comparable to healthy subjects were found. The presence of disuse (i.e., a decrease in the level of physical activities in daily life) in patients with CLBP was not confirmed. The inconclusive findings in the papers reviewed may partly be explained by different measurement methods used in research on PAL in chronic pain. The level of physical fitness of CLBP patients also appeared to be lower or comparable to the fitness level of healthy persons. A discriminating factor between fit and unfit patients with back pain may be the fact that fit persons more frequently are still employed, and as such may be involved more in physical activity. Lastly some suggestions are made for further research in the field of disuse and deconditioning in CLBP.

Activities of Daily Living↗
PubMed2005

Discovery of corticotropin releasing factor 2 receptor selective sauvagine analogues for treatment of skeletal muscle atrophy.

The corticotropin release factor 2 receptor (CRF2R) has many biological activities including modulation of the stress response. Recently, we have demonstrated that CRF2R activation functions to prevent skeletal muscle wasting resulting from a variety of physiological stimuli. Thus we are interested in identifying CRF2R selective agonists with optimal pharmacological properties for use in treating muscle wasting diseases. Several CRF2R agonists are known including the frog peptide sauvagine (Svg), which display superior pharmacological properties compared to other CRF2R agonists. Unfortunately sauvagine is a nonselective CRFR agonist, thus making it of less utility due to side effects resulting from corticotropin release factor 1 receptor (CRF1R) activation. Because our initial modifications of Svg at position 11 improved CRF2R selectivity, we investigated the role of amino acids at positions 12 and 13 in Svg. We observed that phenylalanine, leucine, isoleucine, threonine, glutamine, histidine, and tyrosine at the 12th position were the strongest promoters of CRF2R selectivity whereas phenylalanine, glutamine, trytophane, tyrosine, valine, isoleucine, leucine, and 2-naphthylalanine were the preferred residues at the 13th position. Selective sauvagine peptides demonstrated improved antiatrophy effects in a mouse-casting model when compared to sauvagine itself. Thus, we demonstrate that the CRF2R selectivity can be improved by optimizing amino acids at positions 12 and 13 (all with proline at position 11) and that the selective sauvagine analogues demonstrate better in vivo efficacy than sauvagine itself.

Amino Acid Substitution↗
PubMed2003

Leuprorelin rescues polyglutamine-dependent phenotypes in a transgenic mouse model of spinal and bulbar muscular atrophy.

Spinal and bulbar muscular atrophy (SBMA) is an adult-onset motor neuron disease that affects males. It is caused by the expansion of a polyglutamine (polyQ) tract in androgen receptors. Female carriers are usually asymptomatic. No specific treatment has been established. Our transgenic mouse model carrying a full-length human androgen receptor with expanded polyQ has considerable gender-related motor impairment. This phenotype was abrogated by castration, which prevented nuclear translocation of mutant androgen receptors. We examined the effect of androgen-blockade drugs on our mouse model. Leuprorelin, a lutenizing hormone-releasing hormone (LHRH) agonist that reduces testosterone release from the testis, rescued motor dysfunction and nuclear accumulation of mutant androgen receptors in male transgenic mice. Moreover, leuprorelin treatment reversed the behavioral and histopathological phenotypes that were once caused by transient increases in serum testosterone. Flutamide, an androgen antagonist promoting nuclear translocation of androgen receptors, yielded no therapeutic effect. Leuprorelin thus seems to be a promising candidate for the treatment of SBMA.

Androgen Antagonists↗
PubMed2003

Modelling brain diseases in mice: the challenges of design and analysis.

Genetically engineered mice have been generated to model a variety of neurological disorders. Several of these models have provided valuable insights into the pathogenesis of the relevant diseases; however, they have rarely reproduced all, or even most, of the features observed in the corresponding human conditions. Here, we review the challenges that must be faced when attempting to accurately reproduce human brain disorders in mice, and discuss some of the ways to overcome them. Building on the knowledge gathered from the study of existing mutants, and on recent progress in phenotyping mutant mice, we anticipate better methods for preclinical interventional trials and significant advances in the understanding and treatment of neurological diseases.

Angelman Syndrome↗
PubMed2000

Founder effect in spinal and bulbar muscular atrophy (SBMA) in Scandinavia.

