Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0235394 (wasting)
 8,040 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

1. Duchenne muscular dystrophy (DMD) is the second most common fatal genetic disease and arises as a consequence of an absence or disruption of the protein dystrophin. In addition to wasting of the skeletal musculature, boys with DMD have a significant degree of cognitive impairment. 2. We show here that there is no difference between littermate control and mdx mice (a murine model of DMD) in the overall expression of the GABA(A) receptor a1-subunit, supporting the suggestion that it is the clustering at the synapse that is affected and not the expression of the GABA(A) receptor protein. 3. We report a significant reduction in both the frequency and amplitude of spontaneous inhibitory post-synaptic currents in cerebellar Purkinje cells of mdx mice compared with littermate controls, consistent with the reported reduction in the number and size of GABA(A) receptor clusters immunoreactive for a1- and a2-subunits at the post-synaptic densities. 4. These results may explain some of the behavioural problems and cognitive impairment reported in DMD.
 ...
PMID:GABA(A) receptor expression and inhibitory post-synaptic currents in cerebellar Purkinje cells in dystrophin-deficient mdx mice. 1794 89

Duchenne muscular dystrophy is a severe wasting disease, involving replacement of necrotic muscle tissue by fibrous material and fatty infiltrates. One primary animal model of this human disease is the X chromosome-linked mdx strain of mice. The goals of the present work were to validate and quantify the capability of both energy and entropy metrics of radio-frequency ultrasonic backscatter to differentiate among normal, dystrophic, and steroid-treated skeletal muscle in the mdx model. Thirteen 12-month-old mice were blocked into three groups: 4 treated mdx-dystrophic that received daily subcutaneous steroid (prednisolone) treatment for 14 days, 4 positive-control mdx-dystrophic that received saline injections for 14 days, and 5 negative-control animals. Biceps muscle of each animal was imaged in vivo using a 40-MHz center frequency transducer in conjunction with a Vevo-660 ultrasound system. Radio-frequency data were acquired (1 GHz, 8 bits) corresponding to a sequence of transverse images, advancing the transducer from "shoulder" to "elbow" in 100-micron steps. Data were processed to generate both "integrated backscatter" (log energy), and "entropy" (information theoretic receiver, H(f)) representations. Analyses of the integrated-backscatter values delineated both treated-and untreated-mdx biceps from normal controls (p < 0.01). Complementary analyses of the entropy images differentiated the steroid-treated and positive-control mdx groups (p < 0.01). To our knowledge, this study represents the first reported use of quantitative ultrasonic characterization of skeletal muscle in mdx mice. Successful differentiation among dystrophic, steroid-treated, and normal tissues suggests the potential for local noninvasive monitoring of disease severity and therapeutic effects.
 ...
PMID:Sensitive ultrasonic delineation of steroid treatment in living dystrophic mice with energy-based and entropy-based radio frequency signal processing. 1805 Nov 63

1. Inflammation, particularly the pro-inflammatory cytokine tumour necrosis factor (TNF), increases necrosis of skeletal muscle. Depletion of inflammatory cells, such as neutrophils, cromolyn blockade of mast cell degranulation or pharmacological blockade of TNF reduces necrosis of dystrophic myofibres in the mdx mouse model of the lethal childhood disease Duchenne muscular dystrophy (DMD). 2. Insulin-like growth factor-1 (IGF-1) is a very important cytokine for maintenance of skeletal muscle mass and the transgenic overexpression of IGF-1 within muscle cells reduces necrosis of dystrophic myofibres in mdx mice. Thus, IGF-1 usually has the opposite effect to TNF. 3. Activation of TNF signalling via the c-Jun N-terminal kinase (JNK) can inhibit IGF-1 signalling by phosphorylation and conformational changes in insulin receptor substrate (IRS)-1 downstream of the IGF-1 receptor. Such silencing of IGF-1 signalling in situations where inflammatory cytokines are elevated has many implications for skeletal muscle in vivo. 4. The basis for these interactions between TNF and IGF-1 is discussed with specific reference to clinical consequences for myofibre necrosis in DMD and also for the wasting (atrophy) of skeletal muscles that occurs in very old people and in cachexia associated with inflammatory disorders.
 ...
PMID:Implications of cross-talk between tumour necrosis factor and insulin-like growth factor-1 signalling in skeletal muscle. 1821 80

