ZAKβ is activated by cellular compression and mediates contraction-induced MAP kinase signaling in skeletal muscle

  • EMBO J. 2022 Sep 1;41(17):e111650. doi: 10.15252/embj.2022111650.
Cathrine Nordgaard  1 ,  Anna Constance Vind  1 ,  Amy Stonadge  2 ,  Rasmus Kjøbsted  3 ,  Goda Snieckute  1 ,  Pedro Antas  4 ,  Melanie Blasius  1 ,  Marie Sofie Reinert  1 ,  Ana Martinez Del Val  5 ,  Dorte Breinholdt Bekker-Jensen  5 ,  Peter Haahr  6 ,  Yekaterina A Miroshnikova  7 ,  Abdelghani Mazouzi  6 ,  Sarah Falk  8 ,  Emeline Perrier-Groult  9 ,  Christopher Tiedje  1 ,  Xiang Li  2 ,  Jens Rithamer Jakobsen  10 ,  Nicolas Oldenburg Jørgensen  3 ,  Jørgen Fp Wojtaszewski  3 ,  Frederic Mallein-Gerin  9 ,  Jesper Løvind Andersen  1  10 ,  Cristian Pablo Pennisi  11 ,  Christoffer Clemmensen  8 ,  Moustapha Kassem  12  13 ,  Abbas Jafari  12 ,  Thijn Brummelkamp  6  14  15  16 ,  Vivian Sw Li  4 ,  Sara A Wickström  7 ,  Jesper Velgaard Olsen  5 ,  Gonzalo Blanco  2 ,  Simon Bekker-Jensen  1
Affiliations
  • 1. Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark.
  • 2. Department of Biology, University of York, York, UK.
  • 3. Department of Nutrition, Exercise and Sports, University of Copenhagen, Copenhagen, Denmark.
  • 4. Stem Cell and Cancer Biology Laboratory, The Francis Crick Institute, London, UK.
  • 5. Mass Spectrometry for Quantitative Proteomics, Proteomics Program, Faculty of Health and Medical Sciences, The Novo Nordisk Foundation Center for Protein Research, University of Copenhagen, Copenhagen, Denmark.
  • 6. Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 7. Stem Cells and Metabolism Research Program, Faculty of Medicine and Helsinki Institute of Life Science, University of Helsinki, Helsinki, Finland.
  • 8. Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 9. Institut de Biologie et Chimie des Protéines, CNRS UMR5305, Lyon, France.
  • 10. Department of Orthopedic Surgery M, Institute of Sports Medicine Copenhagen, Bispebjerg Hospital, Copenhagen, Denmark.
  • 11. Regenerative Medicine Group, Department of Health Science and Technology, Aalborg University, Aalborg, Denmark.
  • 12. Department of Cellular and Molecular Medicine, Novo Nordisk Foundation Center for Stem Cell Biology (DanStem), University of Copenhagen, Copenhagen, Denmark.
  • 13. Department of Endocrinology and Metabolism, University Hospital of Odense and University of Southern Denmark, Odense, Denmark.
  • 14. Oncode Institute, Division of Biochemistry, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
  • 15. CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria.
  • 16. Cancer Genomics Center, Amsterdam, The Netherlands.
PMID: 35899396 DOI: 10.15252/embj.2022111650
Abstract

Mechanical inputs give rise to p38 and JNK activation, which mediate adaptive physiological responses in various tissues. In skeletal muscle, contraction-induced p38 and JNK signaling ensure adaptation to exercise, muscle repair, and hypertrophy. However, the mechanisms by which muscle fibers sense mechanical load to activate this signaling have remained elusive. Here, we show that the upstream MAP3K ZAKβ is activated by cellular compression induced by osmotic shock and cyclic compression in vitro, and muscle contraction in vivo. This function relies on ZAKβ's ability to recognize stress fibers in cells and Z-discs in muscle fibers when mechanically perturbed. Consequently, ZAK-deficient mice present with skeletal muscle defects characterized by fibers with centralized nuclei and progressive adaptation towards a slower Myosin profile. Our results highlight how cells in general respond to mechanical compressive load and how mechanical forces generated during muscle contraction are translated into MAP kinase signaling.

Keywords
ZAKβ; mechanobiology; muscle contraction; myopathy.