We haplotyped 13 Finnish, 10 Swedish, 12 Danish and 2 Norwegian SBMA (spinal and bulbar muscular atrophy, Kennedy disease) families with a total of 45 patients and 7 carriers for 17 microsatellite markers spanning a 25.2 cM region around the androgen receptor gene on chromosome Xq11-q12 in search of a genetic founder effect. In addition, the haplotypes of 50 Finnish, 20 Danish and 22 Swedish control males were examined. All the Scandinavian SBMA families shared the same 18 repeat allele for the intragenic GGC repeat, which was present in only 24% of the controls. Linkage disequilibrium was also seen for the closest microsatellite markers. In addition, extended haplotypes of the Finnish, Swedish and Danish SBMA families revealed country-specific common founder haplotypes, which over time became gradually shortened by recombinations. No common haplotype was found among the controls. The data suggest that the SBMA mutation was introduced into western Finland 20 generations ago. Haplotype analysis implies a common ancestor for the majority of Scandinavian SBMA patients.

Alleles↗
PubMed2001

Unilateral fibroadipose degeneration of the masticatory muscles.

A unique case of fatty replacement of the masticatory muscles, causing progressive limitation of mouth opening, is presented. Both CT and MRI revealed an almost total substitution of the masticatory muscles with fatty tissue, confirmed by the histopathology at surgery. Myotomy of masseter and internal pterygoid muscles and coronoidotomy improved his symptoms. There is no known cause of fibroadipose replacement of muscle fibres.

Adipose Tissue↗
PubMed2005

Myostatin: a modulator of skeletal-muscle stem cells.

Myostatin, or GDF-8 (growth and differentiation factor-8), was first identified through sequence identity with members of the BMP (bone morphogenetic protein)/TGF-beta (transforming growth factor-beta) superfamily. The skeletal-muscle-specific expression pattern of myostatin suggested a role in muscle development. Mice with a targeted deletion of the myostatin gene exhibit a hypermuscular phenotype. In addition, inactivating mutations in the myostatin gene have been identified in 'double muscled' cattle breeds, such as the Belgian Blue and Piedmontese, as well as in a hypermuscular child. These findings define myostatin as a negative regulator of skeletal-muscle development. Myostatin binds with high affinity to the receptor serine threonine kinase ActRIIB (activin type IIB receptor), which initiates signalling through a smad2/3-dependent pathway. In an effort to validate myostatin as a therapeutic target in a post-embryonic setting, a neutralizing antibody was developed by screening for inhibition of myostatin binding to ActRIIB. Administration of this antimyostatin antibody to adult mice resulted in a significant increase in both muscle mass and functional strength. Importantly, similar results were obtained in a murine model of muscular dystrophy, the mdx mouse. Unlike the myostatin-deficient animals, which exhibit both muscle hypertrophy and hyperplasia, the antibody-treated mice demonstrate increased musculature through a hypertrophic mechanism. These results validate myostatin inhibition as a therapeutic approach to muscle wasting diseases such as muscular dystrophy, sarcopenic frailty of the elderly and amylotrophic lateral sclerosis.

Animals↗
PubMed2001

Undermasculinized genitalia in a boy with an abnormally expanded CAG repeat length in the androgen receptor gene.

We report an 11-year-old boy with undermasculinized genitalia and an abnormally expanded CAG repeat length at exon 1 of the androgen receptor (AR) gene. He had microphallus and scrotal hypospadias with chordee, and underwent urethroplasty at 4 years of age. At 11 years of age, a gonadotropin releasing hormone (GnRH) test yielded a relatively high leutinizing hormone (LH) response (0.7-->20.4 IU/l) and a relatively low follicle-stimulating hormone (FSH) response (1.7-->4.8 IU/l), and an human chorionic gonadotropin (hCG) test showed sufficient responses of testosterone (0.7-->23.0 nmol/l) and dihydrotestosterone (0.38-->2.95 nmol/l). The CAG repeat length was 44 for the boy and ranged from 12 to 32 for 100 control males. The DNA sequences of the AR gene were normal for the exons 1-8 and for the splice donor, splice acceptor and branch sites. The markedly expanded CAG repeat length appears to be relevant to the undermasculinized genitalia of this boy, because such an expandsion, which has previously been reported only in spinal and bulbar muscular atrophy, is known to reduce AR function.

Age of Onset↗
PubMed2000

Congenital and metabolic myopathies of childhood or adult onset.

