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 F.P.
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 S.W.
AU - Wickström, Sara A.
AU - Olsen, Jesper Velgaard
AU - Blanco, Gonzalo
AU - Bekker-Jensen, Simon
N1 - Funding Information:
We thank Dr. Andres Lopez‐Contreras (University of Copenhagen, Denmark) for support with mouse husbandry, and Drs. Xiaoyun Lu, Ke Ding (both Jinan University, China), and Paul Pryor (University of York, UK) for providing reagents. We thank Drs. Atul Deshmukh and Alba Gonzalez‐Franquesa (both University of Copenhagen, Denmark) for help with C2C12 culture. For providing access to confocal and time‐lapse microscopy we acknowledge the Danstem and NNF‐CPR imaging platform (University of Copenhagen, Denmark). and Michele M. Nava (University of Helsinki) for help with mechanical manipulations. The Genotype‐Tissue Expression (GTEx) Project was supported by the Common Fund of the Office of the Director of the National Institutes of Health, and by NCI, NHGRI, NHLBI, NIDA, NIMH, and NINDS. Work in the Bekker‐Jensen lab was supported by grants from the Lundbeck Foundation (R190‐2014‐4037), The Danish Medical Research Council (9039‐00007B), The Novo Nordisk Foundation (NNF21OC0071475), The NEYE Foundation, The Nordea Foundation, and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement 863911 ‐ PHYRIST). Anna Constance Vind is supported by the BRIDGE—Translational Excellence Program funded by the Novo Nordisk Foundation (NNF20SA0064340). Christoffer Clemmensen receives funding from the Lundbeck Foundation (Fellowship R238‐2016‐2859) and the Novo Nordisk Foundation (grant number NNF17OC0026114). Novo Nordisk Foundation Center for Basic Metabolic Research is an independent Research Center, based on the University of Copenhagen, Denmark, and partially funded by an unconditional donation from the Novo Nordisk Foundation ( www.cbmr.ku.dk ) (Grant number NNF18CC0034900). Work in the Wojtaszewski lab was supported by a grant from the Danish Council for Independent Research—Medical Sciences (FSS 8020‐00288) and a research grant to Rasmus Kjøbsted from the Danish Diabetes Academy, which is funded by the Novo Nordisk Foundation (NFF 17SA0031406). Work in Jesper Olsen's lab at The Novo Nordisk Foundation Center for Protein Research (CPR) is funded in part by a generous donation from the Novo Nordisk Foundation (Grant number NNF14CC0001).
PY - 2022/9/1
Y1 - 2022/9/1
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 - mechanobiology
KW - muscle contraction
KW - myopathy
KW - ZAKβ
U2 - 10.15252/embj.2022111650
DO - 10.15252/embj.2022111650
M3 - Journal article
C2 - 35899396
AN - SCOPUS:85135099218
SN - 0261-4189
VL - 41
JO - EMBO Journal
JF - EMBO Journal
IS - 17
M1 - e111650
ER -