Skeletal muscle contractile properties can be negatively affected with prolonged inactivity and/or muscle wasting disease, leading to severe deteriorations in muscle myofibrillar mass, muscle strength, and mobility (Clark, 2009). Consequently, knowledge on resistance exercise-induced mechanisms involved in stimulating a positive net muscle myofibrillar turnover is important. This turnover is dictated by a balance between protein synthesis and protein degradation, but is contended to be primarily driven by regulation of muscle protein synthesis (MPS) (Atherton and Smith, 2012) and with resistance exercise-induced MPS accentuated by amino acid supplementation (Rasmussen and Phillips, 2003; Wolfe, 2006).

Intriguingly, mechanical force changes inherent of resistance exercise are assumed to exert regulatory action on mechanisms involved in MPS. With regards to resistance exercise, this immediately advance questions such as; (a) how mechanical force changes inherent of resistance exercise is sensed; (b) how resistance exercise-induced mechano-sensing molecules can affect biochemical signaling to directly activate MPS and; (c) how resistance exercise-induced mechano-sensing can exert influence on MPS by means of regulating net supply of muscle myofibrillar gene transcripts to the ribosomal machinery.

Below, we will first summarize the burden of proof that advocate for the significance of mechanotransducing mechanisms. We will then summarize some emerging knowledge on how force changes with resistance exercise may be sensed by mechanosensitive molecules to activate biochemical signaling for MPS and/or muscle myofibrillar gene transcription. Most of the current knowledge on mechanotransduction has been retrieved through employment of in vitro or animal models, whereas less information exists from human resistance exercise studies. Consequently, most of the findings presented, originate from non-human studies. However, human studies that provide support for the implication of similar mechanisms in human skeletal muscle are included, with attention on the influence of resistance exercise modality and intensity.

Mechanistic target of rapamycin complex 1 (mTORC1) is regarded as a nodal point for integration of various stimulators, such as growth factors, nutrients and mechanical forces, to activate downstream signaling for muscle protein translation initiation (Laplante and Sabatini, 2012). Its importance has been justified in different model systems (Bodine et al., 2001; Hornberger et al., 2004; Sandri, 2008; Goodman et al., 2011; Goodman, 2014) and activation of mTORC1 signaling in human skeletal muscle has been shown to be associated with increased MPS during post-exercise recovery from traditional high-intensity resistance exercise (Dreyer et al., 2006, 2008; Drummond et al., 2008) as well as fatiguing low-intensity blood-flow restricted resistance exercise (Fujita et al., 2007; Fry et al., 2010).

mTORC1-inhibitor, rapamycin, has been employed in cell culture and rodent models, to assess whether mTORC1 can be considered outright necessary for activation of MPS subsequent to force changes, with studies on acute responses to single-treatment intervention immediately supporting this (Bodine et al., 2001; Fingar et al., 2002, 2004; Hornberger et al., 2004; Kubica et al., 2005), while results from studies on basal MPS are less conclusive (Kubica et al., 2005; Drummond et al., 2009). The few human studies that have utilized rapamycin in investigation of resistance exercise-induced mTORC1 signaling and MPS provide support that rapamycin exert similar effect upon high-intensity resistance exercise (Drummond et al., 2009) and low intensity blood-flow restricted resistance exercise (Gundermann et al., 2014).

Downstream from mTORC1, 70 kDa ribosomal S6 kinase (P70S6K) seem to provide a stronger proxy of signaling for resistance exercise-induced MPS, than mTORC1 (Baar and Esser, 1999; Nader and Esser, 2001). It can therefore be speculated that P70S6K may be activated by mechanical stress in an mTORC1-independent manner (Klossner et al., 2009), but as the previous studies on this have not included mTORC1 loss-off-function analysis, this requires further investigation.

It has been previously contended that resistance exercise drives muscle hypertrophy by promoting an increase in systemic growth factors like IGF-1, which via its receptor activate a PI3K-Akt-mTORC1 signaling axis to enhance MPS (Yan et al., 1993; Coleman et al., 1995; Goldspink et al., 1995; Adams and Haddad, 1996; Musarò et al., 2001; Rommel et al., 2001). However, more recent studies contradict that systemic growth hormones are vital for driving resistance exercise-induced MPS in the adult muscle. This opposite contention is based on findings including (a); the demonstration of loading-induced PI3K-independent mTORC1 activation through utilization of genetic loss of functions models or PI3K-inhibitor Wortmannin (Hornberger et al., 2004, 2007; O'Neil et al., 2009; Miyazaki et al., 2011), (b); the demonstration that mechanical overload in rodents with a dominant-negative IGF-I receptor do not abolish hypertrophy (Spangenburg et al., 2008), (c); the demonstration that resistance exercise regimens utilizing high vs. low resistance exercise training volumes can accentuate increases in systemic plasma growth factors, but without simultaneously accentuating mTORC1 activation, MPS and/or hypertrophy (West et al., 2009, 2010), and, (d); the observation that human resistance exercise in the fasting state does not seem to activate Akt, yet still promote activation of mTORC1 (Deldicque et al., 2008; Vissing et al., 2013a). The recent skepticism toward an important role of exercise-induced systemic hormones has led to the proposal that intrinsic mechano-sensitive molecules constitute more pivotal drivers of MPS.

