Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026850 (muscular dystrophy)
 5,870 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Carbonic anhydrase activity, a marker of mouse proprioceptive neurons in adult dorsal root ganglia, is first detectable in the perinatal period, increases until postnatal day 60 and remains stable in adulthood. The onset of carbonic anhydrase staining begins after the neurons have made connections with their targets suggesting that neuron-target interactions regulate carbonic anhydrase phenotype development. To examine this possibility, we first analysed carbonic anhydrase expression in mdx mice which are characterized by a massive but reversible degeneration of skeletal muscle concomitant with the carbonic anhydrase ontogenesis. Neuronal carbonic anhydrase expression in mdx mice stopped developing when the period of muscular degeneration-regeneration began. Furthermore this alteration persisted during adulthood. We then analysed carbonic anhydrase expression in fifth lumbar dorsal root ganglion of developing control mice before and after surgical procedures that might interfere with central and peripheral target influences on dorsal root ganglion neurons. Central disconnection (dorsal rhizotomy) did not affect the development of carbonic anhydrase activity. Disrupting neuron-peripheral target interactions by sciatic nerve transection or blocking muscle contraction by tenotomy stopped the development of neuronal carbonic anhydrase content. Finally, recovery was monitored following sciatic nerve crush. In adults, recovery of carbonic anhydrase activity was obtained after functional recuperation; similar manipulations during the first month of life induced irreversible alteration of the carbonic anhydrase phenotype. These results show that the development of carbonic anhydrase activity in proprioceptive neurons is regulated by neuron-muscle interactions (i.e. muscle contraction). They also provide evidence for a critical period in the development of the carbonic anhydrase phenotype. We suggest that these two mechanisms are responsible for the altered carbonic anhydrase phenotype of the dorsal root ganglion neurons in mdx mice, a model of human muscular dystrophy.
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PMID:Early postnatal muscle contractile activity regulates the carbonic anhydrase phenotype of proprioceptive neurons in young and mature mice: evidence for a critical period in development. 886 50

Neuronal nitric oxide synthase (nNOS) is a component of the dystrophin complex in skeletal muscle. The absence of dystrophin protein in Duchenne muscular dystrophy and in mdx mouse causes a redistribution of nNOS from the plasma membrane to the cytosol in muscle cells. Aberrant nNOS activity in the cytosol can induce free radical oxidation, which is toxic to myofibers. To test the hypothesis that derangements in nNOS disposition mediate muscle damage in Duchenne dystrophy, we bred dystrophin-deficient mdx male mice and female mdx heterozygote mice that lack nNOS. We found that genetic deletion of nNOS does not itself cause detectable pathology and that removal of nNOS does not influence the extent of increased sarcolemmal permeability in dystrophin-deficient mice. Thus, histological analyses of nNOS-dystrophin double mutants show pathological changes similar to the dystrophin mutation alone. Taken together, nNOS defects alone do not produce muscular dystrophy in the mdx model.
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PMID:Muscular dystrophy in mdx mice despite lack of neuronal nitric oxide synthase. 968 70

Neuronal nitric oxide synthase (nNOS) is abundantly expressed in skeletal muscle where it associates with the dystrophin complex at the sarcolemma by binding to the PDZ domain of alpha-syntrophin. Nitric oxide (NO) produced by skeletal muscle nNOS is proposed to regulate blood flow in exercising muscle by diffusing from the skeletal muscle fibers to the nearby microvessels where it attenuates alpha-adrenergic vasoconstriction. In the present study, we hypothesized that sarcolemmal localization of nNOS is a critical determinant of the vasoregulatory effect of skeletal muscle-derived NO. To test this hypothesis, we performed experiments in alpha-syntrophin null mice and in transgenic mice expressing a mutated alpha-syntrophin lacking the PDZ domain (DeltaPDZ), both of which are characterized by reduced sarcolemmal nNOS. We found that modulation of alpha-adrenergic vasoconstriction was greatly impaired in the contracting muscles of the alpha-syntrophin null mice and transgenic DeltaPDZ mice compared with wild-type mice and transgenic mice expressing full-length alpha-syntrophin. These in vivo mouse studies highlight the functional importance of appropriate membrane targeting of nNOS by the dystrophin-associated protein alpha-syntrophin and may have implications for the development of potential gene therapy strategies to treat muscular dystrophy or other muscle-related diseases.
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PMID:Vasomodulation by skeletal muscle-derived nitric oxide requires alpha-syntrophin-mediated sarcolemmal localization of neuronal Nitric oxide synthase. 1260 Aug 81

