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Biomedical subjects

W K Engel

Publications and source records attributed to W K Engel.

At least 19 recordsLinked to original sources
PubMed2001

Inclusion-body myositis: newest concepts of pathogenesis and relation to aging and Alzheimer disease.

We review the newest advances related to seeking the pathogenic mechanism(s) of sporadic inclusion-body myositis (s-IBM) and present the pathologic diagnostic criteria of s-IBM. We discuss the possible pathogenic role of several themes, such as 1) increased amyloid-beta precursor protein (AbetaPP) and of its fragment Abeta; 2) phosphorylation of tau protein; 3) oxidative stress; 4) abnormal a) signal-transduction, b) transcription, and c) RNA accumulation; 5) "junctionalization" and myogenous" denervation; and 6) lymphocytic inflammation. Evidence is provided supporting our hypothesis that overexpression of AbetaPP within the aging muscle fibers is an early upstream event causing the subsequent pathogenic cascade. The remarkable pathologic similarities between s-IBM muscle and Alzheimer disease (AD) brain are discussed, and the possible cause and significance are addressed.

Aging↗
PubMed2000

Cyclin-dependent kinase 5 colocalizes with phosphorylated tau in human inclusion-body myositis paired-helical filaments and may play a role in tau phosphorylation.

To investigate the possible role of cyclin-dependent kinase 5 (cdk5) in the formation of paired helical filaments (PHFs) in muscle of patients with inclusion-body myositis (IBM), we immunolocalized cdk5, by light- and electron- microscopy, in muscle biopsies of six IBM patients. Approximately 80-90% of IBM vacuolated muscle fibers, and 10-15% of nonvacuolated fibers, contained well defined cdk5-immunoreactive inclusions that colocalized with phosphorylated tau in 70-80% of those fibers. Immunoelectronmicroscopy revealed the association of cdk5 with tau-immunoreactive PHFs. In all biopsies that contained them, regenerating muscle fibers had diffuse, moderate to strong cdk5 immunoreactivity. At all neuromuscular junctions, there was strong cdk5 immunoreactivity postsynaptically. Our study suggests that cdk5: (1) plays a role in IBM pathogenesis, possibly mediating phosphorylation of PHF-related tau; (2) is involved in muscle regeneration; and (3) has a novel function at normal neuromuscular junctions.

Cyclin-Dependent Kinase 5↗
PubMed2000

Redox factor-1 in muscle biopsies of patients with inclusion-body myositis.

To determine whether redox factor-1 (Ref-1) participates in the pathogenesis of inclusion-body myositis (IBM), we immunolocalized Ref-1 in muscle biopsies of IBM patients by light- and electron-microscopy. Approximately 70-80% of the IBM vacuolated muscle fibers had focal inclusions strongly immunoreactive for Ref-1. By immunoelectronmicroscopy, Ref-1 was localized to paired-helical filaments, 6-10 nm amyloid-like fibrils and amorphous material. Virtually all regenerating and necrotic muscle fibers in various muscle biopsies had diffusely strong Ref-1 immunoreactivity. At all neuromuscular junctions, postsynaptically there was strong Ref-1 immunoreactivity. Our study suggests that Ref-1 plays a role in IBM pathogenesis, and in other pathologic and normal processes of human muscle.

Biopsy↗
PubMed2000

Paired helical filaments of inclusion-body myositis muscle contain RNA and survival motor neuron protein.

Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older persons. Pathologically, the muscle biopsy manifests various degrees of inflammation and specific vacuolar degeneration of muscle fibers characterized by paired helical filaments (PHFs) composed of phosphorylated tau. IBM vacuolated fibers also contain accumulations of several other Alzheimer-characteristic proteins. Molecular mechanisms leading to formation of the PHFs and accumulations of proteins in IBM muscle are not known. We report that the abnormal muscle fibers of IBM contained (i) acridine-orange-positive RNA inclusions that colocalized with the immunoreactivity of phosphorylated tau and (ii) survival motor neuron protein immunoreactive inclusions, which by immuno-electron microscopy were confined to paired helical filaments. This study demonstrates two novel components of the IBM paired helical filaments, which may lead to better understanding of their pathogenesis.

Acridine Orange↗
PubMed2000

Association of active extracellular signal-regulated protein kinase with paired helical filaments of inclusion-body myositis muscle suggests its role in inclusion-body myositis tau phosphorylation.

