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Neprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides

Author

Listed:
  • Ronja Schiemann

    (Osnabrück University)

  • Annika Buhr

    (Osnabrück University)

  • Eva Cordes

    (Osnabrück University)

  • Stefan Walter

    (Center of Cellular Nanoanalytics Osnabrück - CellNanOs)

  • Jürgen J. Heinisch

    (Center of Cellular Nanoanalytics Osnabrück - CellNanOs
    Osnabrück University)

  • Paola Ferrero

    (Center for Cardiovascular Research - CONICET/National University of La Plata)

  • Hendrik Milting

    (University of Bochum, Erich & Hanna Klessmann-Institute for Cardiovascular Research and Development)

  • Achim Paululat

    (Osnabrück University
    Center of Cellular Nanoanalytics Osnabrück - CellNanOs)

  • Heiko Meyer

    (Osnabrück University
    Center of Cellular Nanoanalytics Osnabrück - CellNanOs)

Abstract

Muscle contraction depends on strictly controlled Ca2+ transients within myocytes. A major player maintaining these transients is the sarcoplasmic/endoplasmic reticulum Ca2+ ATPase, SERCA. Activity of SERCA is regulated by binding of micropeptides and impaired expression or function of these peptides results in cardiomyopathy. To date, it is not known how homeostasis or turnover of the micropeptides is regulated. Herein, we find that the Drosophila endopeptidase Neprilysin 4 hydrolyzes SERCA-inhibitory Sarcolamban peptides in membranes of the sarcoplasmic reticulum, thereby ensuring proper regulation of SERCA. Cleavage is necessary and sufficient to maintain homeostasis and function of the micropeptides. Analyses on human Neprilysin, sarcolipin, and ventricular cardiomyocytes indicates that the regulatory mechanism is evolutionarily conserved. By identifying a neprilysin as essential regulator of SERCA activity and Ca2+ homeostasis in cardiomyocytes, these data contribute to a more comprehensive understanding of the complex mechanisms that control muscle contraction and heart function in health and disease.

Suggested Citation

  • Ronja Schiemann & Annika Buhr & Eva Cordes & Stefan Walter & Jürgen J. Heinisch & Paola Ferrero & Hendrik Milting & Achim Paululat & Heiko Meyer, 2022. "Neprilysins regulate muscle contraction and heart function via cleavage of SERCA-inhibitory micropeptides," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-31974-1
    DOI: 10.1038/s41467-022-31974-1
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    References listed on IDEAS

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    1. Stefan M. Gehrig & Chris van der Poel & Timothy A. Sayer & Jonathan D. Schertzer & Darren C. Henstridge & Jarrod E. Church & Severine Lamon & Aaron P. Russell & Kay E. Davies & Mark A. Febbraio & Gord, 2012. "Hsp72 preserves muscle function and slows progression of severe muscular dystrophy," Nature, Nature, vol. 484(7394), pages 394-398, April.
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