Skeletal muscles become atrophied by muscular disorders such as muscular dystrophy, wasting and even aging. In addition to muscle atrophy, progressive muscle damage, inflammation and replacement of muscle fibers with fibrous and fatty tissues are observed in muscular dystrophy. Neuronal innervation is required for skeletal muscle, and muscles become atrophic when motor neurons are affected by neurodegenerative disorders such as amyotrophic lateral sclerosis. Restoring muscle mass and function lost by diseases such as muscular dystrophy and neurodegenerative disorders is important. There are three rational therapies for muscular dystrophy and related diseases: gene therapy, cell therapy and drug therapy. Gene therapies to replace the defective genes have been tried with various degrees of effectiveness. Multiple myogenic stem cells including satellite cells, bone marrow cells, muscle side population cells, muscle-derived stem cells and mesoangioblast have been characterized. Cell therapies using these stem cells are one of the promising therapies for neuromuscular diseases causing muscle atrophy. As pharmacological drug therapies, increasing skeletal muscle mass by myostatin inhibition is quite promising and will be applied clinically in the near future.
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PMID:[Development of therapies against neuromuscular diseases causing muscle atrophy]. 1724 Aug 49

Duchenne muscular dystrophy (DMD) is the most common form of muscular dystrophy with no cure currently available. In this study, using two microarray data sets obtained from the Gene Expression Omnibus database, we conducted a dysfunctional pathway-enrichment analysis and investigated deregulated genes that are specific to different phases of the disease in order to determine pathogenic characteristics in the progression of DMD. We identified 41 and 33 dysfunctional pathways that were enriched with differentially expressed genes in presymptomatic patients and in symptomatic patients, respectively. Over 70% of pathways were shared between both phases and many of them involved the inflammatory process, suggesting that inflammatory cascades were induced soon after the birth of the patients. Further investigation showed that presymptomatic patients performed better with respect to muscle regeneration and cardiac muscle calcium homeostasis maintenance. Neuronal nitric oxide synthase, dihydropyridine receptors, sarcoplasmic/endoplasmic reticulum calcium ATPase, and phospholamban may serve as potential targets for further molecular diagnostic tests. Our results may provide a better understanding for the treatment of DMD.
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PMID:Gene expression profiling of Duchenne muscular dystrophy reveals characteristics along disease progression. 2463 39

Neuronal aging involves a progressive decline in cognitive abilities and loss of motor function. Mutations in human Lamin genes (LMNA, LMNB1, LMNB2) lead to a wide-range of diseases including muscular dystrophy, peripheral neuropathy and progeria. Here we investigate the role of neuronal Lamin in regulating age-related phenotypes. Neuronal targeting of Lamin led to shortened lifespan, progressive impairment of motor function and loss of dopaminergic (DA) neurons within the protocerebral anterior medial (PAM) cluster in the Drosophila melanogaster brain. Loss of neuronal Lamin caused an age-related decline in neural physiology, with slower neurotransmission and increased chance of motor circuit failure with age. Unexpectedly, Lamin-dependent decline in motor function was specific for the chemical synapses of the dorsal longitudinal muscle (DLM). Together these findings highlight a central role for Lamin dysfunction in regulating neuronal survival and motor circuit physiology during aging.
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PMID:Neuronal Lamin regulates motor circuit integrity and controls motor function and lifespan. 3122 90