The possible role of extracellular signal-regulated kinase (ERK) in the pathogenesis of inclusion-body myositis (IBM) was investigated by immunostaining the active phosphorylated form of ERK in muscle biopsies of six IBM and 14 control patients. Between 80% and 90% of IBM vacuolated muscle fibers contained well-defined ERK-immunoreactive inclusions, which were co-localized by light microscopy, with phosphorylated tau in 70 to 80% of those fibers. Immunoelectronmicroscopy colocalized ERK to small amorphous tufts adjacent to the muscle fiber paired-helical filaments. Strong ERK immunoreactivity was also present at the postsynaptic domain of all human neuromuscular junctions. Our study suggests 1) that ERK, a signal transducer, might play a role in IBM pathogenesis, including participation in the pathological phosphorylation of IBM tau; and 2) that signal transduction abnormalities may be a component of the IBM pathogenic cascade. Our novel immunolocalization of ERK at the postsynaptic domain of human neuromuscular junctions supports a role in transcription of junctional-protein genes. The ERK localized in nonjunctional regions of IBM fibers may underlie the known pathological up-regulation of junctional proteins there.

Humans↗
PubMed2000

Novel immunolocalization of alpha-synuclein in human muscle of inclusion-body myositis, regenerating and necrotic muscle fibers, and at neuromuscular junctions.

Alpha-synuclein (alpha-syn) is an important component of neuronal and glial inclusions in brains of patients with several neurodegenerative disorders. Sporadic inclusion-body myositis (s-IBM) is the most common progressive muscle disease of older patients. Its muscle phenotype shows several similarities with Alzheimer disease brain. A distinct feature of s-IBM pathology is specific vacuolar degeneration of muscle fibers characterized by intracellular amyloid inclusions formed by both amyloid-beta (Abeta) and paired-helical filaments composed of phosphorylated tau. We immunostained alpha-syn in muscle biopsies of s-IBM, disease-control, and normal patients. Approximately 60% of Abeta-positive vacuolated muscle fibers (VMF) contained well-defined inclusions immunoreactive with antibodies against alpha-syn. In those fibers. alpha-syn co-localized with Abeta, both by light microscopy, and ultrastructurally. Paired-helical filaments did not contain alpha-syn immunoreactivity. In all muscle biopsies, alpha-syn was strongly immunoreactive at the postsynaptic region of the neuromuscular junctions. alpha-syn immunoreactivity also occurred diffusely in regenerating and necrotic muscle fibers. In cultured human muscle fibers, alpha-syn and its mRNA were expressed by immunocytochemistry, immunoblots, and Northern blots. Our study provides the first demonstration that alpha-syn participates in normal and pathologic processes of human muscle. Therefore. its function is not exclusive to the brain and neurodegenerative diseases.

Cells, Cultured↗
PubMed2000

Inclusion body myositis, muscle blood vessel and cardiac amyloidosis, and transthyretin Val122Ile allele.

Typical of sporadic inclusion body myositis muscle biopsies are vacuolated muscle fibers containing intracellular amyloid deposits and accumulations of "Alzheimer-characteristic" proteins. There is no muscle blood vessel or cardiac amyloidosis. We report on a 70-year-old African-American man homozygous for the transthyretin Val122Ile allele who has both sporadic inclusion body myositis and cardiac amyloidosis. His unique pathological features included transthyretin immunoreactivity in prominent muscle blood vessel amyloid and congophilic amyloid deposits within vacuolated muscle fibers.

Aged↗
PubMed1999

Cultured inclusion-body myositis muscle fibers do not accumulate beta-amyloid precursor protein and can be innervated.

Cultured muscle fibers from patients with sporadic inclusion-body myositis (s-IBM), similar to normal control muscle fibers, 1) did not have beta-amyloid precursor protein (betaAPP) immunoreactivity; and 2) became normally innervated, as evidenced by the following features: full cross-striation, continuous contraction, and acetylcholinesterase and acetylcholine receptors accumulated only at neuromuscular junctions. Thus, factors responsible for betaAPP accumulation and denervation-like changes in s-IBM muscle biopsies are not operative in the relatively short-term, non-aged, cultured s-IBM muscle fibers.

Aged↗
PubMed1999

Localization of survival motor neuron protein in human apoptotic-like and regenerating muscle fibers, and neuromuscular junctions.

