Transcriptome analysis of IFM-specific actin and myosin nulls in Drosophila melanogaster unravels lesion-specific expression blueprints across muscle mutations

Madan, Aditi; Thimmaiya, Divesh; Franco-Cea, Ari; Aiyaz, Mohammed; Kumar, Prabodh; Sparrow, John C.; Nongthomba, Upendra

doi:10.1016/j.gene.2017.07.061

Cited by 4 publications

(3 citation statements)

References 50 publications

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“…All the putative miR-9a targets associated with muscle development proved to be involved in muscle function. Of these miR-9a targets in muscles, 4 genes are reported to be involved in larval muscle development, 19 in the development of pupal and adult muscles (Figure 2A) (Schnorrer et al 2010), and 6 genes are associated with muscle development (Madan et al 2017; https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70252). These putative targets are expressed in the IFMs as demonstrated using the Drosophila IFM microarray (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE70252) (Figure 2B).…”

Section: Resultsmentioning

confidence: 99%

Overexpression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of Troponin-T inDrosophila melanogasterIndirect Flight Muscles

Katti

Thimmaya

Madan

et al. 2017

G3 Genes|Genomes|Genetics

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MicroRNAs (miRNAs) are small noncoding endogenous RNAs, typically 21–23 nucleotides long, that regulate gene expression, usually post-transcriptionally, by binding to the 3′-UTR of target mRNA, thus blocking translation. The expression of several miRNAs is significantly altered during cardiac hypertrophy, myocardial ischemia, fibrosis, heart failure, and other cardiac myopathies. Recent studies have implicated miRNA-9 (miR-9) in myocardial hypertrophy. However, a detailed mechanism remains obscure. In this study, we have addressed the roles of miR-9 in muscle development and function using a genetically tractable model system, the indirect flight muscles (IFMs) of Drosophila melanogaster. Bioinformatics analysis identified 135 potential miR-9a targets, of which 27 genes were associated with Drosophila muscle development. Troponin-T (TnT) was identified as major structural gene target of miR-9a. We show that flies overexpressing miR-9a in the IFMs have abnormal wing position and are flightless. These flies also exhibit a loss of muscle integrity and sarcomeric organization causing an abnormal muscle condition known as “hypercontraction.” Additionally, miR-9a overexpression resulted in the reduction of TnT protein levels while transcript levels were unaffected. Furthermore, muscle abnormalities associated with miR-9a overexpression were completely rescued by overexpression of TnT transgenes which lacked the miR-9a binding site. These findings indicate that miR-9a interacts with the 3′-UTR of the TnT mRNA and downregulates the TnT protein levels by translational repression. The reduction in TnT levels leads to a cooperative downregulation of other thin filament structural proteins. Our findings have implications for understanding the cellular pathophysiology of cardiomyopathies associated with miR-9 overexpression.

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Section: Resultsmentioning

confidence: 99%

Overexpression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of Troponin-T inDrosophila melanogasterIndirect Flight Muscles

Katti

Thimmaya

Madan

et al. 2017

G3 Genes|Genomes|Genetics

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“…In contrast, among the upregulated genes we identified overrepresented groups involved in unfolded protein response, including chaperones, proteasomal components and protein translation machinery components. Many of these genes have recently been reported to become upregulated in the IFM of Act88F -null mutants (Madan et al, 2017; ). It is likely that these genes respond in a stereotypic way to handle the surplus of myofibrillar proteins caused by muscle actin shortage (see Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of fiber-specific actin expression by the Drosophila SRF ortholog Blistered

et al. 2019

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Serum response factor (SRF) has an established role in controlling actin homeostasis in mammalian cells, yet its role in non-vertebrate muscle development has remained enigmatic. Here, we demonstrate that the single Drosophila SRF ortholog, termed Blistered (Bs), is expressed in all adult muscles, but Bs is required for muscle organization only in the adult indirect flight muscles. Bs is a direct activator of the flight muscle actin gene Act88F , via a conserved promoter-proximal binding site. However, Bs only activates Act88F expression in the context of the flight muscle regulatory program provided by the Pbx and Meis orthologs Extradenticle and Homothorax, and appears to function in a similar manner to mammalian SRF in muscle maturation. These studies place Bs in a regulatory framework where it functions to sustain the flight muscle phenotype in Drosophila . Our studies uncover an evolutionarily ancient role for SRF in regulating muscle actin expression, and provide a model for how SRF might function to sustain muscle fate downstream of pioneer factors.

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“…Skeletal muscle accounts for 75% of body mass in flying organisms, such as Drosophila , and flight muscles alone account for 65% of total body mass [ 21 ]. The IFM of the Drosophila thorax is the largest and the only fibrous muscle present in Drosophila [ 22 ]. Furthermore, the constituent proteins of the IFM show a high degree of homology with their vertebrate counterparts at the sequence, structural, and functional levels [ 23 ].…”

Section: Introductionmentioning

confidence: 99%

Regular Exercise Rescues Heart Function Defects and Shortens the Lifespan of Drosophila Caused by dMnM Downregulation

Ding

et al. 2022

IJERPH

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Although studies have shown that myomesin 2 (MYOM2) mutations can lead to hypertrophic cardiomyopathy (HCM), a common cardiovascular disease that has a serious impact on human life, the effect of MYOM2 on cardiac function and lifespan in humans is unknown. In this study, dMnM (MYOM2 homologs) knockdown in cardiomyocytes resulted in diastolic cardiac defects (diastolic dysfunction and arrhythmias) and increased cardiac oxidative stress. Furthermore, the knockdown of dMnM in indirect flight muscle (IFM) reduced climbing ability and shortened lifespan. However, regular exercise significantly ameliorated diastolic cardiac dysfunction, arrhythmias, and oxidative stress triggered by dMnM knockdown in cardiac myocytes and also reversed the reduction in climbing ability and shortening of lifespan caused by dMnM knockdown in Drosophila IFM. In conclusion, these results suggest that Drosophila cardiomyocyte dMnM knockdown leads to cardiac functional defects, while dMnM knockdown in IFM affects climbing ability and lifespan. Furthermore, regular exercise effectively upregulates cardiomyocyte dMnM expression levels and ameliorates cardiac functional defects caused by Drosophila cardiomyocyte dMnM knockdown by increasing cardiac antioxidant capacity. Importantly, regular exercise ameliorates the shortened lifespan caused by dMnM knockdown in IFM.

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Transcriptome analysis of IFM-specific actin and myosin nulls in Drosophila melanogaster unravels lesion-specific expression blueprints across muscle mutations

Cited by 4 publications

References 50 publications

Overexpression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of Troponin-T inDrosophila melanogasterIndirect Flight Muscles

Overexpression of miRNA-9 Generates Muscle Hypercontraction Through Translational Repression of Troponin-T inDrosophila melanogasterIndirect Flight Muscles

Regulation of fiber-specific actin expression by the Drosophila SRF ortholog Blistered

Regular Exercise Rescues Heart Function Defects and Shortens the Lifespan of Drosophila Caused by dMnM Downregulation

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