The missing Akt in the mechanical regulation of skeletal muscle mTORC1 signalling and growth.

The mammalian target of rapamycin complex 1 (mTORC1) signalling pathway is a primary regulator of skeletal muscle growth. Ten years ago it was reported that the overexpression of Akt in mice resulted in an astonishing amount of skeletal muscle hypertrophy in association with an activation of the mTORC1 signalling pathway (Bodine et al. 2001). However, the identification of the upstream pathways regulating mTORC1 has remained somewhat elusive. Among those of us interested in how mechanical overload induces muscle hypertrophy (e.g. synergistic ablation or muscle contraction performed against a load as is done with resistance exercise training) it seemed logical that insulin-like growth factor 1 (IGF-1) production via an autocrine, paracrine or endocrine mechanism most likely activated mTORC1 in vivo. In fact, since 2001 the majority of studies that have examined muscle mTORC1 signalling in response to loading and/or exercise have typically referred to this as the ‘Akt/mTOR’ signalling pathway. This was the accepted dogma for several years until The Journal of Physiology published a paper by Spangenburg et al. showing that IGF-1 signalling was blocked in mice over-expressing a dominant-negative (non-functional) IGF-1 receptor but that in response to mechanical overload mTORC1 signalling and muscle growth were not altered (Spangenburg et al. 2008). This was the first real challenge to the notion that IGF-1 and activation of PI3K/Akt signalling is a requirement for muscle growth in response to mechanical loading. Subsequently, The Journal also published an ex vivo study showing that mTORC1 activation following mechanical strain was also independent of the Akt signalling pathway (O'Neil et al. 2009). In this issue of The Journal of Physiology Miyazaki and colleagues demonstrate in vivo that early mTORC1 activation and muscle growth following mechanical overload in C57BL/6J mice is also independent of IGF-1/PI3K/Akt signalling (Miyazaki et al. 2011). Using the synergistic ablation model, the authors found that over the course of the next 10 days muscle hypertrophy, total RNA content, and protein turnover (synthesis and breakdown rates) increased. Phosphorylation of S6K1, a key downstream effector of mTORC1, increased within the first day following overload whereas Akt phosphorylation and activity did not increase for another 2–3 days. This finding indicated that the early activation of mTORC1 from mechanical overload was not associated with Akt activity. They confirmed this by using wortmannin (a direct inhibitor of PI3K and insulin-dependent signalling to Akt) and verified that inhibition of Akt signalling did not prevent the early activation of mTORC1. On the other hand, rapamycin administration to the mice did block the overload-induced activation of mTORC1 in vivo. With this newest addition to the muscle biology literature the evidence is clear that mechanical stimulation of mTORC1 and muscle growth can occur independently of IGF-1 and Akt signalling. It has been suggested that MAPK signalling through MEK/ERK is more important for cell cycle regulation than for regulating protein synthesis. However, a second and very novel finding from the Miyazaki study was the demonstration that MEK/ERK signalling resulted in the phosphorylation and inhibition of tuberous sclerosis 2 (TSC2), a negative upstream regulator of mTORC1, which suggests that MEK/ERK signalling may contribute to mTORC1 activation following mechanical overload. This is the first evidence in skeletal muscle indicating that MEK/ERK signalling can regulate mTORC1 activity by phosphorylating TSC2 at the serine 664 site. Interestingly, studies in humans also show an association between ERK1/2 signalling and mTORC1 which implies that activation of both the MAPK and the mTORC1 pathway are essential for maximal stimulation of muscle protein synthesis following resistance exercise (Fry et al. 2011). The two primary findings from Miyazaki and colleagues are that: (1) in vivo skeletal muscle mTORC1 activation and muscle growth during early mechanical overload occurs independently of IGF-1/PI3K/Akt signalling; (2) upstream regulation of mTORC1 during early mechanical overload may also be controlled by the activation of the MEK/ERK signalling pathway. These are original findings that significantly improve our understanding of the cellular mechanisms underlying muscle hypertrophy and highlight the central role of the mTORC1 pathway. In addition, the notion that MAPK activation is also essential for fully stimulating muscle protein synthesis is intriguing and will clearly be a focus of future research. The accumulation of evidence from transgenic mice (Spangenburg et al. 2008; Witkowski et al. 2010), ex vivo studies (O'Neil et al. 2009), the current in vivo study (Miyazaki et al. 2011), and resistance exercise in humans (Drummond et al. 2009) overwhelmingly suggests that mTORC1 activation (independent of IGF-1 or Akt signalling) is required for load-induced muscle growth and protein synthesis. I think the time has now come for us in the muscle biology and exercise physiology field to eliminate the usage of the common phrase or term ‘Akt/mTOR’ in order to better highlight the Akt-independent activation of the mTORC1 signalling pathway when referring to load-induced hypertrophy.