Mutations in the gene encoding survival motor neuron (SMN) protein are found in > 98% of patients with autosomal-recessive spinal muscular atrophy. We investigated the possible role of SMN in normal and abnormal human muscle by immunostaining biopsies of 20 patients with various neuromuscular diseases using monoclonal antibodies against SMN. SMN was strongly expressed cytoplasmically in chronic peripheral neuropathies, in about 80% of chronically denervated, very atrophic muscle fibers containing clumps of TUNEL-positive pyknotic nuclei: about 60% of those fibers also had cytoplasmic Bcl-2 and Bax immunoreactivity. In regenerating muscle fibers of various myopathies SMN co-localized with desmin, Bcl-2 and Bax; it was also present at the postsynaptic domain of normal human neuromuscular junctions. Thus, SMN may play a role in normal and pathological processes of adult human muscle fibers.

Apoptosis↗
PubMed1999

Diplopia secondary to aniseikonia associated with macular disease.

OBJECTIVE: To provide an explanation for diplopia and the inability to fuse in some patients with macular disease. METHODS: We identified 7 patients from our practices who had binocular diplopia concurrent with epiretinal membranes or vitreomacular traction. A review of the medical records of all patients was performed. In addition to complete ophthalmologic and orthoptic examinations, evaluation of aniseikonia using the Awaya New Aniseikonia Tests (Handaya Co Ltd, Tokyo, Japan) was performed on all patients. RESULTS: All patients were referred for troublesome diplopia. Six of the patients had epiretinal membranes and 1 had vitreomacular traction. All 7 patients had aniseikonia, ranging from 5% to 18%. In 5 of the patients the image in the involved eye was larger, and in the other 2 patients it was smaller than in the fellow eye. All patients had concomitant small-angle strabismus and at least initially did not fuse when the deviation was offset with a prism. Response to optical management and retinal surgery was variable. CONCLUSIONS: Aniseikonia caused by separation or compression of photoreceptors can be a contributing factor to the existence of diplopia and the inability to fuse in patients with macular disease. Concomitant small-angle strabismus and the inability to fuse with prisms may lead the clinician to the incorrect diagnosis of central disruption of fusion. Surgical intervention does not necessarily improve the aniseikonia.

Adult↗
PubMed1998

Impaired innervation of cultured human muscle overexpressing betaAPP experimentally and genetically: relevance to inclusion-body myopathies.

To investigate whether abnormally accumulated betaAPP may be responsible for denervation of muscle fibers that are present in hereditary inclusion-body myopathy (h-IBM) and sporadic inclusion-body myositis (s-IBM), we cultured five h-IBM and eight normal muscle biopsies. In eight other experiments, a 3 kb human 751-betaAPP-cDNA was transferred, using adenovirus vector, into cultured normal myotubes immediately after myoblast fusion. In all experiments, cultured muscle fibers were co-cultured with fetal rat spinal cord. Controls had no detectable betaAPP epitopes, whereas betaAPP epitopes were greatly increased in cultured h-IBM muscle and in cultured normal muscle after betaAPP-gene transfer. Innervated normal cultured muscle fibers were continuously contracting and fully cross-striated, and they had acetylcholine receptors (AChRs) and acetylcholinesterase (AChE) accumulated only at the neuromuscular junctions (NMJs). By contrast, both groups of betaAPP-overexpressing cultured muscle fibers were not contracting and not cross-striated; and did not have NJMs containing AChRs and AChE. Our results suggest that over-expression of betaAPP in cultured muscle fibers inhibits their innervation, and that the accumulation of betaAPP in muscle fibers of both h- and s-IBM patients may be responsible for their not becoming or remaining properly innervated or reinnervated, i.e. a 'myogenous-dysinnervation' mechanism.

Adult↗
PubMed1998

Immunolocalization of transcription factor NF-kappaB in inclusion-body myositis muscle and at normal human neuromuscular junctions.

To investigate whether nuclear factor kappaB (NF-kappaB) is involved in the pathogenesis of inclusion-body myositis (IBM), we immunostained muscle biopsies of eight patients with IBM with specific antibodies against its p50 and p65 subunits. Approximately 70% of IBM vacuolated muscle fibers had strong focal accumulations of both NF-kappaB p50 and p65, which by immunoelectronmicroscopy, localized mainly to clusters of paired-helical filaments (PHFs). Virtually all necrotic fibers, in various muscle biopsies, had diffusely strong p50 immunoreactivity, whereas p65 immunoreactivity was present only in a small subset of necrotic fibers. At all neuromuscular junctions, postsynaptically there was strong p65 but no p50 immunoreactivity. Our data suggest that NF-kappaB plays a role in IBM pathogenesis. Different distributions of NF-kappaB subunits in necrotic fibers and at normal neuromuscular junctions (NMJs) suggests different roles of each subunit in human muscle pathology and physiology.