1. Duchenne muscular dystrophy (DMD), a severe muscle wasting disease of young boys with an incidence of one in every 3000, results from a mutation in the gene that encodes dystrophin. The absence of dystrophin expression in skeletal muscles and heart results in the degeneration of muscle fibres and, consequently, severe muscle weakness and wasting. The mdx mouse discovered in 1984, with some adjustments for differences, has proven to be an invaluable model for scientific investigations of dystrophy. 2. The development of the diaphagm strip preparation provided an ideal experimental model for investigations of skeletal muscle impairments in structure and function induced by interactions of disease- and age-related factors. Unlike the limb muscles of the mdx mouse, which show adaptive changes in structure and function, the diaphragm strip preparation reflects accurately the deterioration in muscle structure and function observed in boys with DMD. 3. The advent of sophisticated servo motors and force transducers interfaced with state-of-the-art software packages to drive complex experimental designs during the 1990s greatly enhanced the capability of the mdx mouse and the diaphragm strip preparation to evaluate more accurately the impact of the disease on the structure-function relationships throughout the life span of the mouse. 4. Finally, during the 1990s and through the early years of the 21st century, many promising, sophisticated genetic techniques have been designed to ameliorate the devastating impact of muscular dystrophy on the structure and function of skeletal muscles. During this period of rapid development of promising genetic therapies, the combination of the mdx mouse and the diaphragm strip preparation has provided an ideal model for the evaluation of the success, or failure, of these genetic techniques to improve dystrophic muscle structure, function or both. With the 2 year life span of the mdx mouse, the impact of age-related effects can be studied in this model.
 ...
PMID:Diaphragm muscle strip preparation for evaluation of gene therapies in mdx mice. 1821 82

Myostatin has been extensively documented as a negative regulator of muscle growth. Myostatin inhibition is therefore considered an attractive strategy for the treatment of muscle-wasting diseases such as muscular dystrophies. To investigate whether systemic gene delivery of myostatin propeptide (MRPO), a natural inhibitor of myostatin, could enhance body-wide skeletal muscle growth, we used adeno-associated virus serotype 8 (AAV8) vectors to deliver the MRPO gene into either normal mice or mdx mice, a murine model of Duchenne muscular dystrophy (DMD). In normal mice, a significant increase in skeletal muscle mass was observed after either an intraperitoneal injection of AAV-MPRO into neonates, or an intravenous injection of AAV-MPRO76AFc (a modified MPRO fused with IgG Fc) into adults. Enhanced muscle growth occurred because of myofiber hypertrophy, not hyperplasia. In mdx mice, a significant increase in skeletal muscle mass was also observed after AAV-MPRO76AFc injection. The treated mdx mice showed larger and more uniform myofibers, fewer infiltrating mononuclear cells, less fibrosis, and lower serum creatine kinase levels. In addition, a grip force test and an in vitro tetanic contractile force test showed improved muscle strength. A treadmill test, however, showed reduced endurance of the treated mdx mice compared with their untreated counterparts. Importantly, no cardiac hypertrophy was observed in either normal or mdx mice after myostatin inhibition by gene delivery. These results clearly demonstrate the efficacy of AAV8-mediated myostatin propeptide gene delivery in a rodent model of DMD, and warrant further investigation in large animal models and eventually in human patients.
 ...
PMID:Myostatin propeptide gene delivery by adeno-associated virus serotype 8 vectors enhances muscle growth and ameliorates dystrophic phenotypes in mdx mice. 1828 93

Restoring dystrophin expression in the muscles of patients with Duchenne muscular dystrophy (DMD) may halt or reverse the degenerative wasting and weakness that causes premature death. However, the therapeutic efficacy of an intervention may be limited by the extent of disease progression prior to treatment. In this study, we considered the potential for ameliorating the pathology in a mouse model of advanced-stage muscular dystrophy by systemic administration of recombinant adeno-associated viral (rAAV6) vectors encoding a microdystrophin expression construct. The treatment of 20-month-old mdx mice restored body-wide expression of a dystrophin-based protein in striated musculature. In aged mice that received treatment, the resultant dystrophin expression was associated with improved hindlimb and respiratory muscle morphology and function, concomitant with reduced muscle fiber degeneration. The findings demonstrate that an established dystrophic state remains amenable to improvement with appropriate intervention and, by some measures, may even achieve benefits similar to those observed with intervention early in disease progression. The capacity to ameliorate the pathology in an animal model of advanced-stage muscular dystrophy suggests that interventions ultimately proven to exert a therapeutic effect in young patients may offer benefits to older patients or those with advanced conditions of progressive muscular dystrophy.
 ...
PMID:Systemic microdystrophin gene delivery improves skeletal muscle structure and function in old dystrophic mdx mice. 1833 86

