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Biomedical subjects

I Nonaka

Publications and source records attributed to I Nonaka.

At least 37 records · Page 2Linked to original sources
PubMed2002

Gravitational unloading effects on muscle fiber size, phenotype and myonuclear number.

The effects of gravitational unloading with or without intact neural activity and/or tension development on myosin heavy chain (MHC) composition, cross-sectional area (CSA), number of myonuclei, and myonuclear domain (cytoplasmic volume per myonucleus ratio) in single fibers of both slow and fast muscles of rat hindlimbs are reviewed briefly. The atrophic response to unloading is generally graded as follows: slow extensors > fast extensors > fast flexors. Reduction of CSA is usually greater in the most predominant fiber type of that muscle. The percentage of fibers expressing fast MHC isoforms increases in unloaded slow but not fast muscles. Myonuclear number per mm of fiber length and myonuclear domain is decreased in the fibers of the unloaded predominantly slow soleus muscle, but not in the predominantly fast plantaris. Decreases in myonuclear number and domain, however, are observed in plantaris fibers when tenotomy, denervation, or both are combined with hindlimb unloading. All of these results are consistent with the view that a major factor for fiber atrophy is an inhibition or reduction of loading of the hindlimbs. These data also indicate that predominantly slow muscles are more responsive to unloading than predominantly fast muscles.

Animals↗
PubMed2002

Afferent input-associated reduction of muscle activity in microgravity environment.

Responses of electromyogram (EMG) of soleus, lateral portion of gastrocnemius (LG) and tibialis anterior (TA), and both afferent and efferent neurograms at the L(5) segmental level of the spinal cord, to altered gravity levels created by the parabolic flight of a jet airplane were investigated in adult rats. The EMG activity in antigravity soleus muscle gradually increased when the gravity was elevated from 1-G to 1.5-G (+23%) and 2-G (+67%) during the ascending phase of parabolic flight. The activity decreased approximately 72% from the 1-G level immediately when the rat was exposed to microgravity. The EMG level was maintained low during the 20-s microgravity, but it was restored immediately once the gravity level was increased to 1.5-G and then 1-G during the descending and recovery phase. The EMG level of LG also increased gradually when the gravity level was elevated and the level then decreased when the rat was exposed to microgravity (P>0.05). However, the activity level during the 20-s microgravity was identical to that obtained at 1-G. The EMG level of TA even increased insignificantly in response to the exposure to microgravity. The responses of afferent neurogram were similar to those of soleus EMG, even though the magnitude of the reduction of integrated neurogram level in response to microgravity exposure was small (approximately 26% vs. 1-G level) relative to that of soleus EMG. The level of efferent neurogram was also decreased, but only approximately 9% vs. 1-G level, during the 20-s microgravity. The data in the current study suggest that the afferent input is closely associated with the gravity-dependent muscular activity.

Aircraft↗
PubMed2001

Correlation of functional and ultrastructural abnormalities of mitochondria in mouse heart carrying a pathogenic mutant mtDNA with a 4696-bp deletion.

We examined the correlation of functional and structural abnormalities of cardiac mitochondria created by pathogenic mutant mtDNAs using mito-mice with hearts carrying 88% mutant DeltamtDNA4696 with a 4696 deletion. COX histochemistry, quantitative PCR analysis, and electronmicrographs showed that accumulation of 91.6% DeltamtDNA4696 in single cardiac muscle fibers induced progressive reduction of COX activity to form COX-negative fibers. Moreover, hearts carrying 88% DeltamtDNA4696 consisted of three types of cardiac muscle fibers with different functional properties, COX-positive, -negative, and -intermediate fibers, which corresponded respectively to three types of fibers with different structural properties; type A fibers containing mitochondria with only lamellar cristae, type B containing mitochondria with only tubular cristae, and type C possessing mitochondria with both lamellar and tubular cristae. These observations suggest that lamellar cristae with COX activity transform into tubular cristae without COX activity along with the accumulation of DeltamtDNA4696, which would be responsible for insufficient supply of mtDNA products required to keep the normal structure and function of mitochondrial cristae. The correlation of these structural and functional abnormalities of cristae should provide important insight into diagnosis of cardiomyopathies caused by accumulation of pathogenic mutant mtDNAs.

