Identification of marker proteins of muscular dystrophy in the urine proteome from the <i>mdx-4cv</i> model of dystrophinopathy

Gargan, Stephen; Dowling, Paul; Zweyer, Margit; Swandulla, Dieter; Ohlendieck, Kay

doi:10.1039/c9mo00182d

Cited by 13 publications

(15 citation statements)

References 76 publications

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“…The drastic increase of the large subunit of microsomal triglyceride transfer protein is probably due to alterations in the mdx-4cv pancreas, since this protein facilitates the transport of fat molecules between phospholipid surfaces. Previous proteomic surveys revealed decreased pancreatic marker proteins in biofluids, including reduced levels of chymotrypsin-like elastase family member 2A in mdx-4cv serum 23 and pancreatic alphaamylase in mdx-4cv urine, 22 indicating decreased secretion of these enzymes into circulation. However, no altered abundance of these pancreatic proteins was observed in this report.…”

Section: Discussionmentioning

confidence: 98%

“…Mice were kept under standard conditions. 22 For tissue dissection, protein extraction and subsequent proteomic analyses, 12-months old mice were used. Freshly dissected tissue specimens were quick-frozen in liquid nitrogen and transported to Maynooth University in accordance with the Department of Agriculture (animal by-product register number 2016/16 to the Department of Biology, National University of Ireland, Maynooth) on dry ice and stored at -80 o C prior to proteomic analysis.…”

Section: Ethical Approval Animal License and Animal Maintenancementioning

confidence: 99%

“…24 Following centrifugation at 16,000xg for 5 minutes, tissue extracts were processed for mass spectrometry-based proteomic analysis. 22 Protein digestion and further processing of the generated peptides was carried out by filter-aided sample preparation (FASP), as recently described in detail. 25 Label-free liquid chromatography mass spectrometry and proteomic data analysis Protein identification and comparative proteomics was carried out by an optimized label-free liquid chromatography mass spectrometry procedure.…”

Section: Ethical Approval Animal License and Animal Maintenancementioning

confidence: 99%

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Proteomic profiling of the interface between the stomach wall and the pancreas in dystrophinopathy

et al. 2021

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The neuromuscular disorder Duchenne muscular dystrophy is a multi-systemic disease that is caused by a primary abnormality in the X-chromosomal Dmd gene. Although progressive skeletal muscle wasting and cardio-respiratory complications are the most serious symptoms that are directly linked to the almost complete loss of the membrane cytoskeletal protein dystrophin, dystrophic patients also suffer from gastrointestinal dysfunction. In order to determine whether proteome-wide changes potentially occur in the gastrointestinal system due to dystrophin deficiency, total tissue extracts from the interface between the stomach wall and the pancreas of the mdx-4cv model of dystrophinopathy were analysed by mass spectrometry. Following the proteomic establishment of both smooth muscle markers of the gastrointestinal system and key enzymes of the pancreas, core members of the dystrophin-glycoprotein complex, including dystrophin, dystroglycans, sarcoglycans, dystrobrevins and syntrophins were identified in this tissue preparation. Comparative proteomics revealed a drastic reduction in dystrophin, sarcoglycan, dystroglycan, laminin, titin and filamin suggesting loss of cytoskeletal integrity in mdx-4cv smooth muscles. A concomitant increase in various mitochondrial enzymes is indicative of metabolic disturbances. These findings agree with abnormal gastrointestinal function in dystrophinopathy.

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Section: Discussionmentioning

confidence: 98%

Section: Ethical Approval Animal License and Animal Maintenancementioning

confidence: 99%

Section: Ethical Approval Animal License and Animal Maintenancementioning

confidence: 99%

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Proteomic profiling of the interface between the stomach wall and the pancreas in dystrophinopathy

et al. 2021

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“…This includes varying degrees of fiber degeneration, reactive myofibrosis, sterile inflammation, and metabolic disturbances in limb muscles ( Murphy et al., 2019a ), the diaphragm ( Murphy et al., 2019b ), and the heart ( Murphy et al., 2016 ), as well as proteome-wide alterations in the brain ( Murphy et al., 2015 ), the liver ( Murphy et al., 2018a ), and the kidney ( Dowling et al., 2020b ). The concentration of distinct protein biomarkers is also markedly affected in mdx-4cv serum ( Murphy et al., 2017 ), saliva ( Murphy et al., 2018b ), and urine ( Gargan et al., 2020 ). These complex and body-wide changes make the mdx-4cv mouse a suitable model system to study the molecular pathogenesis of dystrophinopathy.…”

