Does aberrant architecture of nuclear LINC complex stop muscle cell development?

The linker of nucleoskeleton and cytoskeleton (LINC) complex is a structure that spans the entire nuclear envelope (NE) and integrates the nuclear interior with the cytoskeleton. Lamin A/C together with nesprins that mainly reside along the inner nuclear membrane (INM) and outer nuclear membrane (ONM) are core components of the LINC complex. Integrity of this specific nuclear structure is critical for muscle cell maturation and function. In the present study, we analyzed the ultrastructure of the LINC complex observed in two neonates with severe hypotonia and respiratory distress. Disruption of the LINC complex manifests in a wide separation of the ONM from the INM; the loss of perinuclear space (PNS) and delayed muscle cell maturation were predominating findings. This nuclear phenomenon has never been reported and provides further support for the appearance of a neonatal form of laminopathy.

Did giant mitochondria delay muscle maturation? An uncommon congenital myopathy.

INTRODUCTION: Mitochondria are semi-autonomous organelles that are able to change their shape, size, location, and number inside the living cell. Mitochondrial division is an extremely important process, because cell survival depends on there being an adequate number of mitochondria in each cell. The dynamics of these organelles are particularly important for normal embryonic cell development. We studied morphological and ultrastructural features of muscle-cell immaturity, with the appearance of abnormal giant mitochondria, in a child with an unusual congenital myopathy. METHODS: The biceps brachii and quadriceps femoris muscles were analyzed at the light and electron microscopy levels. RESULTS: Ultrastructural features of muscle-cell immaturity were manifested in the presence of primary and mature myotubes coexisting with abnormal giant mitochondria. CONCLUSIONS: Failure of mitochondrial fusion/fission machinery at an early stage of development may lead to delayed muscle-cell maturation.

Motor endplate remodeling in some cases with congenital myasthenic syndrome.

The architecture of motor endplates in three cases with congenital myasthenic syndrome (CMS) was compared with ultrastructure of the normal control neuromuscular junction (NMJ). The remodeling of postsynaptic region was observed in all three individuals. The most conspicuous abnormalities seen in the slow channel syndrome was the vacuolization and disorganization of secondary synaptic clefts which extended for beyoned the border of NMJ. Degenerated postsynaptic nuclei and junctional sarcoplasm were an additional feature of presented syndromes. The quite different feature of NMJ was observed in the DOK-7 deficient syndrome. The appearance of small, pale terminal axons, poorly developed postsynaptic membrane with the sparse secondary synaptic clefts and degenerated postsynaptic nuclei suggested impairment of postsynaptic region maturation. The conjunction of postsynaptic membrane paucity and its degeneration was a specific structural feature observed in the third syndrome with no established genetic defects.

Ultrastructural evidence of myocardial capillary remodeling in peripartum cardiomyopathy.

BACKGROUND: The etiology of peripartum cardiomyopathy (PPCM) is not well understood. Potential causal mechanisms include infection, autoimmune disease, and abnormal response to the hemodynamic stress of pregnancy. Recently it was shown that the development of PPCM in an experimental model is associated with the generation of a cleaved antiangiogenic and proapoptotic 16-kDa form of the nursing hormone prolactin, which impairs the cardiac capillary network and its function. The purpose of this study was to evaluate the ultrastructure of the myocardium in a patient with PPCM and in a comparative group of patients and to identify structural characteristics that may predispose to myocardium dysfunction. CASE REPORT: A 28-year-old woman with PPCM had fulminant heart failure leading to the implantation of a biventricular assist device, but no myocarditis was found on histological examination of her myocardial tissue. An ultrastructural study of myocardial tissue taken from three patients (mean age: 22 years, 2 females) with fulminant heart failure not related to PPCM (2 myocarditis, 1 dilated cardiomyopathy) served as a comparison. The ultrastructural analysis revealed the presence of small capillary damage. Vascular lumen occlusion, endothelial cell remodeling, and apoptosis with the appearance of mast cells, plasma cells, and preadipocytes were the most characteristic features of the damaged myocardial tissue with secondary interstitial fibrosis. No vascular pathology of cardiac capillaries was observed in the comparative group. CONCLUSIONS: A myocardial tissue study in PPCM revealed ultrastructural remodeling of small capillaries with the presence of endothelial cell apoptosis and impairment of the microcirculation.