Animals↗
PubMed2001

Infantile autophagic vacuolar myopathy is distinct from Danon disease.

Lysosomal glycogen storage disease with normal acid maltase (Danon) is caused by primary lysosome-associated membrane protein-2 (LAMP-2) deficiency. Typically, the disease begins after the first decade; however, two infantile patients had similar histologic features. The infantile disorder is distinct from Danon disease, because, in both infants, LAMP-2 protein is present in skeletal muscle. Deposition of C5b-9 and multilayered basal lamina in one patient suggest that the infantile disease is pathogenically similar to X-linked myopathy with excessive autophagy.

Antigens, CD↗
PubMed2001

The sarcolemmal proteins dysferlin and caveolin-3 interact in skeletal muscle.

Dysferlin is a surface membrane protein in skeletal muscle whose deficiency causes distal and proximal, recessively inherited, forms of muscular dystrophy designated Miyoshi myopathy (MM) and limb girdle muscular dystrophy type 2B (LGMD2B), respectively. The function of dysferlin is not defined. Caveolin-3 is another skeletal muscle membrane protein which is important in the formation of caveolae and whose mutations cause dominantly inherited limb girdle muscular dystrophy type 1C (LGMD1C). We report that dysferlin co-immunoprecipitates with caveolin-3 from biopsied normal human skeletal muscles. We also describe abnormal localization of dysferlin in muscles from patients with LGMD1C including novel missense mutation (T64P) in the human caveolin-3 gene (CAV3). The immunoprecipitation data are consistent with the parallel observation that dysferlin immunostaining is not normal in LGMD1C muscles. Amino acid sequence analysis of the dysferlin protein reveals seven sites that correspond to caveolin-3 scaffold-binding motifs, and one site that is a potential target to bind the WW domain of the caveolin-3 protein. This is the first description of a possible dysferlin interacting protein; it suggests the hypothesis that one function of dysferlin may be to interact with caveolin-3 to subserve signaling functions of caveolae.

Caveolin 3↗
PubMed2001

Selective deficiency of alpha-dystroglycan in Fukuyama-type congenital muscular dystrophy.

BACKGROUND: Fukuyama-type congenital muscular dystrophy (FCMD) is an autosomal recessive disorder characterized by severe dystrophic muscle wasting from birth or early infancy with structural brain abnormalities. The gene for FCMD is located on chromosome 9q31, and encodes a novel protein named fukutin. The function of fukutin is not known yet, but is suggested to be an enzyme that modifies the cell-surface glycoprotein or glycolipids. OBJECTIVE: To elucidate the roles of fukutin gene mutation in skeletal and cardiac muscles and brain. METHODS: Immunohistochemical and immunoblot analyses were performed in skeletal and cardiac muscles and brain tissue samples from patients with FCMD and control subjects. RESULTS: The authors found a selective deficiency of highly glycosylated alpha-dystroglycan, but not beta-dystroglycan, on the surface membrane of skeletal and cardiac muscle fibers in patients with FCMD. Immunoblot analyses also showed no immunoreactive band for alpha-dystroglycan, but were positive for beta-dystroglycan in FCMD in skeletal and cardiac muscles. CONCLUSION: The current findings suggest a critical role for fukutin gene mutation in the loss or modification of glycosylation of the extracellular peripheral membrane protein, alpha-dystroglycan, which may cause a crucial disruption of the transmembranous molecular linkage of muscle fibers in patients with FCMD.

Adolescent↗
PubMed2001

Schwann cell myelination occurred without basal lamina formation in laminin alpha2 chain-null mutant (dy3K/dy3K) mice.

