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PubMed2006

Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a polyglutamine (polyQ) disease in which the affected males suffer progressive motor neuron degeneration accompanied by signs of androgen insensitivity, such as gynecomastia and reduced fertility. SBMA is caused by CAG repeat expansions in the androgen receptor (AR) gene resulting in the production of AR protein with an extended glutamine tract. SBMA is one of nine polyQ diseases in which polyQ expansion is believed to impart a toxic gain-of-function effect upon the mutant protein, and initiate a cascade of events that culminate in neurodegeneration. However, whether loss of a disease protein's normal function concomitantly contributes to the neurodegeneration remains unanswered. To address this, we examined the role of normal AR function in SBMA by crossing a highly representative AR YAC transgenic mouse model with 100 glutamines (AR100) and a corresponding control (AR20) onto an AR null (testicular feminization; Tfm) background. Absence of endogenous AR protein in AR100Tfm mice had profound effects upon neuromuscular and endocrine-reproductive features of this SBMA mouse model, as AR100Tfm mice displayed accelerated neurodegeneration and severe androgen insensitivity in comparison to AR100 littermates. Reduction in size and number of androgen-sensitive motor neurons in the spinal cord of AR100Tfm mice underscored the importance of AR action for neuronal health and survival. Promoter-reporter assays confirmed that AR transactivation competence diminishes in a polyQ length-dependent fashion. Our studies indicate that SBMA disease pathogenesis, both in the nervous system and the periphery, involves two simultaneous pathways: gain-of-function misfolded protein toxicity and loss of normal protein function.

Androgen-Insensitivity Syndrome↗
PubMed1999

Tau expression in denervated rat muscles.

We studied whether denervation affects the expression of tau, in particular phosphorylated tau, and how it is degraded in rat soleus muscles. Immunoblot analysis showed a high molecular weight, approximately 110 kDa (big tau), in normal muscle. Tau levels increased significantly in denervated muscles treated with chloroquine (a lysosomotrophic agent) and in untreated ones, as compared to levels of similarly treated contralateral, innervated muscles. Most of the tau in the innervated and denervated muscles was phosphorylated. Immunohistochemically, tau and beta-tubulin colocated in the sarcoplasm of innervated, saline-treated (intact) muscle, but the staining intensities were very weak. Both proteins, however, were expressed extensively in these areas in the denervated muscles from saline-treated rats. In the denervated muscle of chloroquine-treated rats there were numerous autophagic vacuoles in the sarcoplasm, and phosphorylated-tau accumulation was marked within these vacuoles, indicative that tau first was taken into autophagic, vacuoles by nonselective autophagy then degraded via the lysosomal as well as the nonlysosomal calpain system. Our findings suggest that phosphorylated big tau accumulates with beta-tubulin in denervated muscular atrophy, possibly in order to maintain or preserve the integrity of the muscle fiber during progressive atrophy or regeneration.

Animals↗
PubMed1997

Skeletal muscle function and its relation to exercise tolerance in chronic heart failure.

OBJECTIVES: This study sought to define the relation between muscle function and bulk in chronic heart failure (HF) and to explore the association between muscle function and bulk and exercise capacity. BACKGROUND: Skeletal muscle abnormalities have been postulated as determinants of exercise capacity in chronic HF. Previously, muscle function in chronic HF has been evaluated in relatively small numbers of patients and with variable results, with little account being taken of the effects of muscle wasting. METHODS: One hundred male patients with chronic HF and 31 healthy male control subjects were studied. They were matched for age (59.0 +/- 1.0 vs. 58.7 +/- 1.7 years [mean +/- SEM]) and body mass index (26.6 +/- 0.4 vs. 26.3 +/- 0.7 kg/m2). We assessed maximal treadmill oxygen consumption (VO2), quadriceps maximal isometric strength, fatigue (20-min protocol, expressed in baseline maximal strength) and computed tomographic cross-sectional area (CSA) at midthigh. RESULTS: Peak VO2 was lower in patients (18.0 +/- 0.6 vs. 33.3 +/- 1.4 ml/min per kg, p < 0.0001), although both groups achieved a similar respiratory exchange ratio at peak exercise (1.15 +/- 0.01 vs. 1.19 +/- 0.03, p = 0.13). Quadriceps (582 vs. 652 cm2, p < 0.05) and total leg muscle CSA (1,153 vs. 1,304 cm2, p < 0.005) were lower in patients with chronic HF. Patients were weaker than control subjects (357 +/- 12 vs. 434 +/- 18 N, p < 0.005) and also exhibited greater fatigue at 20 min (79.1% vs. 92.1% of baseline value, p < 0.0001). After correcting strength for quadriceps CSA, significant differences persisted (5.9 +/- 0.2 vs. 7.0 +/- 0.3 N/cm2, p < 0.005), indicating reduced strength per unit muscle. In patients, but not control subjects, muscle CSA significantly correlated with peak absolute VO2 (R = 0.66, p < 0.0001) and is an independent predictor of peak absolute VO2. CONCLUSIONS: Patients with chronic HF have reduced quadriceps maximal isometric strength. This weakness occurs as a result of both quantitative and qualitative abnormalities of the muscle. With increasing exercise limitation there is increasing muscle weakness. This progressive weakness occurs predominantly as a result of loss of quadriceps bulk. In patients, this muscular atrophy becomes a major determinant of exercise capacity.

