Insight into skeletal muscle mechanotransduction: MAPK activation is quantitatively related to tension

The mechanism by which mechanical forces acting through skeletal muscle cel ls generate intracellular signaling, known as mechanotransduction, and the details of how gene expression and cell size are regulated by this signalin g are poorly understood. Mitogen-activated protein kinases (MAPKs) are know n to be involved in mechanically induced signaling in various cell types, i ncluding skeletal muscle where MAPK activation has been reported in respons e to contraction and passive stretch. Therefore, the investigation of MAPK activation in response to mechanical stress in skeletal muscle may yield im portant information about the mechanotransduction process. With the use of a rat plantaris in situ preparation, a wide range of peak tensions was gene rated through passive stretch and concentric, isometric, and eccentric cont ractile protocols, and the resulting phosphorylation of c-Jun NH2-terminal kinase (JNK), extracellular regulated kinase (ERK), and p38 MAPKs was asses sed. Isoforms of JNK and ERK MAPKs were found to be phosphorylated in a ten sion-dependent manner, such that eccentric. isometric. concentric. passive stretch. Peak tension was found to be a better predictor of MAPK phosphoryl ation than time-tension integral or rate of tension development. Difference s in maximal response amplitude and sensitivity between JNK and ERK MAPKs s uggest different roles for these two kinase families in mechanically induce d signaling. A strong linear relationship between p54 JNK phosphorylation a nd peak tension over a 15-fold range in tension (r(2) = 0.89, n = 32) was o bserved, supporting the fact that contraction-type differences can be expla ined in terms of tension and demonstrating that MAPK activation is a quanti tative reflection of the magnitude of mechanical stress applied to muscle. Thus the measurement of MAPK activation, as an assay of skeletal muscle mec hanotransduction, may help elucidate mechanically induced hypertrophy.