The laminin alpha2 chain is a major component of basal lamina in both skeletal muscle and the peripheral nervous system. Laminin alpha2 chain deficiency causes merosin-deficient congenital muscular dystrophy, which affects not only skeletal muscles, but also the peripheral and central nervous systems. It has been reported that the formation of basal lamina is required for myelination in the peripheral nervous system. In fact, the spinal root of dystrophic mice (dy/dy mice), whose laminin alpha2 chain expression is greatly reduced, shows lack of basal lamina and clusters of naked axons. To investigate the role of laminin alpha2 chain and basal lamina in vivo, we examined the peripheral nervous system of dy3K/dy3K mice, which are null mutants of laminin alpha2 chain. The results indicate the presence of myelination although Schwann cells lacked basal lamina in the spinal roots of dy3K/dy3K mice, suggesting that basal lamina is not an absolute requirement for myelination in vivo. Immunohistochemically, the expression of laminin alpha4 chain was increased and laminin alpha5 chain was preserved in the endoneurium of the spinal root. Laminin alpha4 and alpha5 chains may play the critical role in myelination instead of laminin alpha2 chain in dy3K/dy3K mice. In addition, the motor conduction velocity of the sciatic nerve was significantly reduced compared with that of wild-type littermate. This reduction in conduction velocity may be due to small axon diameter, thin myelin sheath and the patchy disruption of the basal lamina of the nodes of Ranvier in dy3K/dy3K mice.

Animals↗
PubMed2001

Apoptotic muscle fiber degeneration in distal myopathy with rimmed vacuoles.

Rimmed vacuole formation, tubulofilamentous nuclear inclusions and muscle fiber atrophy are the characteristic pathological findings in distal myopathy with rimmed vacuoles (DMRV). Necrotic muscle fibers were few in number and did not appear to account for the muscle weakness, but the nuclear changes with myofibrillar degeneration followed by rimmed vacuole formation appeared to be the major reason for the muscle fiber atrophy in DMRV. To determine whether the nuclear change in DMRV was related to apoptosis, we examined 15 muscle biopsy specimens immunohistochemically, and 7 of them ultrastructurally. The characteristic tubulofilamentous nuclear inclusions were found in 4 and the typical fragmented apoptotic nuclei in 3 of the 7 muscle biopsy samples examined by electron microscopy. TUNEL-positive nuclei reflecting apoptotic DNA fragmentation were found in 13 of 15 biopsies ranging from a few to approximately 1.5% of myonuclei. Apoptosis-specific protein was expressed in the sarcoplasm of atrophic fibers in 13 biopsies both with or without rimmed vacuoles. These findings suggest that the apoptotic process plays a crucial role in myofibrillar degeneration followed by autophagocytosis, i.e., rimmed vacuole formation, in DMRV.

Adult↗
PubMed2001

The significance of type 1 fiber atrophy (hypotrophy) in childhood neuromuscular disorders.

To determine the incidence of selective type 1 fiber atrophy (hypotrophy) and its possible significance in various muscle diseases of childhood, we reviewed 2212 muscle biopsies from children which we had examined in the past 20 years histochemically with ATPase staining. Type 1 fiber atrophy was seen in a variety of neuromuscular disorders, but predominantly in congenital myopathies, including all patients with congenital fiber type disproportion myopathy (20 patients), central core disease (12 patients) and multicore disease (four patients). Although type 1 fiber atrophy was not a constant feature in nemaline myopathy and myotubular myopathy, all patients with these diseases had abnormal fiber type distribution which included type 1 fiber predominance both with and without type 2B fiber deficiency. Together with abnormal fiber type distribution, type 1 fiber atrophy was a common finding in childhood neuromuscular disorders, especially congenital myopathies.

Atrophy↗
PubMed2001

A case of MERRF associated with chronic pancreatitis.

