Concomitant excitation and tension development are required for myocellular gene expression and protein synthesis in rat skeletal muscle

Abstract

Aim Loading‐induced tension development is often assumed to constitute an independent cue to initiate muscle protein synthesis following resistance exercise. However, with traditional physiological models of resistance exercise, changes in loading‐induced tension development also reflect changes in neural activation patterns, and direct evidence for a mechanosensitive mechanism is therefore limited. Here, we sought to examine the importance of excitation and tension development per se on initiation of signalling, gene transcription and protein synthesis in rat skeletal muscle. Methods Isolated rat extensor digitorum longus muscles were allocated to the following interventions: (a) Excitation‐induced eccentric contractions (ECC); (b) Passive stretching without excitation (PAS); (c) Excitation with inhibition of contractions (STIM + IMA) and; (d) Excitation in combination with both inhibition of contractions and PAS (STIM + IMA + PAS). Assessment of transcriptional and translational signalling, gene transcription and acute muscle protein synthesis was compared in stimulated vs contra‐lateral non‐stimulated control muscle. Results Protein synthesis increased solely in muscles subjected to a combination of excitation and tension development (ECC and STIM + IMA + PAS). The same pattern was true for p38 mitogen‐activated protein kinase signalling for gene transcription as well as for gene transcription of immediate early genes FOS and JUN. In contrast, mechanistic target of rapamycin Complex 1 signalling for translation initiation increased in all muscles subjected to increased tension development (ECC and STIM + IMA + PAS as well as PAS). Conclusions The current study suggests that exercise‐induced increases in protein synthesis as well as transcriptional signalling is dependent on the concomitant effect of excitation and tension development, whereas signalling for translation initiation is only dependent of tension development per se.

Excitation and tension development—The Yin & Yang of muscle signalling

“…The skeletal muscle excitation‐contraction coupling leading to tension development and increased mechanical stimuli change in concert, leaving it difficult to study their respective effect on molecular signalling and following adaptations. In the current issue of Acta Physiologica , Rindom and co‐workers 1 further our understanding of these signalling pathways through a series of elegantly designed experiments. They investigated specific effects of the excitation‐contraction coupling and tension development on signals regulating transcription, translation and protein synthesis in isolated rat EDL muscles by performing combinations of: 1) excitation‐induced Ca 2+ ‐ release by standardized electrical stimulation; (2) addition of chemical inhibitors of the myosin ATPase in order to block muscle contractions, and; (3) mechanical manipulation to achieve passive tension equal to actively contracting muscles through extensive muscle stretching.…”

“…Rindom et al 1 suggest that separate signalling pathways are dependent on either excitation or tension development, or both, and that they in sum are all obligatory to increase protein synthesis responsible for hypertrophy (see Figure 1 for summary of findings put into a broader context). One intriguing thought related to their findings, is that succeeding steps in the signalling network projecting from either the muscle excitation or tension development can be modulated by cues from the respective stimuli, like a Yin & Yang of hypertrophic signalling, as well as other interdependent cues such as nutrient availability and other circulating factors.…”

“…Simplistic overview of how the excitation and mechanical stimuli interpolate with each other and other signalling cues, taking part in the complex signalling network involved in protein synthesis and hypertrophy. Results and interpretations from Rindom et al 1 are shown as full‐drawn lines with arrowheads. Dotted lines with arrowheads are based on existing literature.…”

“…One important advantage of the present work by Rindom et al 1 is that they were able to standardize a high peak tension and tension‐time integral both with and without excitation, as signalling is highly dependent on these parameters (see references within 1 ). This is very challenging to achieve intravitally, as the maximum joint excursion limits the amount of passive muscle tension one can obtain 6 .…”

“…This is very challenging to achieve intravitally, as the maximum joint excursion limits the amount of passive muscle tension one can obtain 6 . Yet, a similar approach as used by Rindom et al 1 could be performed with an acute in vivo setup with sedated rats where the muscle is detached distally, but still keeping the blood supply and the rest of the in vivo milieu intact, as, for example, nutrient, energy and oxygen supply can all affect the signalling network 7 . In a recent rat strength straining study 6 where the muscle excitation were standardized in order to investigate acute and long‐term effects of a varying tension development per se, increased tension led to an increased myonuclear number and hypertrophic response, but observed fibre type changes were not affected by degree of tension development.…”