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

Skeletal muscle atrophy/wasting is a serious complication of a wide range of diseases and conditions such as aging, disuse, AIDS, chronic obstructive pulmonary disease, space travel, muscular dystrophy, chronic heart failure, sepsis, and cancer. Emerging evidence suggests that nuclear factor-kappa B (NF-kappaB) is one of the most important signaling pathways linked to the loss of skeletal muscle mass in various physiological and pathophysiological conditions. Activation of NF-kappaB in skeletal muscle leads to degradation of specific muscle proteins, induces inflammation and fibrosis, and blocks the regeneration of myofibers after injury/atrophy. Recent studies employing genetic mouse models have provided strong evidence that NF-kappaB can serve as an important molecular target for the prevention of skeletal muscle loss. In this article, we have outlined the current understanding regarding the role of NF-kappaB in skeletal muscle with particular reference to different models of muscle wasting and the development of novel therapy.
 ...
PMID:Nuclear factor-kappa B signaling in skeletal muscle atrophy. 1857 72

In addition to gene correction therapy and cell transplantation techniques, multidisciplinary approaches to drug discovery and development offer promising therapeutic strategies for intractable genetic muscular disorders including muscular dystrophy. Inhibition of the production and activity of myostatin, a potent growth factor that determines skeletal muscle size, is a novel strategy for the treatment of muscle-wasting disorders such as muscular dystrophy, cachexia and sarcopenia. Myostatin blockers include myostatin-blocking antibodies, myostatin propeptide, follistatin and follistatin-related proteins, soluble myostatin receptors, small interfering RNA and small chemical inhibitors. This review describes the discovery and development of myostatin inhibitors.
 ...
PMID:Targeting myostatin for therapies against muscle-wasting disorders. 1860 May 66

Recessive X-linked amyotrophic spinobulbar muscular atrophy (SBMA) or Kennedy disease is a neuroendocrine disorder with a slowly progressive phenotype, caused by an expansion of a polymorphic tandem CAG repeat of the androgen receptor gene. Classical clinical hallmarks include onset in the third decade of life, weakness and wasting predominantly in proximal extremity muscles, variable weakness of bulbar muscles, abundant muscle fasciculations, sensory nerve action potential abnormalities and signs of androgen insensitivity such as gynecomastia and testicular atrophy. The diagnosis has been recently made easier by the availability of genetic testing but Kennedy disease is probably still underdiagnosed because of phenotypic variability. We report 11 new cases, of which seven had atypical initial manifestations presenting respectively with myasthenia, cramps and fasciculation syndrome, polyneuropathy, post-trauma monomelic neuronopathy, effort-dependent muscle intolerance and/or muscular dystrophy, with the aim to enlarge the phenotypic spectrum of the published series.
 ...
PMID:[Multiple phenotypic manifestations of X-linked spinobulbar muscular atrophy]. 1866 19

Inhibition or blockade of myostatin, a negative growth factor of skeletal muscle, enhances muscle growth and therefore is considered a promising strategy for the treatment of muscle-wasting diseases such as the muscular dystrophies. Previously, we showed that myostatin blockade in both normal and dystrophin-deficient mdx mice by systemic delivery of the myostatin propeptide (MPRO) gene by an adeno-associated virus serotype 8 (AAV8) vector could enhance muscle growth and ameliorate dystrophic lesions. Here, we further investigate whether the muscle growth effect of myostatin blockade can be achieved in dogs by gene transfer. First, we cloned the canine MPRO gene, packaged it in the AAV8 vector, and showed robust muscle-enhancing effects after systemic delivery into neonatal mice. This vector was then further tested in two 3-month-old normal dogs (weighing 9.7 and 6.3 kg). The vector was delivered to one limb by hydrodynamic vein injection, and the contralateral limb served as a control. The delivery procedure was safe, without discernible adverse effects. AAV vector DNA and MPRO gene expression were detected by quantitative polymerase chain reaction, Western blotting, and immunofluorescence staining of muscle biopsies. Overexpression of MPRO resulted in enhanced muscle growth without a cytotoxic T lymphocytic immune response, as evidenced by larger myofibers in multiple muscles, increased muscle volume determined by magnetic resonance imaging, and the lack of CD4+ and CD8+ T cell infiltration in the vector-injected limbs. Our preliminary study thus supports further investigation of this therapeutic strategy in the dystrophin-deficient golden retriever muscular dystrophy dog model.
 ...
PMID:Hydrodynamic limb vein injection of adeno-associated virus serotype 8 vector carrying canine myostatin propeptide gene into normal dogs enhances muscle growth. 1882 9