With regards to mechano-sensing, several excellent reviews has previously addressed how mechanical force imposed on a muscle cell can be envisaged to induce conformational changes on specific muscle proteins interlinking extracellular matrix (ECM) (e.g., collagen or laminin), sarcolemmal (e.g., integrins or cadherins), focal adhesion (e.g., FAK or actin filaments), costamere (e.g., dystrophin and vinculin) and/or Z-disk (e.g., titin or phospholipase D) proteins (Patel and Lieber, 1997; Burkholder, 2007; Ingber, 2010).

For the sake of simplicity, one may distinguish between tensile and/or compressive stresses that are expectedly generated during resistance exercise/muscle loading. In accordance, if a muscle cell is exposed to tensile stress in one direction, it creates a state of internal stress that causes constriction in the perpendicular plane, while compressive stress in the transverse plane will develop internal stresses that cause lengthening and therefore, once again, a tensile stress (Burkholder, 2007). In essence, tensile stress therefore likely constitute one very important trigger of deformation of mechano-sensing muscle proteins during resistance exercise, with different modes of resistance exercise, likely imposing partially different effects on specific mechano-sensing proteins. Thus, with regards to contraction mode, tensile stress inherent of eccentric contractions may e.g., be sensed by sarcolemmal/transmembranal receptor proteins (such as integrins) that tie the extracellular matrix (ECM) to focal adhesion complex proteins (Chicurel et al., 1998; Ingber, 2010; Olson and Nordheim, 2010), whereas concentric contractions can be speculated to produce a tensile stress that is predominantly sensed by proteins inherent of the sarcomere (Hornberger et al., 2006b). As for fatiguing low intensity resistance exercise with or without blood flow restriction, this has been shown to produce accumulation of metabolites and/or increased muscle water retention (Qin and Hu, 2014; Farup et al., 2015). Accordingly, with reference to the literature on endothelial cells, shear stress inherent of such fluid shifts may be sensed by some of the same ECM and focal adhesion proteins that are speculated to sense a mechanical stress on muscle cells during resistance exercise (Hirakawa et al., 2004; Petzold et al., 2009). However, evaluation on whether eccentric vs. concentric resistance exercise affect mechano-sensing molecules differentially is challenging, as it inevitable necessitate simultaneous considerations on the intensity with which the specific contraction modes are performed (i.e., the higher the relative intensity/load inherent of a given resistance exercise regime, the higher the expected stimulatory effect on mechanosensitive proteins; Eliasson et al., 2006).

Knowledge on resistance exercise-induced mechanotransduction for MPS in humans is still relatively sparse. Some indicatory information can e.g., be retrieved from comparative studies on the differential effects of differentiated exercise (MacNeil et al., 2010; Vissing and Schjerling, 2014; Petriz et al., 2016). However, the knowledge on specific mechanotransducing mechanisms presented below (see also Figure 1), is predominantly based on findings from in vitro or animal studies.

While direct regulation of MPS obviously constitutes an important rate-limiting level of myocellular muscle protein accretion, MPS also depends on the magnitude and/or rate of delivery of muscle myofibrillar mRNA to the ribosomes. In this regard, recent knowledge on specific pathways is presented below that may link mechanical stress to myofibrillar gene expression (see also Figure 2).

Most of the knowledge on potential mechanotransduction mechanisms summarized in the current review is derived from in vitro or animal models. The advantages of such models are that they offer genetic homogeneity, manipulation through genetic engineering and easy use of compounds such as wortmanin and rapamycin. On the other hand, the stimulation protocols utilized in those studies typically do not ideally mimic resistance exercise regimens as they are genuinely practiced in humans. In this regard, animal models that can render voluntary resistance exercise possible would offer an experimental advantage. Moreover, animal models that employ surgical ablation models and electrical stimulation likely impose non-exercise related stressors and/or omit true stressors inherent of voluntary human resistance exercise. In this regard, non-intervention control models would improve the ability to deduce potential separate effects of invasive procedures and/or dietary premises inherent of stimulation protocols that potentially obscure interpretation of results. Human studies offer volitional resistance exercise, but imply genetic heterogeneity and a similar need to for non-intervention control models to control for e.g., systemic effectors. Furthermore, loss of function and/or overexpression manipulation is difficult to apply to human studies. Consequently, results from human studies are often most quite descriptive unless of comprehensive comparative designs. However, comparative studies introduce difficult considerations on sample size and whether/how to match exercise protocols for volume, intensity and/or whether exercise is performed to a state of fatigue. In this regard, increased use of administration of rapamycin and wortmanin in future human resistance exercise studies might help provide more causal information.

As previously suggested, the ability to address these challenges would benefit from a multi-site consortium of scientists, to facilitate translational studies through use of non-human and human model systems (Neufer et al., 2015).

All authors listed, have made substantial, direct and intellectual contribution to the work, and approved it for publication.