TY - JOUR
T1 - ZAKβ is activated by cellular compression and mediates contraction-induced MAP kinase signaling in skeletal muscle
AU - Nordgaard, Cathrine
AU - Vind, Anna Constance
AU - Stonadge, Amy
AU - Kjøbsted, Rasmus
AU - Snieckute, Goda
AU - Antas, Pedro
AU - Blasius, Melanie
AU - Reinert, Marie Sofie
AU - Del Val, Ana Martinez
AU - Bekker-Jensen, Dorte Breinholdt
AU - Haahr, Peter
AU - Miroshnikova, Yekaterina A
AU - Mazouzi, Abdelghani
AU - Falk, Sarah
AU - Perrier-Groult, Emeline
AU - Tiedje, Christopher
AU - Li, Xiang
AU - Jakobsen, Jens Rithamer
AU - Jørgensen, Nicolas Oldenburg
AU - Wojtaszewski, Jørgen
AU - Mallein-Gerin, Frederic
AU - Andersen, Jesper Løvind
AU - Pennisi, Cristian Pablo
AU - Clemmensen, Christoffer
AU - Kassem, Moustapha
AU - Jafari, Abbas
AU - Brummelkamp, Thijn
AU - Li, Vivian Sw
AU - Wickström, Sara A
AU - Olsen, Jesper Velgaard
AU - Blanco, Gonzalo
AU - Bekker-Jensen, Simon
N1 - © 2022 The Authors. Published under the terms of the CC BY NC ND 4.0 license.
PY - 2022
Y1 - 2022
N2 - 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.
AB - 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.
KW - Faculty of Science
KW - Mechanobiology
KW - Muscle contraction
KW - Myopathy
KW - ZAKβ
U2 - 10.15252/embj.2022111650
DO - 10.15252/embj.2022111650
M3 - Journal article
C2 - 35899396
VL - 41
JO - E M B O Journal
JF - E M B O Journal
SN - 0261-4189
IS - 17
M1 - e111650
ER -