Case-Control Studies↗
PubMed2002

Neuro-inflammation as a therapeutic target in amyotrophic lateral sclerosis.

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neuromuscular disease that destroys both upper and lower motor neurons, resulting in spasticity, diffuse muscular atrophy, weakness, and ultimately death from respiratory failure. It is presumed that in the vast majority of cases, ALS is acquired and occurs sporadically, although the exact etiology is unknown. Recent, emerging evidence suggests that neuro-inflammation may be a pathological characteristic of this disease; this could represent a potential therapeutic target for a pharmacological agent to help treat this severe disease. This article reviews the current research in this area and discusses theoretical and clinical ramifications of these recent findings.

Amyotrophic Lateral Sclerosis↗
PubMed1990

[Assessment of "coping with disease" in patients with amyotrophic lateral sclerosis (ALS): on the use of an interviewer assessment rating scale].

Theories on "Coping" try to explain which resources people use to master crises and conflict situations. Reactions to challenges of life are considered as "coping strategies". In psychosomatic research, the notion of "coping" serves to describe how patients can handle physical or mental illness. Myatrophic (or amyothrophic) lateral sclerosis (ALS) is a rare chronic progressive disease of the nervous system with a gradual loss of motor neurons, resulting in muscular atrophy, weakness and spasticity. Since the etiology is unknown and no curative treatment available, most patients die from respiratory failure within a few years. In a follow-up study on physical disability, medical care and social support in 21 patients with advanced ALS, we tried to address the question how patients get along with such a threatening condition. After semi-standardized clinical interviews with patients and close relatives, two investigators gave independent descriptions of reported or observed "coping strategies" (rated as "not at all-barely-possibly-probably-very probably present"). Considering 17 patients assessed by both raters, significant agreement (Kendall's W) was achieved in three patients only. A comparison of aggregated answers (chi 2-Test) revealed different response sets, since one rater tended to choose extreme scale points, while the other preferred undecided answers. Differences of mean scores were observed in 8 out of 21 items, while significant correlations between investigators were obtained in another 8, including, though, only 2 of those 5 items which both had rated as "probably present" in no less than 50% of the patient sample ("Dejection & Flight-Brooding-Keeping the Situation Open-Distraction-Self-Isolation").(ABSTRACT TRUNCATED AT 250 WORDS)

Adaptation, Psychological↗
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↗
PubMed2000

High incidence of 550delA mutation of CAPN3 in LGMD2 patients from Russia.

Autosomal recessive limb gird muscular dystrophy (LGMD2) is a clinically and genetically heterogeneous group of diseases that are characterized by progressive atrophy and weakness of the proximal limb muscles. At least eight genetic loci leading to LGMD2 are recognized. The proportion of particular gene involved in producing different forms of LGMD2 shows a marked geographical variation. We studied 19 LGMD2 patients from Russia (15 families) and found calpain 3 (CAPN3) gene mutations in most of the patients studied. Sequence analysis of the fourth exons revealed two sibs - heterozygous compound for a 15-bp deletion (nt598-612) and 550 adenine deletion, and two sibs homozygous for a 550delA. We developed assay based on allele specific amplification (ASA) for rapid screening of the 550delA. The ASA assay of the LGMD2 patients under study showed that 7 patients from 6 families were homozygous for 550delA and 7 patients from 4 families were heterozygous for 550delA. A linkage analysis employing four microsatellites flanking the LGMD2A locus was performed. We found complete haplotype identity in most cases what favors the possibility of a common founder. Heterozygous carriers of 550delA were found in general population. The crude estimate of the mutation frequency is 1/150. Hum Mutat 15:295, 2000.

