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Dissection of Drosophila melanogaster Flight Muscles for Omics Approaches
Published on: October 17, 2019
Expression profiling of a hypercontraction-induced myopathy in Drosophila suggests a compensatory cytoskeletal
Enrico S Montana1, J Troy Littleton
1Department of Biology, The Picower Institute for Learning and Memory, Massachusetts Institute of Technology, Cambridge 02139, USA.
Abstract:
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.
Insights
Mutations in Myosin Heavy Chain (Mhc) cause muscle degeneration in fruit flies. This study reveals how gene expression changes, particularly involving actin, contribute to muscle repair and disease.
Area of Science:
- Muscle physiology and genetics
- Molecular biology and disease pathogenesis
- Drosophila melanogaster as a model organism
Background:
- Muscle contraction defects cause various diseases like muscular dystrophies.
- Downstream pathways in hereditary muscle diseases are not fully understood.
- Myosin Heavy Chain (Mhc) mutations lead to flight muscle hypercontraction and degeneration in Drosophila.
Purpose of the Study:
- To characterize the genomic response to hypercontraction-induced myopathy in Drosophila Mhc mutants.
- To identify genes and pathways involved in muscle degeneration and compensatory remodeling.
- To explore the role of actin cytoskeleton in muscle pathogenesis.
Main Methods:
- Gene expression analysis using Affymetrix high-density oligonucleotide microarrays.
- Comparison of transcriptional profiles between wild-type and Mhc mutant Drosophila muscles.
- Subcellular localization studies of identified proteins.
Main Results:
- Identified an altered transcriptional profile in dystrophic Mhc muscles.
- Found significant up-regulation of actin-related genes and proteins involved in cytoskeletal support.
- Discovered previously uncharacterized proteins with actin-interaction domains that are upregulated.
- Observed specific subcellular localization of proteins like MSP-300 and ARC in dystrophic muscles.
Conclusions:
- Muscle hypercontraction triggers an actin-dependent remodeling of the muscle cytoskeleton.
- Candidate genes and proteins involved in muscular dystrophy pathogenesis and repair have been identified.
- Modulation of the actin cytoskeleton plays a crucial role in compensatory muscle repair pathways.