We report the first case to our knowledge of chronic pancreatitis associated with mitochondrial encephalopathy with the A8344G mitochondrial DNA (mtDNA) mutation. This 10-year-old-girl had suffered from recurrent abdominal pain with elevated serum amylase and lipase since the age of 6, and easy fatigability, tremor and astatic seizures since the age of 8. A biopsy of quadriceps muscle revealed ragged-red-fibers and cytochrome c oxidase deficiency. Analysis of mtDNA in peripheral blood identified an A8344G mutation in the mitochondrial tRNA(Lys) gene. Taken together with physical signs of myoclonic seizures and cerebellar dysfunction, we diagnosed her as myoclonic epilepsy with ragged-red fibers associated with chronic pancreatitis. Although no association between mitochondrial disease and pancreatitis has yet been established, this case suggests it is necessary to consider the participation of mitochondrial abnormality in the pathogenesis of recurrent pancreatitis.

Brain↗
PubMed2001

Massive muscle cell degeneration in the early stage of merosin-deficient congenital muscular dystrophy.

Primary merosin-deficient congenital muscular dystrophy (CMD) is a severe form of congenital muscular disorder which is caused by mutations in the laminin alpha2 chain gene (LAMA2). The disease is characterized by marked dystrophic changes in skeletal muscles during early infancy, while little is known about the pathological process of the muscle fiber degeneration. Here, we report the immunohistochemical analysis of skeletal muscle in ten patients with primary merosin-deficient CMD using a panel of molecular markers for skeletal muscle proteins, cellular necrosis, and apoptosis. In the youngest patient (a 52 day old baby), prominent massive muscle cell degeneration occurred in association with the deposition of the C5-9 complement membrane attack complex (MAC). Most of the MAC-positive muscle fibers showed a severely deranged immunoreaction to dystrophin, dystroglycans, and other sarcolemmal proteins. In addition, we found scattered positive signals for apoptosis. Similar but milder changes were also observed in six other patients younger than 1 year. In the patients older than 3 years, muscle fibers positive for MAC and apoptotic signals were barely detectable. These findings imply that massive muscle fiber degeneration occurs in the very early stage of merosin-deficient CMD and may contribute to the severe dystrophic changes in muscle from early infancy.

Biopsy↗
PubMed2001

A mitochondrial encephalo-myo-neuropathy with a nucleotide position 3271 (T-C) point mutation in the mitochondrial DNA.

We report three members of a family, who exhibited a phenotype similar to 'myoclonus epilepsy with ragged-red fibers' but had a genotype usually associated with 'mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes'. The patients, a 48-year-old female, and her two sons, aged 21 and 19 respectively, presented with photo-reactive syncopal episodes, disturbances of gait and writing, dysarthria and finger tremor since the 3rd and 2nd decade of life, respectively, that were accompanied also by numbness and weakness of the extremities. Subsequently, cerebellar ataxia and myoclonus were also noted. Electromyography revealed both myogenic and neurogenic muscular changes, and nerve conduction studies demonstrated a sensory-motor neuropathy. Biopsy showed ragged-red fibers with strongly stained SDH-positive vessels in skeletal muscles, and a marked loss of myelinated fibers of the sural nerves. Mitochondrial (mt) DNA analyses of peripheral blood, muscles and nerves revealed that all members had a heteroplasmic np3271 (T-C) point mutation in the mitochondrial tRNA-Leu gene (UUR). This family is unique, in that all patients presented with a myoclonus epilepsy with ragged-red fibers-like phenotype and had a distinctive peripheral neuropathy, while the detected mtDNA 327l (T-C) mutation has been reported to date only in rare cases of mitochondrial encephalomyopathy with lactic acidosis and stroke-like episodes

Adult↗
PubMed2001

Calpain 3 gene mutations: genetic and clinico-pathologic findings in limb-girdle muscular dystrophy.