Nuclear architecture remodelling in cardiomyocytes with lamin A deficiency.

We analysed the architecture of cardiomyocyte nuclei lacking lamin A activity in three patients with dilated cardiomyopathy. The diagnosis was established on the basis of clinical and electrophysiological examinations, chest radiography and electrocardiography. An ultrastructural study of affected cardiomyocytes showed dramatic alterations in nuclear distribution and organization affecting nuclear shape, lamina structure, chromatin and nuclear interior organization. The most specific hallmark of nuclei with lamin A deficiency was the reorganization of the nuclear interior, the appearance of a various number of mitochondria within the nuclear matrix, and focal or total lack of nuclear membrane.

Nuclear architecture remodelling in envelopathies.

We performed ultrastructural studies on nuclear abnormalities in muscle from 8 patients with X-linked and autosomal dominant form of Emery-Dreifuss muscular dystrophy (EDMD) and one case with progeroid syndrome. The diagnosis was based on clinical and molecular findings. We detected various degrees of nuclear architecture remodelling ranging from misshapen shape, nuclear disintegration, nuclear chromatin condensation and decondensation, focal chromatin loss to complete nuclear fragmentation. The most interesting finding was the appearance of tubulofilamentous inclusions inside the nuclear matrix of X-linked EDMD patients. All these nuclear aberrations are considered to be structural indicators of nuclear dysfunction evoked by envelope protein deficiency.

Rimmed vacuoles with beta-amyloid and tau protein deposits in the muscle of children with hereditary myopathy.

We investigated whether beta-amyloid and tau protein are involved in the formation of inclusion body myositis (IBM)-like inclusions found in children with rimmed vacuoles and congenitally affected muscles. We immunostained muscle biopsy specimens from four children and one 18-year-old boy with congenital myopathy containing rimmed vacuoles and IBM-like inclusions with antibodies against beta-amyloid, tau protein and ubiquitin. Focal accumulations of both beta-amyloid and phosphorylated tau coexisted with tubulofilamentous structures in all cases. Our studies demonstrate for the first time that the full morphological phenotype of IBM including beta-amyloid and tau protein deposits may also develop in children, and that congenital, probably genetic, muscle defects may lead to abnormal protein aggregation in IBM-like inclusions.

Is the normal content of sulfhydryl groups attributable to sparing from dystrophic pathology in dystrophin-deficient muscles?

Deficiency of dystrophin in skeletal muscles is supposed to be responsible for all the symptoms associated with Duchenne dystrophy (DMD) and Becker dystrophy (BMD). The dystrophin-deficient mdx mice, however, are clinically almost asymptomatic. Hence, other factor(s) might be responsible for the muscle pathology in DMD and BDM. As sulfhydryl groups are involved in maintaining the structure of membranes and the protein-phospholipid interactions, total, protein-bound and free sulfhydryl groups (-SH) in DMD, BMD, limb-girdle dystrophy (LGMD) and the mdx mice muscles have been determined. A significant decrease of total and protein-bound -SH groups content and an increased proportion of free -SH groups in DMD and BMD was found. In LGMD the changes of total and protein-bound -SH groups content were less expressed. In the mdx mice muscles the content of -SH groups was generally normal, only a higher than normal proportion of free-SH groups content in old and senile animals, especially in their diaphragm, was present. To test the sarcolemmal integrity, albumin/creatine kinase (CK) influx/efflux was determined. In early stages of DMD and BMD the albumin influx was increased. In advanced stages of these diseases albumin influx was not observed. In LGMD albumin penetration was present only in a few fibres. CK efflux in vitro was increased both in early and advanced DMD cases. In BMD and LGMD CK efflux was increased only in early stages of the diseases. In mdx mice an increased influx/efflux of albumin/CK was stated in adult animals. The changes persisted in the mdx hind limb muscles up to the senile age of the animals. In the mdx diaphragm of senile animals albumin did not penetrate the muscle cell and no increase of CK efflux was observed. It is suggested that changes in the distribution of -SH groups take part in the molecular disorganisation of the sarcolemma in course dystrophinopathies. Normal content of the sulfhydryl groups is supposed to be attributable to sparing from dystrophic pathology in dystrophin-deficient mdx mice muscles.