Duchenne muscular dystrophy (DMD) is a fatal, progressive, muscle-wasting disease caused by defects in the dystrophin. No viral vector except the helper-dependent adenovirus vector (HDAdv) can package 14-kilobase (kb) full-length dystrophin complementary DNA (cDNA), and HDAdv is considerably safer than old-generation adenovirus vectors because of the large-size deletion in its genome. We have generated HDAdv that carries myc-tagged murine full-length dystrophin cDNA (HDAdv-myc-mFLdys). We injected it into multiple proximal muscles of 7-day-old utrophin/dystrophin double knockout mice (dko mice) (which typically show symptoms quite similar to human DMD) because the proximal muscles are affected in DMD patients. Eight weeks after the injections, the transduced dystrophin was widely expressed, and we found a significant reduction in centrally nucleated myofibers and the restoration of the dystrophin-associated proteins, beta-dystroglycan (beta-DG) and alpha-sarcoglycan (alpha-SG), as well as neuronal nitric oxide synthase (nNOS). The injected dko mice also showed an increase in body weight, an improvement in motor performance, and a prolongation of life span. Using HDAdv, we could treat DMD model mice even by transferring the therapeutic gene into multiple skeletal muscles. Our results suggest that multiple intramuscular administrations of HDAdv carrying full-length dystrophin cDNA may reduce symptoms and compensate for lost functions in DMD patients.
 ...
PMID:Transduction of full-length dystrophin to multiple skeletal muscles improves motor performance and life span in utrophin/dystrophin double knockout mice. 1833 87

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disease that causes respiratory or cardiac failure and results in death at about 20 years of age. An animal model of DMD, the mdx mouse, is commonly used to estimate dystrophic pathology. The pathological features of limb muscles are relatively mild, however the diaphragm is severely affected and exhibits a degenerative pattern similar to that observed in human DMD. Although, the muscle strength assay of the dystrophic diaphragm has been used to estimate mdx respiratory impairment, systemic functional assessments compared with histopathological analysis have not been demonstrated. Here, we report a sensitive procedure using whole-body plethysmography to monitor respiratory parameters detected during early respiratory insufficiency in the mdx mouse. The dystrophic changes in the diaphragm lead to respiratory dysfunctions. These methods may be useful to assess the therapeutic approaches for the mdx mouse.
 ...
PMID:Mdx respiratory impairment following fibrosis of the diaphragm. 1835 22

Duchenne muscular dystrophy is a fatal muscle-wasting disorder. Lack of dystrophin compromises the integrity of the sarcolemma and results in myofibers that are highly prone to contraction-induced injury. Recombinant adeno-associated virus (rAAV)-mediated dystrophin gene transfer strategies to muscle for the treatment of Duchenne muscular dystrophy (DMD) have been limited by the small cloning capacity of rAAV vectors and high titers necessary to achieve efficient systemic gene transfer. In this study, we assess the impact of codon optimization on microdystrophin (DeltaAB/R3-R18/DeltaCT) expression and function in the mdx mouse and compare the function of two different configurations of codon-optimized microdystrophin genes (DeltaAB/R3-R18/DeltaCT and DeltaR4-R23/DeltaCT) under the control of a muscle-restrictive promoter (Spc5-12). Codon optimization of microdystrophin significantly increases levels of microdystrophin mRNA and protein after intramuscular and systemic administration of plasmid DNA or rAAV2/8. Physiological assessment demonstrates that codon optimization of DeltaAB/R3-R18/DeltaCT results in significant improvement in specific force, but does not improve resistance to eccentric contractions compared with noncodon-optimized DeltaAB/R3-R18/DeltaCT. However, codon-optimized microdystrophin DeltaR4-R23/DeltaCT completely restored specific force generation and provided substantial protection from contraction-induced injury. These results demonstrate that codon optimization of microdystrophin under the control of a muscle-specific promoter can significantly improve expression levels such that reduced titers of rAAV vectors will be required for efficient systemic administration.
 ...
PMID:Codon and mRNA sequence optimization of microdystrophin transgenes improves expression and physiological outcome in dystrophic mdx mice following AAV2/8 gene transfer. 1876 74

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


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