Mutations in the calpain 3 gene have been proven to be responsible for limb-girdle muscular dystrophy (LGMD) type 2A. To determine the incidence and genotypes of the calpain 3 (p94) gene mutations in Japanese LGMD patients, we sequenced the gene in 80 patients with clinical characteristics of autosomal recessive or sporadic LGMD. We identified 13 distinct pathogenic mutations in 21 patients (26%), including seven missense mutations, four splice-site mutations and two insertions in which six were novel mutations. Among the 21 patients, 15 (71%) had three types of the common missense (G233V, R461C, D707G) and one insertion (1795-1796insA) mutation. The patients had slowly progressive muscle weakness with age of onset of the disease varying from 6 to 52 years, averaging 20.9. The most striking pathologic findings were the presence of lobulated fibers in 14 patients, especially in the advanced stages. Differing from Duchenne and Becker muscular dystrophy, opaque (hypercontracted) fibers were very rarely seen. These findings may be helpful in establishing diagnostic screening strategies in Japanese LGMD patients.

Adolescent↗
PubMed2001

Oculopharyngodistal myopathy is genetically heterogeneous and most cases are distinct from oculopharyngeal muscular dystrophy.

The question whether oculopharyngodistal myopathy (MIM 164310) is a distinct disease entity or a variant of oculopharyngeal muscular dystrophy (MIM 164300) persists. To answer this question, we examined five patients with the clinical characteristics of oculopharyngodistal myopathy for GCG expansion in poly(A)-binding protein nuclear 1 gene (previously called poly(A)-binding protein 2), the causative gene defect for oculopharyngeal muscular dystrophy. Only one of our five patients had the significant GCG expansion. Thus, oculopharyngodistal myopathy is a genetically heterogeneous disorder, which includes patients with oculopharyngeal muscular dystrophy but, for the most part, is different genetically from oculopharyngeal muscular dystrophy.

Aged↗
PubMed2001

Novel exon 11 skipping mutation in a patient with glycogen storage disease type IIId.

We report the molecular genetic abnormalities of a patient with GSD IIId presenting with progressive myopathy and cardiopathy leading to a fatal outcome. We identified two independent deletions including a 4 bp deletion (117-1120) and a 98 bp deletion (1135-1232) in cDNA. Sequencing of the genomic DNA of the corresponding region revealed a 4 bp deletion in exon 10; however, the other 98 bp deletion corresponding to exon 11, which was deleted in cDNA, was present in genomic DNA. We therefore concluded that skipping of exon 11 occurred in the cDNA of the patient. Intron/exon boundary analysis of the skipped exon 11 revealed no mutation in the consensus splice-site sequence. If normal splicing had occurred, a stop codon would have appeared within exon II due to frameshift mutation. The mechanism of exon skipping observed in our patient is as yet unknown, and it is still not clear whether intraexonal mutation of the preceding exon can influence splice-site selection. It is possible that a unique exon skipping occurred, preventing the appearance of a stop codon in our patient.

Adult↗
PubMed2001

Inter-mitochondrial complementation: Mitochondria-specific system preventing mice from expression of disease phenotypes by mutant mtDNA.

Here we investigated the pathogenesis of deletion mutant mitochondrial (mt)DNA by generating mice with mutant mtDNA carrying a 4696-basepair deletion (DeltamtDNA4696), and by using cytochrome c oxidase (COX) electron micrographs to identify COX activity at the individual mitochondrial level. All mitochondria in tissues with DeltamtDNA4696 showed normal COX activity until DeltamtDNA4696 accumulated predominantly; this prevented mice from expressing disease phenotypes. Moreover, we did not observe coexistence of COX-positive and -negative mitochondria within single cells. These results indicate the occurrence of inter-mitochondrial complementation through exchange of genetic contents between exogenously introduced mitochondria with DeltamtDNA4696 and host mitochondria with normal mtDNA. This complementation shows a mitochondria-specific mechanism for avoiding expression of deletion-mutant mtDNA, and opens the possibility of a gene therapy in which mitochondria possessing full-length DNA are introduced.

Animals↗