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

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 ZAK beta is activated by cellular compression induced by osmotic shock and cyclic compression in vitro, and muscle contraction in vivo. This function relies on ZAKO'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.Peer reviewe

Larger interface area at the human myotendinous junction in type 1 compared to type 2 muscle fibers

The myotendinous junction (MTJ) is structurally specialized to transmit force. The highly folded muscle membrane at the MTJ increases the contact area between muscle and tendon and potentially the load tolerance of the MTJ. Muscles with a high content of type II fibers are more often subject to strain injury compared with muscles with type I fibers. It is hypothesized that this is explained by a smaller interface area of MTJ in type II compared with type I muscle fibers. The aim was to investigate by confocal microscopy whether there is difference in the surface area at the MTJ between type I and II muscle fibers. Individual muscle fibers with an intact MTJ were isolated by microscopic dissection in samples from human semitendinosus, and they were labeled with antibodies against collagen XXII (indicating MTJ) and type I myosin (MHCI). Using a spinning disc confocal microscope, the MTJ from each fiber was scanned and subsequently reconstructed to a 3D-model. The interface area between muscle and tendon was calculated in type I and II fibers from these reconstructions. The MTJ was analyzed in 314 muscle fibers. Type I muscle fibers had a 22% larger MTJ interface area compared with type II fibers (p < 0.05), also when the area was normalized to fiber diameter. By the new method, it was possible to analyze the structure of the MTJ from a large number of human muscle fibers. The finding that the interface area between muscle and tendon is higher in type I compared with type II fibers suggests that type II fibers are less resistant to strain and therefore more susceptible to injury