Evidence that mechanosensors with distinct biomechanical properties allow for specificity in mechanotransduction.

Various cell types can sense and convert mechanical forces into biochemical signaling events through a process called mechanotransduction, and this process is often highly specific to the types of mechanical forces applied. However, the mechanism(s) that allow for specificity in mechanotransduction remain undefined. Thus, the goal of this study was to gain insight into how cells distinguish among specific types of mechanical information. To accomplish this goal, we determined if skeletal myoblasts can distinguish among differences in strain, strain rate, and strain-time integral (STI). Our results demonstrate that mechanically induced signaling through the c-jun N-terminal kinase 2 [JNK2] is elicited via a mechanism that depends on an interaction between the magnitude of strain and strain rate and is independent of STI. In contrast to JNK2, mechanically induced signaling through the ribosomal S6 kinase [p70(389)] is not strain rate sensitive, but instead involves a magnitude of strain and STI dependent mechanisms. Mathematical modeling also indicated that mechanically induced signaling through JNK2 and p70(389) can be isolated to separate viscous and elastic mechanosensory elements, respectively. Based on these results, we propose that skeletal myoblasts contain multiple mechanosensory elements with distinct biomechanical properties and that these distinct biomechanical properties provide a mechanism for specificity in mechanotransduction.

The role of phosphoinositide 3-kinase and phosphatidic acid in the regulation of mammalian target of rapamycin following eccentric contractions.

Resistance exercise induces a hypertrophic response in skeletal muscle and recent studies have begun to shed light on the molecular mechanisms involved in this process. For example, several studies indicate that signalling by the mammalian target of rapamycin (mTOR) is necessary for a hypertrophic response. Furthermore, resistance exercise has been proposed to activate mTOR signalling through an upstream pathway involving the phosphoinositide 3-kinase (PI3K) and protein kinase B (PKB); however, this hypothesis has not been thoroughly tested. To test this hypothesis, we first evaluated the temporal pattern of signalling through PI3K-PKB and mTOR following a bout of resistance exercise with eccentric contractions (EC). Our results indicated that the activation of signalling through PI3K-PKB is a transient event (<15 min), while the activation of mTOR is sustained for a long duration (>12 h). Furthermore, inhibition of PI3K-PKB activity did not prevent the activation of mTOR signalling by ECs, indicating that PI3K-PKB is not part of the upstream regulatory pathway. These observations led us to investigate an alternative pathway for the activation of mTOR signalling involving the synthesis of phosphatidic acid (PA) by phospholipase D (PLD). Our results demonstrate that ECs induce a sustained elevation in [PA] and inhibiting the synthesis of PA by PLD prevented the activation of mTOR. Furthermore, we determined that similar to ECs, PA activates mTOR signalling through a PI3K-PKB-independent mechanism. Combined, the results of this study indicate that the activation of mTOR following eccentric contractions occurs through a PI3K-PKB-independent mechanism that requires PLD and PA.