A MAP kinase‐driven mechanical stress response mediates the hypertrophic response in skeletal muscle

Abstract

When cells are exposed to unfavorable conditions they cope by activating cellular stress responses. Such signaling depends on activation of the p38 and JNK MAP kinases and is crucial for both general tissue homeostasis and a range of physiological reactions. However, the mechanisms linking diverse stress stimuli to MAP kinase activation remain poorly understood.Here we show how a specific MAP3 kinase mediates activation of p38 and JNK upon hyperosmotic‐ and mechanical stress. Employing fluorescence microscopy techniques, we show that this MAP3 kinase translocates from the cytoplasm to the nuclear lamina and other detergent‐resistant structures in the nucleus upon osmotic stress induction. Here, it co‐localizes with structures rich in DNA damage response factors such as 53BP1, but void of DNA strand breaks, which were shown to constitute nuclear sensor domains for mechanical stress.Mechanical stress is experienced in skeletal muscle due to the repeated contraction of muscle fibers upon physical exercise. The signaling from these events underlie the hypertrophic response, where muscles respond to exercise by growing larger and stronger. We show that the above signaling pathway operates during exercise‐associated stimulus of C2C12 myotubes, where it is responsible for the production of a range of inflammatory transcripts and myokines (such as IL6). Consequently, in a mouse model deficient for the MAP3 kinase, we see clear signs of pathology associated with decreased muscle repair and adaptation to exercise.In conclusion, our work provides novel insight into the mechanisms by which cells sense and react to mechanical stress stimuli and identify skeletal muscle as a major target organ upon deficiency in these responses.