Calpain↗
PubMed2000

Myoadenylate deaminase deficiency with progressive muscle weakness and atrophy caused by new missense mutations in AMPD1 gene: case report in a Japanese patient.

A 46-year-old woman with exertional myalgia developed slowly progressive weakness in her lower extremities. She had slight muscle weakness in her facial and upper extremities, and severe muscle weakness and atrophy in lower extremities more marked in the proximal portions. Serum creatine kinase was slightly elevated. After ischemic forearm exercise test, blood ammonia had no elevation although lactate level increased normally. The computed tomography revealed that a characteristic distribution of skeletal muscle involvement with proximal and flexor muscles more severely affected than distal and extensor in the lower extremities. In addition, the left sternocleidomastoid muscle showed marked atrophy with an asymptomatic weakness of over 20 years duration suggesting abnormal development. Needle EMG examination showed a large number of easily recruited, short-duration, low-amplitude motor unit potentials in all extremities. Muscle biopsy showed absence of adenosine monophosphate deaminase activity with normal cytochrome c oxidase and phosphorylase activity. With the muscle enzyme activity assay, adenosine monophosphate deaminase activity was found to be lower than 0.2% of the controls. The DNA analysis revealed that she was compound heterozygote involving two missense mutations (R388W and R425H) in exon 9 and exon 10 of AMPD1 gene. This is the first report of primary myoadenylate deaminase deficiency with progressive weakness and atrophy caused by novel compound heterozygous mutations of AMPD1 gene, and suggests that adenosine monophosphate deaminase is closely related not only to energy metabolism but also to the development of skeletal muscle.

AMP Deaminase↗
PubMed2005

Physical complaints in ageing persons with spinal muscular atrophy.

OBJECTIVE: While life expectancy is improving for persons with spinal muscular atrophy, new physical complaints may arise. To investigate this, we studied persons with a long duration and severe course (high functional limitations) of the disease. DESIGN: Cross-sectional descriptive study. SUBJECTS/PATIENTS: Persons with spinal muscular atrophy. METHODS: Questionnaires and structured interviews on prevalence of physical complaints and their duration. Of 190 questionnaires 99 were returned; of 23 persons (with the longest disease duration and high functional limitation level) selected for structured medical interviews 9 participated. RESULTS: Patterns common within and different between the different types of spinal muscular atrophy were identified. Of the 10 most common complaints, types 1-2 had a significantly higher prevalence of kyphoscoliosis, difficulty in coughing, joint contractures and voice/speech problems, while type 3 had a significantly higher prevalence of fatigue. No statistically significant correlation was found between the appearance of physical complaints and disease duration. However, sleeping and swallowing problems were in the 5 most common complaints with the shortest mean time of appearance. The structured interview revealed hypermobility in the hand, suffusion of the eyes, and itching as new complaints with high prevalence. CONCLUSION: There are indications that the frequency of less well-known physical complaints increases with ageing.

Adult↗
PubMed1996

[Study of androgen receptor expression and neuronal vulnerability in X-linked spinal and bulbar muscular atrophy].

