Proteomic Profiling of the mdx Animal Model for Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy is a lethal childhood disorder which results in progressive muscle weakness and wasting due to genetic abnormalities in the dystrophin gene. While the primary abnormality lies with the loss of the crucial membrane cytoskeletal protein dystrophin and the reduction of its associated glycoprotein complex, secondary alterations in cellular signalling, ion homeostasis regulation and metabolic pathways lead to fiber degeneration and subsequent fibrosis. These changes result in loss of ambulation and sufferers being wheelchair bound in early adulthood. Severe diaphragm and cardiac complications in later life tend to be fatal. The aim of this project was to create a detailed proteomic profile of differentially affected dystrophic tissues using the mdx mouse model; from severely dystrophic diaphragm; moderately affected hind limb to naturally protected interosseus muscle were used to investigate the pathogenesis of the disease. Proteomic analysis of the muscle subtypes indicated that skeletal muscles are differentially affected by the absence of dystrophin protein. Naturally protected interosseus exhibited very little histological and proteomic changes. In contrast to the moderately affected mdx hind limb muscles, the dystrophic diaphragm exhibits severe symptoms of skeletal muscle fiber degeneration that more closely resembles that of the neuromuscular pathology exhibited in Duchenne patients than any other muscle. Novel molecular insights into dystrophic changes suggest increased cellular stress, impaired calcium buffering, cytostructural alterations and disturbances of mitochondrial metabolism in dystrophin-deficient muscle tissue. Thus, the absence of the dystrophin isoform Dp427 and resulting reduction in dystrophin-associated glycoproteins in the dystrophic sarcolemma seems to trigger a variety of secondary abnormalities in muscular dystrophy. This work has successfully established a detailed biomarker signature that maybe used to evaluate new treatments, improve understanding of the pathobiochemical process and supports the use of mdx mouse as a suitable model for Duchenne muscular dystrophy

Calnexin, an ER-induced protein, is a prognostic marker and potential therapeutic target in colorectal cancer.

BACKGROUND: Colorectal cancer (CRC) is a leading cause of cancer mortality in the Western world and commonly treated with genotoxic chemotherapy. Stress in the endoplasmic reticulum (ER) was implicated to contribute to chemotherapeutic resistance. Hence, ER stress related protein may be of prognostic or therapeutic significance. METHODS: The expression levels of ER stress proteins calnexin, calreticulin, GRP78 and GRP94 were determined in n = 23 Stage II and III colon cancer fresh frozen tumour and matched normal tissue samples. Data were validated in a cohort of n = 11 rectal cancer patients treated with radiochemotherapy in the neoadjuvant setting. The calnexin gene was silenced using siRNA in HCT116 cells. RESULTS: There were no increased levels of ER stress proteins in tumour compared to matched normal tissue samples in Stage II or III CRC. However, increased calnexin protein levels were predictive of poor clinical outcome in the patient cohort. Data were validated in the rectal cancer cohort treated in the neoadjuvant setting. Calnexin gene-silencing significantly reduced cell survival and increased cancer cell susceptibility to 5FU chemotherapy. CONCLUSION: Increased tumour protein levels of calnexin may be of prognostic significance in CRC, and calnexin may represent a potential target for future therapies

Erratum to: Calnexin, an ER stress-induced protein, is a prognostic marker and potential therapeutic target in colorectal cancer

Erratum to: Calnexin, an ER stress-induced protein, is a prognostic marker and potential therapeutic target in colorectal cancer

