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Proteomic profiling of mdx-4cv serum reveals highly elevated levels of the inflammation-induced plasma marker haptoglobin in muscular dystrophy.

ABSTRACT: X-linked muscular dystrophy is caused by primary abnormalities in the Dmd gene and is characterized by the almost complete loss of the membrane cytoskeletal protein dystrophin, which triggers sarcolemmal instability, abnormal calcium homeostasis, increased proteolysis and impaired excitation?contraction coupling. In addition to progressive necrosis, crucial secondary pathologies are represented by myofibrosis and the invasion of immune cells in damaged muscle fibres. In order to determine whether these substantial changes within the skeletal musculature are reflected by an altered rate of protein release into the circulatory system or other plasma fluctuations, we used label?free mass spectrometry to characterize serum from the mdx?4cv model of Duchenne muscular dystrophy. Comparative proteomics revealed a large number of increased vs. decreased protein species in mdx?4cv serum. A serum component with greatly elevated levels was identified as the inflammation?inducible plasma marker haptoglobin. This acute phase response protein is usually secreted in relation to tissue damage and sterile inflammation. Both immunoblot analyses and enzyme?linked immunosorbent assays confirmed the increased concentration of haptoglobin in crude mdx?4cv serum. This suggests that haptoglobin, in conjunction with other altered serum proteins, represents a novel diagnostic, prognostic and/or therapy?monitoring biomarker candidate to evaluate the inflammatory response in the mdx?4cv animal model of dystrophinopathy.

SUBMITTER: Murphy S

PROVIDER: S-EPMC5428965 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Proteomic profiling of mdx-4cv serum reveals highly elevated levels of the inflammation-induced plasma marker haptoglobin in muscular dystrophy.

Murphy Sandra S Dowling Paul P Zweyer Margit M Henry Michael M Meleady Paula P Mundegar Rustam R RR Swandulla Dieter D Ohlendieck Kay K

International journal of molecular medicine 20170418 6

X-linked muscular dystrophy is caused by primary abnormalities in the Dmd gene and is characterized by the almost complete loss of the membrane cytoskeletal protein dystrophin, which triggers sarcolemmal instability, abnormal calcium homeostasis, increased proteolysis and impaired excitation‑contraction coupling. In addition to progressive necrosis, crucial secondary pathologies are represented by myofibrosis and the invasion of immune cells in damaged muscle fibres. In order to determine whethe ...[more]

PMID: 28440464

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Project description:BACKGROUND:X-linked muscular dystrophy is a primary disease of the neuromuscular system. Primary abnormalities in the Dmd gene result in the absence of the full-length isoform of the membrane cytoskeletal protein dystrophin. Besides progressive skeletal muscle wasting and cardio-respiratory complications, developmental cognitive deficits and behavioural abnormalities are clinical features of Duchenne muscular dystrophy. In order to better understand the mechanisms that underlie impaired brain functions in Duchenne patients, we have carried out a proteomic analysis of total brain extracts from the mdx-4cv mouse model of dystrophinopathy. RESULTS:The comparative proteomic profiling of the mdx-4cv brain revealed a significant increase in 39 proteins and a decrease in 7 proteins. Interesting brain tissue-associated proteins with an increased concentration in the mdx-4cv animal model were represented by the glial fibrillary acidic protein GFAP, the neuronal Ca(2+)-binding protein calretinin, annexin AnxA5, vimentin, the neuron-specific enzyme ubiquitin carboxyl-terminal hydrolase isozyme L1, the dendritic spine protein drebrin, the cytomatrix protein bassoon of the nerve terminal active zone, and the synapse-associated protein SAP97. Decreased proteins were identified as the nervous system-specific proteins syntaxin-1B and syntaxin-binding protein 1, as well as the plasma membrane Ca(2+)-transporting ATPase PMCA2 that is mostly found in the brain cortex. The differential expression patterns of GFAP, vimentin, PMCA2 and AnxA5 were confirmed by immunoblotting. Increased GFAP levels were also verified by immunofluorescence microscopy. CONCLUSIONS:The large number of mass spectrometrically identified proteins with an altered abundance suggests complex changes in the mdx-4cv brain proteome. Increased levels of the glial fibrillary acidic protein, an intermediate filament component that is uniquely associated with astrocytes in the central nervous system, imply neurodegeneration-associated astrogliosis. The up-regulation of annexin and vimentin probably represent compensatory mechanisms involved in membrane repair and cytoskeletal stabilization in the absence of brain dystrophin. Differential alterations in the Ca(2+)-binding protein calretinin and the Ca(2+)-pumping protein PMCA2 suggest altered Ca(2+)-handling mechanisms in the Dp427-deficient brain. In addition, the proteomic findings demonstrated metabolic adaptations and functional changes in the central nervous system from the dystrophic phenotype. Candidate proteins can now be evaluated for their suitability as proteomic biomarkers and their potential in predictive, diagnostic, prognostic and/or therapy-monitoring approaches to treat brain abnormalities in dystrophinopathies.

Dataset Information

Proteomic profiling of mdx-4cv serum reveals highly elevated levels of the inflammation-induced plasma marker haptoglobin in muscular dystrophy.

Publications

Proteomic profiling of mdx-4cv serum reveals highly elevated levels of the inflammation-induced plasma marker haptoglobin in muscular dystrophy.

Similar Datasets

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