X-linked spinal and bulbar muscular atrophy (SBMA), a rare adult onset form of motor neuron disease, is clinically characterized by slowly progressive muscle weakness and atrophy, and endocrinopathy such as gynecomastia, testicular atrophy and oligospermia. Androgens are known to play an important role in motor neuron growth, development and regeneration. The genetic mutation of androgen receptor (AR) gene in SBMA has been disclosed and thought to lead to degeneration of lower motor neurons. However, the mechanism of neuronal death and the basis for the regional specificity of neuropathology observed in SBMA are not clear. At first, we proved the existence of androgen receptor (AR) in the motor neurons of the rat spinal cord by the immunohistochemical stain and Western blotting. The possibility that AR protein in spinal cord is expressed in tissue-specific form is proposed, being different from other androgen-dependent tissue. Northern blotting data showed that AR is expressed in not only rat spinal cord but also cerebrum and cerebellum, which are spared in SBMA. Then, specimens from 2 SBMA patients were examined and compared with those from normal controls (n = 4). AR was widely expressed in central nervous system. Anterior horn cells, which are severely affected in SBMA, were stained intensely. Even the remaining atrophic motor neurons in SBMA had AR. To our interest, the neurons of cranial nerves III, IV, VI, dentate nucleus, posterior horn and Onufrowicz nucleus etc., which are spared in SBMA, contained AR moderately. These data did not show any difference between SBMA and controls. Our immunohistochemical study showed that not only the neurons affected in SBMA but the unaffected in this disease process express AR. The question why motor neurons are selectively involved in SBMA if AR is present in almost neurons should further be clarified.

Aged↗
PubMed1975

"Myotubular Myopathy" and "type I fiber atrophy" in a family.

An 11-month-old girl and her mother had similar muscular weakness and wasting shich started in early life and were non-progressive throughout the course of the illness. Muscle biopsy in the girl revealed muscle fibers with central nuclei and surrounding clear areas compatible with myotubular, centronuclear or peri-centri-nuclear myopathy, whereas the biopsy from the mother showed a selective atrophy of Type I fibers without central nuclei. Since the grandfather also had similar clinical features, a heredofamilial neuromuscular disease was thought likely, and it is postulated that the pathological change in the girl represented an earlier, and in the mother a later manifestation of the same disease.

Creatine Kinase↗
PubMed1998

Alterations in cyclin-dependent protein kinase 5 (CDK5) protein levels, activity and immunocytochemistry in canine motor neuron disease.

Hereditary canine spinal muscular atrophy (HCSMA) is a dominantly inherited motor neuron disease in Brittany spaniels that is clinically characterized by progressive muscle weakness leading to paralysis. Histopathologically, degeneration is confined to motor neurons with accumulation of phosphorylated neurofilaments in axonal internodes. Cyclin-dependent kinase 5 (CDK5), a kinase related to the cell cycle kinase cdc2, phosphorylates neurofilaments and regulates neurofilament dynamics. We examined CDK5 activity, protein levels, and cellular immunoreactivity in nervous tissue from dogs with HCSMA, from closely age-matched controls and from dogs with other neurological diseases. On immunoblot analysis, CDK5 protein levels were increased in the HCSMA dogs (by approximately 1.5-fold in both the cytosolic and the particulate fractions). CDK5 activity was significantly increased (by approximately 3-fold) in the particulate fractions in the HCSMA dogs compared to all controls. The finding that CDK5 activity was increased in the young HCSMA homozygotes with the accelerated form of the disease, who do not show axonal swellings histologically, suggests that alterations in CDK5 occurs early in the pathogenesis, prior to the development of significant neurofilament pathology. Immunocytochemically, there was strong CDK5 staining of the nuclei, cytoplasm and axonal processes of the motor neurons in both control dogs and dogs with HCSMA. Further immunocytochemical studies demonstrated CDK5 staining where neurofilaments accumulated, in axonal swellings in the dogs with HCSMA. Our observations suggest phosphorylation-dependent events mediated by CDK5 occur in canine motor neuron disease.

Animals↗
PubMed2004

Association of spinal and bulbar muscular atrophy with myotonic dystrophy type 1.

A man with spinal and bulbar muscular atrophy (SBMA) had a short (CTG)n expansion in the myotonic dystrophy protein kinase gene as well as (CAG)n expansion in the androgen receptor gene in leukocytes. The patient had the characteristic clinical findings of SBMA, but none of myotonic dystrophy type 1 (DM1). All of his three children (a son and two daughters) had the DM1 phenotype with long (CTG)n expansions. The daughters also had heterozygous long (CAG)n expansions. Postmortem examination of the patient revealed the characteristic pathological changes of SBMA as well as muscle degeneration compatible with DM1. Gene analysis of the organs disclosed unstable long expansions of the (CTG)n repeats, in contrast to the stable (CAG)n expansions. We have assumed that SBMA and DM1 developed independently in our patient, but cannot exclude the possibility that interactive gene effects increased somatic instability.

Adult↗