OBJECTIVES: To investigate the clinical presentation, histological findings, and outcome of patients with congenital and metabolic myopathies (CM and MM) in whom the disease was diagnosed in childhood or adulthood. PATIENTS AND METHODS: We reviewed the diagnosis of all skeletal muscle biopsies performed by our group between 1984 and 1996 (13 years). All patients with CM and MM of childhood or adult onset were included in the study. Patients with mitochondrial myopathies were excluded because they are multisystemic disorders with a more distinct picture than that observed in other MM. We retrospectively reviewed the clinical history, with special emphasis on the clinical patterns of presentation, histological findings, and outcome. RESULTS: Among 1,865 biopsies, 28 (1.5%) fulfilled the diagnostic criteria for CM (seven nemaline myopathies, four multicore myopathies, three centronuclear myopathies) or MM (five adult-onset acid maltase deficiency, three myophosphorylase deficiency, three phosphofructokinase deficiency, two carnitine palmitoyl transferase deficiency, and one carnitine deficiency). In nearly half of the patients, mild stable weakness was the major complaint, whereas in one third muscular symptoms were intermittent and related to exercise. In a small number of cases, a persistently raised serum creatine kinase in an asymptomatic patient was the reason for muscle biopsy. Histological examination of skeletal muscle was highly indicative of a specific muscle disease in 26 of the 28 cases. After a mean follow-up of 7 years, the outcome has generally been good, and in most patients the myopathy did not worsen, most remaining ambulatory. CONCLUSION: CM and MM presenting in childhood or adulthood are infrequent; the symptoms are usually mild or moderate, and the prognosis generally is good.

Adolescent↗
PubMed1999

Genetic disorders of motor neurons.

Disorders of the motor neuron are etiologically and clinically heterogeneous and cause serious disability and death. Whereas mendelian inheritance can be demonstrated in a subset of these disorders, the genetic contribution to the sporadic forms of motor neuron degeneration are not well understood. In families with spinal muscular atrophy, Kennedy disease and amyotrophic lateral sclerosis, genetic linkage analysis and positional cloning have proven to be extremely productive. The genetics of these neurodegenerative disorders are reviewed.

Amyotrophic Lateral Sclerosis↗
PubMed2006

Soluble androgen receptor oligomers underlie pathology in a mouse model of spinobulbar muscular atrophy.

In polyglutamine diseases such as X-linked spinobulbar muscular atrophy (SBMA), it is unknown whether the toxic form of the protein is an insoluble or soluble aggregate or a monomer. We have addressed this question by studying a full-length androgen receptor (AR) mouse model of SBMA. We used biochemistry and atomic force microscopy to immunopurify oligomers soluble after ultracentrifugation that are comprised of a single approximately 50-kDa N-terminal polyglutamine-containing AR fragment. AR oligomers appeared several weeks prior to symptom onset, were distinct and temporally dissociated from intranuclear inclusions, and disappeared rapidly after castration, which halts disease. This is the first demonstration of soluble AR oligomers in vivo and suggests that they underlie neurodegeneration in SBMA.

Aging↗
PubMed2005

Dementia of frontal lobe type in Kennedy's disease.

The pathomorphological correlate of Kennedy's disease (KD) is a degeneration of spinal and bulbar alpha-motor neurons. The disease is caused by a CAG repeat expansion in the first exon of the X-chromosomal androgene receptor gene. Contrary to the common belief that cognitive disorders in motor neuron diseases (MND) are either rare or only mild, there is now an increasing number of case reports on dementia in amyotrophic lateral sclerosis (ALS). In ALS, dementia of the frontal lobe type (frontotemporal dementia, FTD) seems to be the characteristic pattern. However, in KD cognitive dysfunction has not been studied systematically. Here we present a case with clinical characteristics of FTD in a patient with genetically confirmed KD. It remains speculative whether there is an association between KD and FTD comparable to a genetic linkage between ALS and FTD, which has been proposed in recent years. However, we suggest that cognitive dysfunction may be more common in KD than reported until today.

Adult↗
PubMed2003

Cancer rehabilitation: particularly with aspects on physical impairments.

Cancer can cause multiple impairments, activity limitations and participation restrictions. According to individual case findings and needs, rehabilitation treatment is varied. The review mainly focuses on specific problems. Because of functional deficits cancer patients suffer from persistent emotional and social distress and a reduced quality of life (QOL). QOL encompasses at least the four dimensions of physical, emotional, social and cognitive function, which may be positively influenced by physical exercise. Physical exercise also has been shown to prevent or minimise inactivity/ disuse problems and to reduce fatigue. The management of sexuality dysfunction has to begin with a thorough history taking and a consequent sexuality counselling. The goals of rehabilitation procedures under palliative care are not only to control physical pain but also to help with mental, social and spiritual pain, together with other symptoms. Rehabilitation problems in head and neck cancer, sexuality, lung cancer, prostate cancer, breast cancer and lymphedema can be improved by rehabilitation. The review mainly focuses on impairment and activity limitation. Social, psychological and vocational aspects are left aside in this review.

