No role for early IGF‐1 signalling in stimulating acute ‘muscle building’ responses

The molecular controls governing load-induced changes in rates of muscle protein synthesis muscle protein synthesis leading to fibre hypertrophy involve a multitude of signals. It appears that many of these signals converge at the mammalian target of rapamycin complex 1 (mTORC1), a kinase directly downstream of the protein kinase B (Akt). Acute activation of mTORC1 signalling has been reported to be essential for mediating increased rates of muscle protein synthesis after resistance exercise (Drummond et al. 2009); however, the upstream intramuscular signalling events that serve to phosphorylate and activate mTORC1 after an anabolic stimulus to muscle, such as after resistance exercise in humans or synergist ablation-induced overload in rodents, remain enigmatic. A contentious topic in this debate is one related to the necessity of insulin-like growth factor-1 (IGF-1) in initiating PI3K/Akt/mTORC1 signalling events leading to hypertrophy (Spangenburg et al. 2008). Also, it is clear that arguments for exercise-induced elevations in circulating ‘anabolic’ hormones, such as growth hormone, IGF-1, or testosterone, in facilitating increases in phosphorylation of Akt–mTORC1 signalling and subsequent stimulation of myofibrillar protein synthesis are misguided (West et al. 2009). Thus, a need exists to decipher whether upstream signals are necessary or synergistic to mTORC1 signalling. So the question still remains, if increased IGF-1/PI3K/Akt pathway activation is not compulsory for the phosphorylation of mTORC1 after a muscle growth promoting stimulus, then how is mTORC1 activation accomplished? A recent article in The Journal of Physiology by Miyazaki et al.(2011) provides new insight into the link between growth-promoting stimuli and the regulation of mTORC1 activity by examining multiple pathways involved in this response. Specifically, the researchers employed a synergist ablation mouse model to induce skeletal muscle hypertrophy and combined measurements of dynamic variables, such as muscle protein synthesis and breakdown, with ‘static snapshot’ surrogates to gain better mechanistic insight in the regulation of muscle hypertrophy during a growth-promoting stimulus. As expected, the researchers observed a near-linear increase in plantaris muscle weight over the 10 days of chronic overload; this response was consistent with the positive net muscle protein balance reported at 7 days. Moreover, mTORC1 was phosphorylated at 1 day of overload, a response that was not concomitant with increased Akt phosphorylation (Ser473 or Thr308), which did not become significantly up-regulated until 2 or 3 days of functional overload, respectively. It was also observed that PI3K inhibition, via wortmannin, was successful in eliminating Akt activation, but had no affect on p70S6K phosphorylation (Ser389 or Thr421/424) at 1 day. However, treatment with rapamycin completely eliminated p70S6K phosphorylation on Ser389, with no blockade of Akt phosphorylation. Collectively, these data support the thesis that early mTOR signalling can progress independent of the PI3K/Akt signalling pathway activation. Although, there are dramatic differences between a synergist ablation stimulus in rodents as compared to a resistance exercise stimulus in humans, these data (Miyazaki et al. 2011) also ‘downplay’ the importance of upstream elements, such as IGF-1, as being essential for the acute stimulation of muscle protein synthesis after an anabolic stimulus, such as resistance exercise (West et al. 2009). However, it cannot be completely dismissed that Akt signalling events may become fundamental in facilitating the growth response in the days after an anabolic stimulus. The work by Miyazaki et al.(2011) highlights this notion and suggests that separate, but redundant, mechanisms may exist that facilitate the acute and longer-term growth responses. A novel aspect of the study, albeit not a direct confirmation, was the observation that increased MAPK signalling protein phosphorylation coincided with the localization of phosphorylated TSC2, a suppressor of mTORC1 activity, at the sarcolemma at 1 day of overload. These data point to a thesis that MAPK signalling may be responsible for the early activation of mTORC1 immediately after a hypertrophic stimulus, as opposed to a PI3K/Akt signalling pathway mechanism. As the authors point out, however, this hypothesis will require a more direct approach (e.g. genetic manipulation) to make a firm conclusion. It should be mentioned that the finding reported by Miyazaki et al.(2011) demonstrating that pharmaceutical blockade of initial PI3K growth factor-dependent signalling events (1 day of overload) did not influence longer-term hypertrophic signalling responses is not entirely surprising considering a chronic overload model was employed. However, what remains to be determined is if elimination of initial mTORC1 signalling events after other anabolic stimuli, such as acute resistance exercise, influences longer term (i.e. the following day after exercise) intramuscular signalling responses, which can become apparent during 24 h exercise recovery (Burd et al. 2010). In summary, the investigators are to be congratulated for highlighting the multifaceted regulation of mTORC1 signalling by demonstrating that MAPK signalling events may be mediating the initial activation of mTORC1 after a growth stimulus, and this effect proceeds independent of PI3K/Akt signalling. These findings are consistent with our laboratories’ current thesis that the acute stimulation of muscle protein synthesis is not dependent on circulating growth factors, such as IGF-1, immediately after resistance exercise (West et al. 2009). Indeed, all too often a narrow approach is employed with the desire to uncover a single ‘master regulatory switch’ to explain dynamic processes such as muscle protein synthesis. However, in reality the acute regulation of muscle protein synthesis involves a multiplicity of signals that overlap to orchestrate long-term muscle hypertrophy. Thus, examination of multiple signalling pathways (e.g. growth hormone sensitive PI3K/Akt and MAPK pathways), coupled with comprehensive kinetic measurements of anabolism, and more detailed information concerning the time course of intramuscular signalling responses, which include the immediate acute (hours) and long-term (days) responses, will be critical in understanding the regulation of muscle mass after loading. It is clear the rodent model is of tremendous value to illuminate potential regulatory signalling mechanisms that may aide in the development of therapeutic interventions (e.g. resistance exercise paradigms) that target these pathways and ultimately be applied to humans in search of non-pharmacological interventions to maintain muscle mass (i.e. sarcopaenia or cachexia populations).