Humans↗
PubMed1998

Sporadic inclusion-body myositis and its similarities to Alzheimer disease brain. Recent approaches to diagnosis and pathogenesis, and relation to aging.

Sporadic inclusion-body myositis (s-IBM) is the most common, debilitating and progressive muscle disease beginning at the age 50 or later. The most characteristic pathologic feature is vacuolar degeneration of muscle fibers accompanied by intrafiber congophilia and clusters ("tangles") of paired-helical filaments, containing phosphorylated tau. An unusual feature of sporadic inclusion-body myositis is accumulation within its abnormal muscle fibers of several proteins that are characteristic of Alzheimer disease brain, including epitopes of beta-amyloid precursor protein (betaAPP), phosphorylated tau, alpha-1-antichymotrypsin, apolipoprotein E, and presenilin-1. Indicators of oxidative stress are also present within abnormal s-IBM muscle fibers. In this review, we describe new advances seeking the pathogenic mechanism of sporadic inclusion-body myositis. We hypothesize on the possible pathogenic role of abnormally accumulated proteins, and we propose that important contributory factors leading to inclusion-body myositis are the milieu of muscle-fiber aging and oxidative stress. In addition, we present evidence that overexpression of adenovirus-transferred betaAPP gene in cultured human muscle fibers induces aspects of the inclusion-body myositis phenotype, and suggest that betaAPP-overexpression is an early event in the pathogenic cascade causing inclusion-body myositis.

Alzheimer Disease↗
PubMed1998

Nitric oxide-induced oxidative stress in autosomal recessive and dominant inclusion-body myopathies.

Autosomal-recessive and autosomal-dominant hereditary inclusion-body myopathies are severe, progressive muscle diseases, characterized pathologically by vacuolated muscle fibres containing paired helical filaments. We immunostained muscle biopsy specimens from quadriceps-sparing autosomal-recessive and autosomal-dominant inclusion-body myopathy subjects, disease-control subjects and normal patients, utilizing isoform-specific antibodies against the neuronal and inducible forms of nitric oxide synthase, and antibodies against nitrotyrosine. Approximately 75% of the vacuolated muscle fibres in all recessive and dominant inclusion-body myopathy patients contained inclusions strongly immunoreactive with antibodies against neuronal and inducible nitric oxide synthase which, by immunoelectron microscopy, were colocalized to clusters of tubulofilaments (previously shown, by us, to be paired helical filaments). Strong nitrotyrosine immunoreactivity was in the form of multiple dots and large granular patches, which ultrastructurally did not immunolocalize to tubulofilaments. Excess intracellular nitric oxide can combine with superoxide to produce highly toxic peroxynitrite, which can nitrate tyrosines of proteins. The presence of nitrotyrosine is indicative of nitric oxide-induced oxidative stress. Our data suggest that oxidative stress plays a role in the pathogenic cascade of hereditary inclusion-body myopathies.

Genes, Dominant↗
PubMed1998

Sporadic inclusion-body myositis and hereditary inclusion-body myopathies: current concepts of diagnosis and pathogenesis.

We discuss the pathologic diagnostic criteria and review the major new advances related to seeking the pathogenic mechanism of sporadic inclusion-body myositis (s-IBM) and hereditary inclusion-body myopathy (h-IBM). A classification of the various h-IBM syndromes is also presented. The several forms of the h-IBMs have different genetic transmissions and probably different genetic defects. In neither s-IBM nor the h-IBMs are the sequential steps of the pathogenic cascade understood. Because s-IBM and the h-IBMs have a number of characteristic pathologic features in common, we postulate that their different causes trigger the same upstream aberration leading to a similar downstream cascade of pathologic events, which are ultimately responsible for the characteristic muscle-fiber degeneration. Muscle-biopsy and experimental evidence is given supporting our hypothesis that overexpression of beta-amyloid precursor protein within abnormal muscle fibers is an early upstream event causing the pathogenic cascade. We also present evidence supporting our concept that muscle aging and oxidative stress are important factors contributing to the s-IBM-specific muscle fiber destruction. Additionally, the intriguing parallels between the pathologic phenotype of IBM muscle fibers and Alzheimer's disease brain are summarized.

Aging↗