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

Functional adaptation of tendon and skeletal muscle to resistance training in three patients with genetically verified classic Ehlers Danlos Syndrome

Background: tendon and skeletal muscle function adapts to physical training of resistive nature, but it is unknown to what extent persons with genetically altered connective tissue – who have a higher than normal tendon extensibility – will obtain any effect upon their tendon and muscle when undergoing muscle strength training. We investigated patients with classical Ehlers Danlos Syndrome (EDS) (collagen type V defect) who display articular hypermobility, skin extensibility and tissue fragility. Methods: subjects underwent strength training 3 times a week for 4 months and were tested before and after intervention in regards to muscle strength, tendon mechanical properties, and muscle function. Results: three subjects completed the scheduled 48 sessions and had no major adverse events. Mean isometric leg extension force and leg extensor power both increased by 8 and 11% respectively (358 to 397 N, and 117 to 123 W). The tendon stiffness was tested and an average increase in response to physical training, from 1795 to 2519 N/mm was found. On average, the training loads both in upper and lower body exercises increased by around 30% over the training period. When testing balance, the average sway-area of the participants decreased by 26% (0.144 to 0.108 m2). On the subscale of CIS20 the participants lowered their average subjective fatigue score from 33 to 25. Conclusion: in this small pilot study, heavy resistance training was both feasible and effective in classic Ehlers Danlos patients, and the results indicated that both tendon and skeletal muscle properties can be improved also in this patient group when they are subjected to resistance trainin