Skeletal muscle is sensitive to the tension–time integral but not to the rate of change of tension, as assessed by mechanically induced signaling

Mechanical forces regulate many cellular processes. Mechanotransduction, however, is poorly understood. In skeletal muscle, mechanical forces have a major impact on the regulation of cellular volume, yet the nature of the mechanical stimulation to which muscle is most sensitive is unknown. It was recently demonstrated that activation of the mechanically-sensitive kinase p54 jun-N-terminal-kinase (JNK), is a quantitative marker of mechanical stimulation in skeletal muscle. This marker was shown to be more sensitive to peak tension than to other tension-related parameters such as the tension–time integral (TTI) and the rate of change of tension (dT/dt). The purpose of the present study was to parcel out the contribution of TTI and dT/dt to mechanical stimulation of muscle under conditions of constant peak tension. The rat medial gastrocnemius in situ was subjected to one of four 5-min passive stretch protocols consisting of equal length excursions, but differing in displacement–time integral (4%, 40%, or 100%) and/or rate of stretch (0, 3, or 30 mm/s), and the resulting p54-JNK phosphorylation was assessed. A linear relationship between TTI and p54-JNK signaling was observed. However, no effect of dT/dt was observed. It is concluded that peak tension and TTI are necessary parameters for modeling the mechanical stimulus-response of muscle. Additionally, the mechanism of mechanotransduction is sensitive to peak tension and TTI, but not to dT/dt, and thus exhibits spring-like behavior. These findings may contribute to the refinement of disuse atrophy countermeasures.