High frequency electrical stimulation reveals a p38-mTOR signaling module correlated with force-time integral

Abstract

SUMMARYHigh-frequency electrical stimulation (HFES) leads to muscle hypertrophy, and attention has been drawn to the high forces involved. However, both mechanical and metabolic stresses occur simultaneously, and both stimuli influence signaling cascades related to protein synthesis. This study aimed to identify the immediate signaling correlates of contraction-induced force and metabolic stresses under the hypothesis that HFES induces growth-related signaling through mechanical stimulation. Force-time integral (FTI) signaling in mouse tibialis anterior muscle was examined by separately manipulating the time of contraction to emphasize the metabolic aspect or the force of contraction to emphasize the mechanical aspect. When FTI was manipulated by changing the total time of activation, phosphorylation of p54 JNK, ERK and p70S6k T421/S424 was independent of FTI, while phosphorylation of acetyl-CoA carboxylase and p38 correlated with FTI. When FTI was manipulated by changing the force of contraction, p54 JNK, ERK and p70S6k T421/S424 were again independent of FTI, while phosphorylation of p38 and FAK correlated with FTI. Factor analysis identified a p38-mTOR signaling module that correlated with FTI in both experiments. The consistent link among p38, mTOR and FTI suggests that they form a connected signaling module sensitive to the mechanical aspects of FTI, separate from markers of metabolic load.

The Application of Neuromuscular Electrical Stimulation Training in Various Non‐neurologic Patient Populations: A Narrative Review

“…A NMES study in mice found positive correlations of the p38 and mTOR signaling with the force‐time integral independently from markers of metabolic load. These findings suggest that maximizing the force‐time integral during NMES training may be important for achieving muscle hypertrophy [8]. We therefore suggest that postexercise protein synthesis increases as a consequence of NMES and, similarly to volitional training, depends on training parameters.…”

“…This study has shown that there was a significantly greater increase in knee extension torque after 8 weeks of NMES training at 75 Hz compared with the same training volume at 15 Hz in patients with COPD [9]. A different approach to optimize muscle strength gains has been suggested by a recent study, which indicated that the NMES force‐time integral has to be maximized [8]. Force‐time integral depends on the choice of stimulation parameters and is maximized when fatigue is minimized.…”

Focal adhesion kinase and its role in skeletal muscle

“…FAK is inactivated by cytoskeletal forces (Rahnert and Burkholder 2013). The cellular localization of FAK, principally along the cytoplasmic surface of the sarcolemma (Wilson et al 2014, 2012), allows it to be readily available for activation by integrins.…”

Hallmarks of frailty and osteosarcopenia in prematurely aged PolgAD257A/D257Amice

“…Although there is no universally accepted definition of frailty [1], it is considered as an age- 53 related syndrome characterized by the decline of multiple physiological functions, leading to Henseleit buffer + 1xMEM amino acid mixture and 25mM glucose before snap-freezing 1h 175 after the last contraction. The control EDL from the contralateral leg was kept in the same 37°C 176 Krebs-Henseleit buffer during the complete ECC period.…”

“…Moreover, basal pRPS6 was 323 higher in PolgA (1257±427%, p<0.05) compared to WT ( Figure 3E), suggesting both basal and 324 contraction-induced hyper activation of mTORC1 in PolgA mutated muscle. 325 One of the proposed pathways for high-load contractions to regulate mTORC1 is via activation 326 of the stress responsive mitogen-activated protein kinase (MAPK) pathway [53]. To investigate 327 whether the hyperactive mTORC1 signaling in the PolgA muscle was related to increased 328 MAPK response, we measured activation of (Stress-Activated Protein Kinase/Jun-amino- PolgA (p<0.0001) TA, whereas pS6K1 was also increased in PolgA (p<0.001).…”