Expression Profiling of a Hypercontraction-induced Myopathy in Drosophila Suggests a Compensatory Cytoskeletal Remodeling Response

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 dystrophinrelated protein, MSP-300, and the homolog of the neuronal activityregulated 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.

Muscle wasted: a novel component of theDrosophilahistone locus body required for muscle integrity

“…6A; P<0.1). CG6972, an uncharacterised gene, has been proposed to be positively regulated by Mef2 and is expressed specifically in the somatic muscles (Elgar et al, 2008;Sandmann et al, 2006) but has also been shown to be upregulated in response to hypertrophyinduced muscular degeneration (Montana and Littleton, 2006). It is possible that the higher levels of CG6972 observed in mute 1281 is due to the muscle-wasting defect.…”

TheDrosophilamuscle LIM protein, Mlp84B, cooperates with D-titin to maintain muscle structural integrity

“…These mutant flight muscles experience a lot of strain and usually tear, resulting in muscle damage (Naimi et al, 2001;Nongthomba et al, 2003;Montana and Littleton, 2004). Transcriptional profiling of two hypercontraction mutants revealed an upregulation of several actin-associated muscle proteins, suggesting the existence of a cytoskeletal remodeling program in injured flight muscle, perhaps similar to the remodeling program in damaged cardiomyocytes (Montana and Littleton, 2006). Intriguingly, mlp84B, mlp60A and D-titin transcripts are upregulated in these mutants, suggesting that the mlp and Dtitin promoters are coresponsive to an undefined muscle damage signal.…”

Drosophila melanogaster muscle LIM protein and alpha‐actinin function together to stabilize muscle cytoarchitecture: A potential role for Mlp84B in actin‐crosslinking

“…These observations suggest that the upregulation of MLP in damaged muscle may be a critical response, either to strengthen the cell during times of increased mechanical load, or to stabilize the cell infrastructure during repair. In the fly, there is a modest increase in Mlp84B RNA levels in muscle damaged from genetically-induced hypercontraction (Montana and Littleton 2006), but no corresponding increase in protein (data not shown). However, Mlp60A, the other MLP family member in Drosophila, shows a robust increase at both the RNA and protein levels in the hypercontraction mutants (Montana and Littleton 2006); (data not shown).…”