Gene expression profiling of diaphragm muscle in alpha2-laminin (merosin)-deficient dy/dy dystrophic mice.
ABSTRACT Deficiency of alpha2-laminin (merosin) underlies classical congenital muscular dystrophy in humans and dy/dy muscular dystrophy in mice and causes severe muscle dysfunction in both species. To gain greater insight into the biochemical and molecular events that link alpha2-laminin deficiency with muscle fiber necrosis, and the associated compensatory responses, gene expression profiles were characterized in diaphragm muscle from 8-wk-old dy/dy mice using oligonucleotide microarrays. Compared with age-matched normal muscle, dystrophic diaphragm was characterized by predominantly augmented gene expression, irrespective of the fold-change threshold. Among the 69 genes with at least plus or minus twofold significantly altered expression, 30 belonged to statistically overrepresented Gene Ontology (GO) biological process groups. These covered four specific themes: development including muscle development, cell motility with an emphasis on muscle contraction, defense/immune response, and cell adhesion. An additional 11 gene transcripts were assigned to more general overrepresented GO biological process groups (e.g., cellular process, organismal physiological process); the remaining 28 did not belong to any overrepresented groups. GO cellular constituent assignment resulted in the highest degree of overrepresentation in extracellular and muscle fiber locations, whereas GO molecular function assignment was most notable for various types of binding. RT-PCR was performed on 38 of 41 genes with at least plus or minus twofold significantly altered expression that were assigned to overrepresented GO biological process groups, with expression changes verified for 36 of 38 genes. These results indicate that several specific groups of genes have altered expression in response to genetic alpha2-laminin deficiency, with both similarities and differences compared with data reported for dystrophin-deficient muscular dystrophies.
- [Show abstract] [Hide abstract]
ABSTRACT: To increase our understanding of profibrotic mechanisms in dystrophic muscle. Extracellular matrix, fibrosis-related molecules and histopathology were assessed in skeletal muscle of patients with Duchenne muscular dystrophy (DMD), Becker muscular dystrophy (BMD), and congenital muscular dystrophy type 1A (MDC1A).Osteopontin expression was much higher in DMD and MDC1A than in BMD and control muscle. Osteopontin was expressed in mononuclear cell infiltrates, on some muscle fibre surfaces, in regenerating fibres, and in calcified fibres. In all pathological muscles, matrix metalloproteinase (MMP)-1 was increased around groups of fibres that were also characterized by absence of collagen 1. The amounts of MMP-2, MMP-9 and tissue inhibitor of MMP -1 transcripts were also increased, whereas their proteins were variably expressed in muscle fibres (surface or cytoplasm) and at foci of necrosis and regeneration. Inflammatory cells, fibroblasts and myofibroblasts were more numerous in DMD and MDC1A than in BMD muscle. Several fibrosis-related factors are greatly altered in severely dystrophic skeletal muscle. Osteopontin was the most conspicuously upregulated, both as transcript and as protein, in muscle fibres and infiltrating cells, indicating an intimate involvement in fibrosis, and also in inflammation and muscle regeneration, although its precise roles in these processes remain to be elucidated.Histopathology 12/2011; 59(6):1215-28. · 2.86 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Congenital muscular dystrophy type 1A, a severe neuromuscular disease characterized by early-onset muscle weakness and degeneration, is caused by insufficient levels of laminin α2 (LAMA2) in the basal lamina surrounding muscle fibers and other cells. A better understanding of the molecular mechanisms leading to muscle loss is needed to develop therapeutic interventions for this disease. Here, the authors show that inflammation is an early feature of pathogenesis in Lama2-deficient mouse muscle, indicated by elevated expression of tenascin C in the endomysium around muscle fibers, infiltration of macrophages, and induction of the inflammatory cytokines tumor necrosis factor α (TNFα) and IL-1β. In addition, the expression of lymphatic vessel endothelial hyaluronan receptor-1 (LYVE-1), a specific marker for lymphatic vessel endothelial cells, is dramatically reduced early in Lama2-deficient muscle pathogenesis. LYVE-1 expression, which is inhibited by TNFα, is also decreased in muscles undergoing degeneration due to dystrophin deficiency and cardiotoxin damage. LYVE-1 expression thus provides a useful biomarker to monitor the onset of muscle pathogenesis, likely serving as an indicator of inflammatory signals present in muscles. Together, the data show that inflammatory pathways are activated in the earliest stages of Lama2-deficient disease progression and could play a role in early muscle degeneration.Journal of Histochemistry and Cytochemistry 09/2010; 59(2):167-79. · 2.26 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Diabetes profoundly affects gene expression in organs such as heart, skeletal muscle, kidney and liver, with areas of perturbation including carbohydrate and lipid metabolism, oxidative stress, and protein ubiquitination. Type 1 diabetes impairs lung function, but whether gene expression alterations in the lung parallel those of other tissue types is largely unexplored. Lung from a rat model of diabetes mellitus induced by streptozotocin was subjected to gene expression microarray analysis. Glucose levels were 67 and 260 mg/dl (p < 0.001) in control and diabetic rats, respectively. There were 46 genes with at least +/- 1.5-fold significantly altered expression (19 increases, 27 decreases). Gene ontology groups with significant over-representation among genes with altered expression included apoptosis, response to stress (p = 0.03), regulation of protein kinase activity (p = 0.04), ion transporter activity (p = 0.01) and collagen (p = 0.01). All genes assigned to the apoptosis and response to stress groups had increased expression whereas all genes assigned to the collagen group had decreased expression. In contrast, the protein kinase activity and ion transporter activity groups had genes with both increased and decreased expression. Gene expression in the lung is affected by type 1 diabetes in several specific areas, including apoptosis. However, the lung is resistant to changes in gene expression related to lipid and carbohydrate metabolism and oxidative stress that occur in other tissue types such as heart, skeletal muscle and kidney.BMC Endocrine Disorders 01/2014; 14(1):5. · 2.65 Impact Factor