The Francis Crick Institute
The EMBO Journal - 2022 - Nordgaard - ZAK is activated by cellular compression and mediates contraction‐induced MAP kinase.pdf (3.4 MB)

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

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journal contribution
posted on 2022-08-10, 10:48 authored by Cathrine Nordgaard, Anna Constance Vind, Amy Stonadge, Rasmus Kjøbsted, Goda Snieckute, Pedro Antas, Melanie Blasius, Marie Sofie Reinert, Ana Martinez Del Val, Dorte Breinholdt Bekker-Jensen, Peter Haahr, Yekaterina A Miroshnikova, Abdelghani Mazouzi, Sarah Falk, Emeline Perrier-Groult, Christopher Tiedje, Xiang Li, Jens Rithamer Jakobsen, Nicolas Oldenburg Jørgensen, Jørgen FP Wojtaszewski, Frederic Mallein-Gerin, Jesper Løvind Andersen, Cristian Pablo Pennisi, Christoffer Clemmensen, Moustapha Kassem, Abbas Jafari, Thijn Brummelkamp, Vivian SW Li, Sara A Wickström, Jesper Velgaard Olsen, Gonzalo Blanco, Simon Bekker-Jensen
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.