Duchenne muscular dystrophy (DMD) is the most common, lethal, muscle-wasting disease of childhood. Previous investigations have shown that muscle macrophages may play an important role in promoting the pathology in the mdx mouse model of DMD. In the present study, we investigate the mechanism through which macrophages promote mdx dystrophy and assess whether the phenotype of the macrophages changes between the stage of peak muscle necrosis (4 weeks of age) and muscle regeneration (12 weeks). We find that 4-week-old mdx muscles contain a population of pro-inflammatory, classically activated M1 macrophages that lyse muscle in vitro by NO-mediated mechanisms. Genetic ablation of the iNOS gene in mdx mice also significantly reduces muscle membrane lysis in 4-week-old mdx mice in vivo. However, 4-week mdx muscles also contain a population of alternatively activated, M2a macrophages that express arginase. In vitro assays show that M2a macrophages reduce lysis of muscle cells by M1 macrophages through the competition of arginase in M2a cells with iNOS in M1 cells for their common, enzymatic substrate, arginine. During the transition from the acute peak of mdx pathology to the regenerative stage, expression of IL-4 and IL-10 increases, either of which can deactivate the M1 phenotype and promote activation of a CD163+, M2c phenotype that can increase tissue repair. Our findings further show that IL-10 stimulation of macrophages activates their ability to promote satellite cell proliferation. Deactivation of the M1 phenotype is also associated with a reduced expression of iNOS, IL-6, MCP-1 and IP-10. Thus, these results show that distinct subpopulations of macrophages can promote muscle injury or repair in muscular dystrophy, and that therapeutic interventions that affect the balance between M1 and M2 macrophage populations may influence the course of muscular dystrophy.
 ...
PMID:Shifts in macrophage phenotypes and macrophage competition for arginine metabolism affect the severity of muscle pathology in muscular dystrophy. 1899 17

Muscular dystrophies refer to a group of inherited disorders characterized by progressive muscle weakness, wasting and degeneration. So far, there is no effective treatment but new gene-based therapies are currently being developed with particular noted advances in using conventional gene replacement strategies, RNA-based approaches, or cell-based gene therapy with a main focus on Duchenne muscular dystrophy (DMD). DMD is the most common and severe form of muscular dystrophy and current treatments are far from adequate. However, genetic and cell-based therapies, in particular exon skipping induced by antisense strategies, and corrective gene therapy via functionally engineered dystrophin genes hold great promise, with several clinical trials ongoing. Proof-of-concept of exon skipping has been obtained in animal models, and most recently in clinical trials; this approach represents a promising therapy for a subset of patients. In addition, gene-delivery-based strategies exist both for antisense-induced reading frame restoration, and for highly efficient delivery of functional dystrophin mini- and micro-genes to muscle fibres in vivo and muscle stem cells ex-vivo. In particular, AAV-based vectors show efficient systemic gene delivery to skeletal muscle directly in vivo, and lentivirus-based vectors show promise of combining ex vivo gene modification strategies with cell-mediated therapies.
 ...
PMID:Gene therapy for muscular dystrophy: current progress and future prospects. 1952 8

Muscular dystrophy is a general term encompassing muscle disorders that cause weakness and wasting, typically leading to premature death. Membrane instability, as a result of a genetic disruption within the dystrophin-glycoprotein complex (DGC), is thought to induce myofiber degeneration, although the downstream mechanism whereby membrane fragility leads to disease remains controversial. One potential mechanism that has yet to be definitively proven in vivo is that unregulated calcium influx initiates disease in dystrophic myofibers. Here we demonstrate that calcium itself is sufficient to cause a dystrophic phenotype in skeletal muscle independent of membrane fragility. For example, overexpression of transient receptor potential canonical 3 (TRPC3) and the associated increase in calcium influx resulted in a phenotype of muscular dystrophy nearly identical to that observed in DGC-lacking dystrophic disease models, including a highly similar molecular signature of gene expression changes. Furthermore, transgene-mediated inhibition of TRPC channels in mice dramatically reduced calcium influx and dystrophic disease manifestations associated with the mdx mutation (dystrophin gene) and deletion of the delta-sarcoglycan (Scgd) gene. These results demonstrate that calcium itself is sufficient to induce muscular dystrophy in vivo, and that TRPC channels are key disease initiators downstream of the unstable membrane that characterizes many types of muscular dystrophy.
 ...
PMID:Calcium influx is sufficient to induce muscular dystrophy through a TRPC-dependent mechanism. 1986 20