Proteomic Profiling of the mdx Animal Model for Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy is a lethal childhood disorder which results in progressive muscle weakness and wasting due to genetic abnormalities in the dystrophin gene. While the primary abnormality lies with the loss of the crucial membrane cytoskeletal protein dystrophin and the reduction of its associated glycoprotein complex, secondary alterations in cellular signalling, ion homeostasis regulation and metabolic pathways lead to fiber degeneration and subsequent fibrosis. These changes result in loss of ambulation and sufferers being wheelchair bound in early adulthood. Severe diaphragm and cardiac complications in later life tend to be fatal. The aim of this project was to create a detailed proteomic profile of differentially affected dystrophic tissues using the mdx mouse model; from severely dystrophic diaphragm; moderately affected hind limb to naturally protected interosseus muscle were used to investigate the pathogenesis of the disease. Proteomic analysis of the muscle subtypes indicated that skeletal muscles are differentially affected by the absence of dystrophin protein. Naturally protected interosseus exhibited very little histological and proteomic changes. In contrast to the moderately affected mdx hind limb muscles, the dystrophic diaphragm exhibits severe symptoms of skeletal muscle fiber degeneration that more closely resembles that of the neuromuscular pathology exhibited in Duchenne patients than any other muscle. Novel molecular insights into dystrophic changes suggest increased cellular stress, impaired calcium buffering, cytostructural alterations and disturbances of mitochondrial metabolism in dystrophin-deficient muscle tissue. Thus, the absence of the dystrophin isoform Dp427 and resulting reduction in dystrophin-associated glycoproteins in the dystrophic sarcolemma seems to trigger a variety of secondary abnormalities in muscular dystrophy. This work has successfully established a detailed biomarker signature that maybe used to evaluate new treatments, improve understanding of the pathobiochemical process and supports the use of mdx mouse as a suitable model for Duchenne muscular dystrophy

Proteomic Profiling of the mdx Animal Model for Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy is a lethal childhood disorder which results in progressive muscle weakness and wasting due to genetic abnormalities in the dystrophin gene. While the primary abnormality lies with the loss of the crucial membrane cytoskeletal protein dystrophin and the reduction of its associated glycoprotein complex, secondary alterations in cellular signalling, ion homeostasis regulation and metabolic pathways lead to fiber degeneration and subsequent fibrosis. These changes result in loss of ambulation and sufferers being wheelchair bound in early adulthood. Severe diaphragm and cardiac complications in later life tend to be fatal. The aim of this project was to create a detailed proteomic profile of differentially affected dystrophic tissues using the mdx mouse model; from severely dystrophic diaphragm; moderately affected hind limb to naturally protected interosseus muscle were used to investigate the pathogenesis of the disease. Proteomic analysis of the muscle subtypes indicated that skeletal muscles are differentially affected by the absence of dystrophin protein. Naturally protected interosseus exhibited very little histological and proteomic changes. In contrast to the moderately affected mdx hind limb muscles, the dystrophic diaphragm exhibits severe symptoms of skeletal muscle fiber degeneration that more closely resembles that of the neuromuscular pathology exhibited in Duchenne patients than any other muscle. Novel molecular insights into dystrophic changes suggest increased cellular stress, impaired calcium buffering, cytostructural alterations and disturbances of mitochondrial metabolism in dystrophin-deficient muscle tissue. Thus, the absence of the dystrophin isoform Dp427 and resulting reduction in dystrophin-associated glycoproteins in the dystrophic sarcolemma seems to trigger a variety of secondary abnormalities in muscular dystrophy. This work has successfully established a detailed biomarker signature that maybe used to evaluate new treatments, improve understanding of the pathobiochemical process and supports the use of mdx mouse as a suitable model for Duchenne muscular dystrophy

Proteomic Profiling of the mdx Animal Model for Duchenne Muscular Dystrophy

Duchenne Muscular Dystrophy is a lethal childhood disorder which results in progressive muscle weakness and wasting due to genetic abnormalities in the dystrophin gene. While the primary abnormality lies with the loss of the crucial membrane cytoskeletal protein dystrophin and the reduction of its associated glycoprotein complex, secondary alterations in cellular signalling, ion homeostasis regulation and metabolic pathways lead to fiber degeneration and subsequent fibrosis. These changes result in loss of ambulation and sufferers being wheelchair bound in early adulthood. Severe diaphragm and cardiac complications in later life tend to be fatal. The aim of this project was to create a detailed proteomic profile of differentially affected dystrophic tissues using the mdx mouse model; from severely dystrophic diaphragm; moderately affected hind limb to naturally protected interosseus muscle were used to investigate the pathogenesis of the disease. Proteomic analysis of the muscle subtypes indicated that skeletal muscles are differentially affected by the absence of dystrophin protein. Naturally protected interosseus exhibited very little histological and proteomic changes. In contrast to the moderately affected mdx hind limb muscles, the dystrophic diaphragm exhibits severe symptoms of skeletal muscle fiber degeneration that more closely resembles that of the neuromuscular pathology exhibited in Duchenne patients than any other muscle. Novel molecular insights into dystrophic changes suggest increased cellular stress, impaired calcium buffering, cytostructural alterations and disturbances of mitochondrial metabolism in dystrophin-deficient muscle tissue. Thus, the absence of the dystrophin isoform Dp427 and resulting reduction in dystrophin-associated glycoproteins in the dystrophic sarcolemma seems to trigger a variety of secondary abnormalities in muscular dystrophy. This work has successfully established a detailed biomarker signature that maybe used to evaluate new treatments, improve understanding of the pathobiochemical process and supports the use of mdx mouse as a suitable model for Duchenne muscular dystrophy

