... These data suggest that there is a reserve capacity built into signalling pathways. This raises the question "is this reserve capacity important and physiologically relevant?"

MY ANSWER: Signalling pathways are enzyme pathways and enzymes are essentially never active at their Vmax; rather, they are active at around their Km, so that small changes in substrate concentration result in significant changes in the rate of product formation and so metabolism is finely tuned.

Similarly, the hearth has a performance reserve of 400%, the brain's is even higher. The reserve capacity is the basis of adaptation of the cell or the organism to the changing environment. No reserve, no adaptation, no survival (no surprise).

"only 30% of maximal PKB activity is required to saturate GLUT4 translocation" - if GLUT4 translocation responded linearly to the presumed maximum of PKB activation that would imply pulling more glucose into the cell. What would the cell do with that 'extra' glucose? Maybe the maximal GLUT4 translocation seen is a safety cut off to prevent excessive glucose getting into the cell, overwhelming metabolic pathways, escaping and causing glycosylation-type damage. The maximal set switch might be different for different cell-types - or (as pointed out by @Tommy Lundberg) between different people/mice/whatever.

Alternatively partitioning of activity for PKB and S6K1 could account for some of these observations. That might be the suggestion from the feeding v RT work. Simply these two (quite different) stimuli drive the same process (MPS) but by somewhat different pathways. So S6K1 activated by RT gets partitioned into a subtly different process(es) than S6K1 activated by feeding alone.

"do we need to develop new theories and methods to assess the molecular control of muslce metabolism and growth? "

Yes - then we'll all have jobs ;-)

... These data suggest that there is a reserve capacity built into signalling pathways. This raises the question "is this reserve capacity important and physiologically relevant?"

MY ANSWER: Signalling pathways are enzyme pathways and enzymes are essentially never active at their Vmax; rather, they are active at around their Km, so that small changes in substrate concentration result in significant changes in the rate of product formation and so metabolism is finely tuned.

Similarly, the hearth has a performance reserve of 400%, the brain's is even higher. The reserve capacity is the basis of adaptation of the cell or the organism to the changing environment. No reserve, no adaptation, no survival (no surprise).

Some really great points here. Thanks to everyone who contributed. I have a few points to add to the discussion myself.

There are several reasons as to why I think molecular signals may not correlate to end measures:

1) @Iain Gallagher touched on the idea of localisation. PKB is well known to translocate to the nucleus upon activation and this is something that has been touched on in the context of exercise in a number of studies and most of the examples I know of relate to enduracne exercise. For instance in response endurance exericse AMPKalpha2 translocates to the nucleus (McGee et al, 2003 http://diabetes.diabetesjournals.org/content/52/4/926.long), additionally PGC1alpha translocates to the mitochondria (Smith et al, 2013 http://www.ncbi.nlm.nih.gov/pubmed/23297307) and to the nucleus in response to exercise (Philp et al, 2011 http://www.jbc.org/content/286/35/30561.long). With resistance exercise phosphorylated S6K1 appears in the nucleus (Koopman et al, 2006 http://ajpendo.physiology.org/content/290/6/E1245.long). So part of the discordance between S6K1 and protein synthesis maybe because of S6K1's apperance in the nucleus. It may still be active but due to being in the nucleus may no longer be acutely regulating protein synthesis.

2) The kinetics of end measures are completely different from the kinetics of molecular pathway activation. PKB activation can occur on the order of minutes in response to insulin and S6K1 activity is activated immediately post resistance exercise in rodents. However, the activation of a process like protein synthesis is dependant upon many more protein interactions than say the activation of PKB or S6K1 and so it is conceivable that the two processes would have different kinetics. Additionally in protein synthesis is almost always measured with quantitative processes with highly sensitive techniques requireing mass spctrometry. The signalling kinetics are generally measured using semi-quantitative and often problematic technques such as western blotting which don't afford the same kind of accuracy or reproduciblity as the protein synthesis measures and therefore it is no suprise that they don't always agree.

3) Like most systems in physiology there are effective negative feedback loops in place to control homeostasis. We still know very little about the negative feedback loops in molecular physiology, the mechanisms in some cases are known (S6K1 inhibiting IRS1 function for instance) but the time courses leading to inactivation are very poorly charcterised in vivo in response to physiological stimuli.The time course of S6K1 activation in response to resistance exericse is thought to be tri-phasic (Mackenzie et al, https://www.researchgate.net/publication/23479454_mVps34_is_activated_following_high-resistance_contractions?ev=prf_pub) with potentially different mechanismis of activation at each phase but the induction of negative feedback loops in this context is poorly understood.

To summarise Molecualr pathways often control a number of other processes other than a single end measure like protein synthesis, the molecules may be activated and partitioned away from the molecules which regulate the process of interest and the existance of negative feedback loops and the number of layers of control makes it difficult to definitively use molecular signals as correlates of end measures. However in the case of anabolism S6K1 activity is certainly a good marker of an anabolic stimulus and AMPK activity is a good marker of energy stress but using either as a marker of protein synthesis or glucose uptake may not be a valid approach. Finally our current tools for assessing molecualr signalling are mismatched with those for protein synthesis, glucose uptake i.e. one is semi-quantitatiave with problems around reproducibility whist the other is fully quantitatvie and highly reproducible. We therefore need to develop and apply to physiological scenarios old (like in vitro kinase assays in the case of kinases) and new (quantitative proteomics for post-translational modifications) techniques. These measures are fully quantitative and more reproducible.

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Article mVps34 is activated following high-resistance contractions

To touch on @Sabina Passamonti's point about enzymes working in the range of their Km as opposed to Vmax. This is a great point and I also completely agree with your other point about the reserve capacity being required for adaptability. However you mention small changes in substrate concnetration as being a conrol mechanism. This is indeed an important control mechanism in terms of metabolism as an example to our student readers for instance GLUT2 transporters in the beta cells are constituteivley active and the glucose flux into beta cells is controlled by and increase in circulating glucose levels increasing towards the Km of the transporter therefore it is changes in the substrate concentration that controls the transport not necessarily a change in the transporter. With molecular signalling however the networks are much more static in that the balance between substrates and enzyme concentrations in most cases is much more stable and it seems that in a lot of cases that it is a range of post-translational modifications which regualte enzyme activity as opposed to changes in substrate concentration per se. The problem in this field is that the stoichimometry between substrate and enzyme is so poorly understood in vivo. Western blotting tells us nothing about the absolute concentration of a substrate and the phosphorylation of a kinase tells us noting about the stoichiometry of how much of the kinase is active/inactive or how active it actually has become or how that change in activity translates to down stream activation. This is why we need to utilise quantitative measures like quantitative enzyme assays and quantitatvie proteomics to try to answer these questions to better understand how molecular pathways are coupled and how they ultimately control homeostasis and adaptive responses to disturbances like exercise.