Breast Neoplasms↗
PubMed2006

A phenotypic-genetic study of a group of Polish patients with spinal and bulbar muscular atrophy.

We studied phenotype-genotype correlation in a group of Polish males with spinal and bulbar muscular atrophy (SBMA) and in female carriers. Eleven males with suspected SBMA phenotype and three suspected female carriers were examined. Male patients presented with the predominant signs of progressive, symmetrical distal limb weakness with amyotrophy, facial muscular weakness with orofacial fasciculations, nasal voice and slight dysphagia, gynaecomastia, decreased potency, as well as hand tremor and distal peripheral sensory disturbances in a few cases. One of the carriers presented with a 30-year history of fasciculations and minimal distal weakness and cramps in the legs, while the other two were asymptomatic. DNA analysis revealed expanded size of CAG repeats in Xq11-12 in the AR gene in 10 out of 11 men (range 45-52 CAG repeats) and in the women (range 46-48 CAG repeats). There was no correlation between CAG repeat size and the age of disease onset and duration of the disease. A rare, predominantly distal distribution of weakness and amyotrophy was found in our group of the SBMA patients (8 out of 11 cases) from three unrelated kindreds and also in the remaining two sporadic cases. The extended CAG repeats within families were stable.

Adult↗
PubMed1999

Tissue-specific somatic mosaicism in spinal and bulbar muscular atrophy is dependent on CAG-repeat length and androgen receptor--gene expression level.

The factors influencing the tissue-specific pattern of somatic mosaicism in CAG-repeat diseases have not yet been fully resolved. We performed a detailed analysis of the degree of somatic mosaicism in various tissues from 20 patients with spinal and bulbar muscular atrophy (SBMA), including 4 who were deceased. The most outstanding feature was the prominent somatic mosaicism observed in the cardiac and skeletal muscles, composed predominantly of postmitotic cells, and in the skin, prostate, and testis. The CNS tissues, liver, and spleen showed the least mosaicism. The tissue distribution of somatic mosaicism in patients with SBMA was markedly different from that in patients with Huntington disease (HD) and from that in patients with dentatorubral-pallidoluysian atrophy (DRPLA). The degree of somatic mosaicism correlated with the CAG-repeat number but not with age at examination. Furthermore, tissues with a higher mosaicism level corresponded well to those with a higher expression level of androgen receptor protein. The tissue-specific pattern of somatic mosaicism related not only to cell composition with different cell turnover rates but to repeat size and gene expression levels, and postnatal cell division is unlikely to be a major cause of somatic mosaicism probably because of the relative stability of CAG repeat in SBMA.

Adult↗
PubMed2001

Skeletal muscle disuse induces fibre type-dependent enhancement of Na(+) channel expression.

Slow-twitch and fast-twitch muscle fibres have specific contractile properties to respond to specific needs. Since sodium current density is higher in fast-twitch than in slow-twitch fibres, sodium channels contribute to the phenotypic feature of myofibres. Phenotype determination is not irreversible: after periods of rat hindlimb unloading (HU), a model of hypogravity, a slow-to-fast transition occurs together with atrophy in the antigravity slow-twitch soleus muscle. Using cell-attached patch-clamp and northern blot analyses, we looked at sodium channel expression in soleus muscles after 1-3 weeks of HU in rats. We found that sodium channels in fast-twitch flexor digitorum brevis muscle fibres, soleus muscle fibres and 1- to 3-week HU soleus muscle fibres showed no difference in unitary conductance, open probability and voltage-dependencies of activation, fast inactivation and slow inactivation. However, muscle disuse increased sodium current density in soleus muscle fibres 2-fold, 2.5-fold and 3-fold after 1, 2 and 3 weeks of HU, respectively. The concentration of mRNA for the skeletal muscle sodium channel alpha subunit increased 2-fold after 1 week of HU but returned to the control level after 3 weeks of HU. In contrast, the concentration of mRNA for the ubiquitous sodium channel beta(1) subunit was unchanged after 1 week and had increased by 30% after 3 weeks of HU. The tetrodotoxin sensitivity of sodium currents in 3-week HU soleus muscles and the lack of mRNA signal for the juvenile skeletal muscle sodium channel alpha subunit excluded denervation in our experiments. The observed increase in sodium current density may reduce the resistance to fatigue of antigravity muscle fibres, an effect that may contribute to muscle impairment in humans after space flight or after long immobilization.

Animals↗