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John D Porter

Publications and source records attributed to John D Porter.

23 records · Page 2Linked to original sources
PubMed2002

A chronic inflammatory response dominates the skeletal muscle molecular signature in dystrophin-deficient mdx mice.

Mutations in dystrophin cause Duchenne muscular dystrophy (DMD), but absent dystrophin does not invariably cause necrosis in all muscles, life stages and species. Using DNA microarray, we established a molecular signature of dystrophinopathy in the mdx mouse, with evidence that secondary mechanisms are key contributors to pathogenesis. We used variability controls, adequate replicates and stringent analytic tools, including significance analysis of microarrays to estimate and manage false positive rates. In leg muscle, we identified 242 differentially expressed genes, >75% of which have not been previously reported as altered in human or animal dystrophies. Data provide evidence for coordinated activity of numerous components of a chronic inflammatory response, including cytokine and chemokine signaling, leukocyte adhesion and diapedesis, invasive cell type-specific markers, and complement system activation. Selective chemokine upregulation was confirmed by RT-PCR and immunoblot, and may be a key determinant of the nature of the inflammatory response in dystrophic muscle. Up-regulation of secreted phosphoprotein 1 (minopontin, osteopontin) mRNA and protein in dystrophic muscle identified a novel linkage between inflammatory cells and repair processes. Extracellular matrix genes were up-regulated in mdx to levels similar to those in DMD. Since, unlike DMD, mdx exhibits little fibrosis, data suggest that collagen regulation at post-transcriptional stages mediates extensive fibrosis in DMD. Taken together, these data identify a relatively neglected aspect of DMD, suggest new treatment avenues, and highlight the value of genome-wide profiling in study of complex disease processes.

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PubMed2002

Extraocular muscle: cellular adaptations for a diverse functional repertoire.

Oculomotor control systems are considerably more complex and diverse than are spinal skeletomotor systems. Moreover, individual skeletal muscles are frequently functional role-specific, while all extraocular muscles operate across a very wide dynamic range. We contend that the novel phenotype of the extraocular muscles is a direct consequence of the functional demands imposed upon this muscle group by the central eye movement controllers. This review highlights five basic themes of extraocular muscle biology that set them apart from more typical skeletal muscles, specifically, the (a) novel innervation pattern, (b) heterogeneity in contractile proteins, (c) structural and functional compartmentalization of the rectus and oblique muscles, (d) diversity of extraocular muscle fiber types, and (e) relationship between the novel muscle phenotype and the differential response of these muscles in neuromuscular and endocrine disease. Finally, new data from broad genome-wide profiling studies are reviewed, with global gene expression patterns lending substantial support to the notion that the extraocular muscles are fundamentally different from traditional skeletal muscle. This novel eye muscle phenotype represents an adaptation that exploits the full range of variability in skeletal muscle to meet the needs of visuomotor systems.

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PubMed2002

Transcriptional profile of rat extraocular muscle by serial analysis of gene expression.

PURPOSE: Although extraocular muscle (EOM) is skeletal muscle, aspects of its biology are unlike other striated muscle. In this study, the broad molecular genetics profile underlying the novel EOM phenotype was examined. METHODS: Serial analysis of gene expression (SAGE) was used to quantify adult rat EOM gene transcripts. SAGE isolates and sequences 10-bp tags from defined locations in mRNA-derived cDNA. Tag sequence-location was used to extract transcript identity from a curated SAGE database, and detection frequencies reflected abundance of corresponding mRNAs. RESULTS: The 54,764 expressed sequence tags generated and sequenced from EOM included 17,602 unique tags. Of the unique tags, 7.8% were detected at high to intermediate levels (>or=5 copies), 19.3% at lower levels (2-4 copies), and 72.9% as single copies; 40% of the tags matched known expressed sequence tags (ESTs), most of which (85.7%) represented a unique EST. Tags without matches in the SAGE database and those expressed as single copies only were not considered further. SAGE tags expressed at more than 0.1% of total transcripts reflected several aspects of muscle biology, including sarcomeric structure, energy metabolism, and ribosomal protein expression. Genes highly expressed in EOM were compared with other existing muscle expression databases to identify conserved and novel patterns in EOM. CONCLUSIONS: The data provide a normative gene expression database and a novel molecular signature that will facilitate study of EOM development and function and of the mechanisms behind its preferential targeting or sparing in neuromuscular disease.

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