The broad category of neuromuscular diseases covers conditions that involve the weakness or wasting of the body muscles. These problems may occur in the spinal cord, the peripheral nerves or the muscle fibers. Some may be hereditary, while others are acquired. Commonly recognized conditions fall into the categories of myopathies, which are diseases of the muscle like muscular dystrophy, disorders of the junction where the nerve impulses are transmitted to the muscle like myasthenia gravis, and neuropathies, which are diseases of the peripheral nervous system. The diagnosis of most neuromuscular diseases rest on careful clinical evaluation of the patient, electromyography, the muscle biopsy, and in some instances, molecular genetic studies. Muscle biopsy, associated to histochemical and immunohistological techniques, plays a key role in diagnosis of many neuromuscular disorders. A number of morphological abnormalities of muscle can be recognized on histological stains such as haematoxylin and eosin and Engel trichrome. Histochemical techniques are essential for the study of muscle biopsies for four main reasons. First, they demonstrate the non-uniform nature of the muscle highlighting the different biochemical properties of specific fibre type and their selective involvement in certain disease processes. Second, they may show an absences of a particular enzyme. Third, an excess of a particular substrate can be demonstrated. Fourth, they may show structural changes in the muscle which would not be apparent with routine histological stains, such as the enzyme-deficient cores in central core disease "mouth-eaten" fibers, and abnormalities in the distribution of mitochondria. In some neuromuscular disorders there could be only non-specific myopathological features. However, a number of proteins, including sarcolemmal, sarcomeric, and nuclear proteins as well as enzymes with defects responsible for neuromuscular disorders, have been identified during the past two decades, allowing a more specific and firm diagnosis of muscle diseases. Identification of protein defects relies predominantly on immunohistochemical preparations and on Western blot analysis. While immunohistochemistry is very useful in identifying abnormal expression of primary protein abnormalities in recessive conditions, it is less helpful in detecting primary defects in dominantly inherited disorders. Abnormal immunohistochemical expression patterns can be confirmed by Western blot analysis which may also be informative in dominant disorders. Besides identification of specific protein defects, immunohistochemistry is also helpful in the differentiation of inflammatory myopathies by subtyping cellular infiltrates and demonstrating up-regulation of subtle immunological parameters. This review will summarize and describe the impact that histochemistry and immunohistochemistry has had and the possibilities it has opened up in the diagnosis of neuromuscular disorders in human as well as in veterinary myology.
 ...
PMID:Histochemical and immunohistological approach to comparative neuromuscular diseases. 1999 99

Mutations in the gene encoding skeletal muscle alpha-actin (ACTA1) account for approx. 20% of patients with the muscular disorder nemaline myopathy. Nemaline myopathy is a muscular wasting disease similar to muscular dystrophy, but distinguished by deposits of actin and actin-associated proteins near the z-line of the sarcomere. Approx. one-third of the over 140 myopathy actin mutations have been characterized either biochemically or in cultured cells to determine their effects on the actin cytoskeleton. However, the actin defects causing myopathy are likely to be heterogeneous, with only a few common trends observed among the actin mutants, such as reduced polymerization capacity or an inability to fold properly. Notably, the transcriptional programme regulated by serum-response factor, which is instrumental in muscle development and maintenance, is directly controlled by the balance of actin assembly and disassembly in cells. In the present study, we explored the impact of myopathy mutations in actin on the control of the transcriptional response by serum-response factor and found that the majority of mutants examined have altered serum-response factor signalling. We propose that altered serum-response factor signalling could be a major factor in actin-based nemaline myopathy, and that this area could be exploited to develop therapies for sufferers.
 ...
PMID:Myopathy-causing actin mutations promote defects in serum-response factor signalling. 2008 24

The diaphragm muscles in vivo are subjected to mechanical forces both in the direction of the muscle fibers and in the direction transverse to the fibers. However, the effect of directional mechanical forces in skeletal muscle gene regulation is completely unknown. Here, we identified that stretch in the longitudinal and transverse directions to the diaphragm muscle fibers up-regulated Ankrd2 gene expression by two distinct signaling pathways in wild-type (WT) and mdm, a mouse model of muscular dystrophy with early-onset of progressive muscle-wasting. Stretch in the longitudinal direction activated both NF-kappaB and AP-1 transcription factors, whereas stretch in the transverse direction activated only AP-1 transcription factor. Interestingly, longitudinal stretch activated Ankrd2 promoter only by NF-kappaB, whereas transverse stretch activated Ankrd2 promoter by AP-1. Moreover, we found that longitudinal stretch activated Akt, which up-regulated Ankrd2 expression through NF-kappaB. However, transverse stretch activated Ras-GTP, Raf-1, and Erk1/2 proteins, which up-regulated Ankrd2 expression through AP-1. Surprisingly, the stretch-activated NF-kappaB and AP-1 signaling pathways was not involved in Ankrd2 regulation at the basal level, which was high in the mdm mouse diaphragm. Taken together, our data show the anisotropic regulation of Ankrd2 gene expression in the diaphragm muscles of WT and mdm mice via two distinct mechanosensitive signaling pathways.
 ...
PMID:Anisotropic regulation of Ankrd2 gene expression in skeletal muscle by mechanical stretch. 2044 16


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>