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Cofilin loss in Drosophila contributes to myopathy through defective sarcomerogenesis and aggregate formation during muscle growth

View ORCID ProfileMridula Balakrishnan, Shannon F. Yu, Samantha M. Chin, David B. Soffar, Stefanie E. Windner, View ORCID ProfileBruce L. Goode, View ORCID ProfileMary K. Baylies
doi: https://doi.org/10.1101/825448
Mridula Balakrishnan
1Biochemistry, Cell and Developmental Biology, and Molecular Biology (BCMB) program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065
2Program in Developmental Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, 10065
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  • ORCID record for Mridula Balakrishnan
Shannon F. Yu
2Program in Developmental Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, 10065
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Samantha M. Chin
3Department of Biology, Rosenstiel Basic Medical Science Research Center, Brandeis University, Waltham, MA 02454
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David B. Soffar
2Program in Developmental Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, 10065
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Stefanie E. Windner
2Program in Developmental Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, 10065
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Bruce L. Goode
3Department of Biology, Rosenstiel Basic Medical Science Research Center, Brandeis University, Waltham, MA 02454
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  • ORCID record for Bruce L. Goode
Mary K. Baylies
1Biochemistry, Cell and Developmental Biology, and Molecular Biology (BCMB) program, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065
2Program in Developmental Biology, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, 10065
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  • For correspondence: m-baylies@ski.mskcc.org
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SUMMARY

Sarcomeres, the fundamental contractile units of muscles, are conserved structures composed of actin thin filaments and myosin thick filaments. How sarcomeres are formed and maintained is not well understood. Here, we show that knockdown of Drosophila Cofilin (DmCFL), an actin depolymerizing factor, leads to the progressive disruption of sarcomere structure and muscle function in vivo. Loss of DmCFL also results in the formation of sarcomeric protein aggregates and impairs sarcomere addition during growth. Strikingly, activation of the proteasome delayed muscle deterioration in our model. Further, we investigate how a point mutation in CFL2 that causes nemaline myopathy (NM) in humans, affects CFL function and leads to the muscle phenotypes observed in vivo. Our data provide significant insights to the role of CFLs during sarcomere formation as well as mechanistic implications for disease progression in NM patients.

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Posted October 31, 2019.
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Cofilin loss in Drosophila contributes to myopathy through defective sarcomerogenesis and aggregate formation during muscle growth
Mridula Balakrishnan, Shannon F. Yu, Samantha M. Chin, David B. Soffar, Stefanie E. Windner, Bruce L. Goode, Mary K. Baylies
bioRxiv 825448; doi: https://doi.org/10.1101/825448
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Cofilin loss in Drosophila contributes to myopathy through defective sarcomerogenesis and aggregate formation during muscle growth
Mridula Balakrishnan, Shannon F. Yu, Samantha M. Chin, David B. Soffar, Stefanie E. Windner, Bruce L. Goode, Mary K. Baylies
bioRxiv 825448; doi: https://doi.org/10.1101/825448

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