Section: Discussionmentioning

confidence: 99%

“…Previous mass spectrometric investigations focusing on the mdx-4cv mouse have established differential changes in the tissue proteome from various skeletal muscles, the heart, the brain, the liver, and the kidney ( Murphy et al., 2015 , 2016 ; 2018a , 2019a ; 2019b ; Dowling et al., 2020b ) and have identified elevated levels of biofluid-associated markers in saliva, serum, and urine ( Murphy et al., 2017 , 2018b ; Gargan et al., 2020 ). In this study, we have extended the proteomic characterization of body-wide alterations in the mdx-4cv mouse model of dystrophinopathy to the spleen, a secondary lymphoid organ that consists of two main types of tissue, the blood-filled red pulp and the lymphatic white pulp ( Mebius and Kraal, 2005 ).…”

Section: Introductionmentioning

confidence: 99%

Proteome-wide Changes in the mdx-4cv Spleen due to Pathophysiological Cross Talk with Dystrophin-Deficient Skeletal Muscle

et al. 2020

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Summary Duchenne muscular dystrophy is primarily characterized by progressive muscle wasting due to deficiency in the membrane cytoskeletal protein dystrophin but is also associated with body-wide cellular disturbances in a variety of non-muscle tissues. In this study, we have focused on the comparative proteomic analysis of the spleen and established considerable changes in this crucial secondary lymphoid organ from the genetic mdx-4cv mouse model of dystrophinopathy. An apparent short isoform of dystrophin and associated glycoproteins were identified in spleen by mass spectrometry but appear not be affected in muscular dystrophy. In contrast, the mdx-4cv spleen showed significant proteome-wide changes in other protein species that are involved in metabolism, signaling, and cellular architecture. Since the spleen plays a key role in the immune response, these proteomic alterations may reflect pathophysiological cross talk between the lymphoid system and dystrophic muscles, which are affected by both fiber degeneration and inflammation.

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Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy

Ohlendieck

Swandulla

2021

Pflugers Arch - Eur J Physiol

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Duchenne muscular dystrophy is a highly progressive muscle wasting disorder due to primary abnormalities in one of the largest genes in the human genome, the DMD gene, which encodes various tissue-specific isoforms of the protein dystrophin. Although dystrophinopathies are classified as primary neuromuscular disorders, the body-wide abnormalities that are associated with this disorder and the occurrence of organ crosstalk suggest that a multi-systems pathophysiological view should be taken for a better overall understanding of the complex aetiology of X-linked muscular dystrophy. This article reviews the molecular and cellular effects of deficiency in dystrophin isoforms in relation to voluntary striated muscles, the cardio-respiratory system, the kidney, the liver, the gastrointestinal tract, the nervous system and the immune system. Based on the establishment of comprehensive biomarker signatures of X-linked muscular dystrophy using large-scale screening of both patient specimens and genetic animal models, this article also discusses the potential usefulness of novel disease markers for more inclusive approaches to differential diagnosis, prognosis and therapy monitoring that also take into account multi-systems aspects of dystrophinopathy. Current therapeutic approaches to combat muscular dystrophy are summarised.

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Identification of marker proteins of muscular dystrophy in the urine proteome from the mdx-4cv model of dystrophinopathy

Abstract: Proteomic analysis of urine from the mdx-4cv model of dystrophinopathy establishes a large number of non-invasive markers of muscle degeneration.

Cited by 13 publications

References 76 publications

Proteomic profiling of the interface between the stomach wall and the pancreas in dystrophinopathy

Proteomic profiling of the interface between the stomach wall and the pancreas in dystrophinopathy

Proteome-wide Changes in the mdx-4cv Spleen due to Pathophysiological Cross Talk with Dystrophin-Deficient Skeletal Muscle

Complexity of skeletal muscle degeneration: multi-systems pathophysiology and organ crosstalk in dystrophinopathy

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