Expression profiling of a hypercontraction-induced myopathy in Drosophila suggests a compensatory cytoskeletal remodeling response.
Mutations that alter muscle contraction lead to a large array of diseases, including muscular dystrophies and cardiomyopathies. Although the molecular lesions underlying many hereditary muscle diseases are known, the downstream pathways that contribute to disease pathogenesis and compensatory muscle remodeling are poorly defined. We have recently identified and characterized mutations in Myosin Heavy Chain (Mhc) that lead to hypercontraction and subsequent degeneration of flight muscles in Drosophila. To characterize the genomic response to hypercontraction-induced myopathy, we performed expression analysis using Affymetrix high density oligonucleotide microarrays in Drosophila Mhc hypercontraction alleles. The altered transcriptional profile of dystrophic Mhc muscles suggests an actin-dependent remodeling of the muscle cytoskeleton. Specifically, a subset of the highly up-regulated transcripts is involved in actin regulation and structural support for the contractile machinery. In addition, we identified previously uncharacterized proteins with putative actin-interaction domains that are up-regulated in Mhc mutants and differentially expressed in muscles. Several of the up-regulated proteins, including the dystrophin-related protein, MSP-300, and the homolog of the neuronal activity-regulated protein, ARC, localize to specific subcellular muscle structures that may provide key structural sites for cytoskeletal remodeling in dystrophic muscles. Defining the genome-wide transcriptional response to muscle hypercontraction in Drosophila has revealed candidate loci that may participate in the pathogenesis of muscular dystrophy and in compensatory muscle repair pathways through modulation of the actin cytoskeleton.
Montana
Enrico S
ES
Department of Biology, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge 02139, USA.
Littleton
J Troy
JT
D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000483:Alleles; D000818:Animals; D001665:Binding Sites; D009202:Cardiomyopathies / Q000473:pathology; D003599:Cytoskeleton / Q000378:metabolism*; D018076:DNA, Complementary / Q000378:metabolism; D015536:Down-Regulation; D004330:Drosophila / Q000378:metabolism*; D004331:Drosophila melanogaster / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D017403:In Situ Hybridization; D008954:Models, Biological; D008956:Models, Chemical; D008957:Models, Genetic; D008958:Models, Molecular; D015233:Models, Statistical; D009119:Muscle Contraction; D009132:Muscles / Q000378:metabolism; D009154:Mutation; D009206:Myocardium / Q000166:cytology; D018995:Myosin Heavy Chains / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D009841:Oligonucleotides / Q000737:chemistry; D011487:Protein Conformation; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013329:Structure-Activity Relationship; D013997:Time Factors; D014018:Tissue Distribution; D019076:Transgenes; D015854:Up-Regulation
D000199:Actins; D018076:DNA, Complementary; D009841:Oligonucleotides; D012333:RNA, Messenger; D018995:Myosin Heavy Chains