Revista nacional de educación

Repaso de la vida del músico Ernesto Halffter, a través de las crónicas y críticas de su época. Se analiza el conjunto de su obra musical, sus peculiaridades como discípulo de Manuel de Falla y la evolución de su carrera artística.Ministerio Educación CIDEBiblioteca de Educación del Ministerio de Educación, Cultura y Deporte; Calle San Agustín, 5 - 3 Planta; 28014 Madrid; Tel. +34917748000; [email protected]

Proteomics reveals drastic increase of extracellular matrix proteins collagen and dermatopontin in the aged mdx diaphragm model of Duchenne muscular dystrophy

Duchenne muscular dystrophy is a lethal genetic disease of childhood caused by primary abnormalities in the gene coding for the membrane cytoskeletal protein dystrophin. The mdx mouse is an established animal model of various aspects of X-linked muscular dystrophy and is widely used for studying fundamental mechanisms of dystrophinopathy and testing novel therapeutic approaches to treat one of the most frequent gender-specific diseases in humans. In order to determine global changes in the muscle proteome with the progressive deterioration of mdx tissue with age, we have characterized diaphragm muscle from mdx mice at three ages (8-weeks, 12-months and 22-months) using mass spectrometry-based proteomics. Altered expression levels in diaphragm of 8-week vs. 22-month mice were shown to occur in 11 muscle-associated proteins. Aging in the mdx diaphragm seems to be associated with a drastic increase in the extracellular matrix proteins, collagen and dermatopontin, the molecular chaperone αB-crystallin, and the intermediate filament protein vimentin, suggesting increased accumulation of connective tissue, an enhanced cellular stress response and compensatory stabilization of the weakened membrane cytoskeleton. These proteomic findings establish the aged mdx diaphragm as an excellent model system for studying secondary effects of dystrophin deficiency in skeletal muscle tissue

Profiling of Age-Related Changes in the Tibialis Anterior Muscle Proteome of the mdx Mouse Model of Dystrophinopathy

X-linked muscular dystrophy is a highly progressive disease of childhood and characterized by primary genetic abnormalities in the dystrophin gene. Senescent mdx specimens were used for a large-scale survey of potential age-related alterations in the dystrophic phenotype, because the established mdx animal model of dystrophinopathy exhibits progressive deterioration of muscle tissue with age. Since the mdx tibialis anteriormuscle is a frequently used model system in muscular dystrophy research, we employed this particular muscle to determine global changes in the dystrophic skeletal muscle proteome. The comparison of mdx mice aged 8 weeks versus 22 months by mass-spectrometry-based proteomics revealed altered expression levels in 8 distinct protein species. Increased levels were shown for carbonic anhydrase, aldolase, and electron transferring flavoprotein, while the expressions of pyruvate kinase, myosin, tropomyosin, and the small heat shock protein Hsp27 were found to be reduced in aged muscle. Immunoblotting confirmed age-dependent changes in the density of key muscle proteins in mdx muscle. Thus, segmental necrosis in mdx tibialis anteriormuscle appears to trigger age-related protein perturbations due to dystrophin deficiency. The identification of novel indicators of progressive muscular dystrophy might be useful for the establishment of a muscle subtype-specific biomarker signature of dystrophinopathy