Intermittent Thoughts On Intermittent Fasting - Exercise (3/3): How Training Solves the AMPK/mTOR Antagonism.

Image 1: Just like Two-Face, a character from the Batman comic books, AMPK turns out to have two faces,... ah I mean isoforms the differential expression of which explain why exercise, contrary to starving yourself, maintains or even builds muscle mass while reducing your love handles (img batman.wikia.com).

In the last installment of the Intermittent Thoughts on Intermittent Fasting series, we have revisited the idea of different training modalities, i.e. endurance and strength training, for the promotion of AMPK-related reductions in body fat and mTOR-dependent increases in muscle mass. We have also busted the long-standing myth of the "anabolic window of opportunity", which, upon closer examination, turned out to have the size of a barn door (>24h) that is unlocked with the key of exercise and nutrition sciences. Related findings showed that even in the absence of additional nutritional stimuli a single intense strength training session led to a profound and (>24h sustained) increase in mTOR phosphorylation in 24 untrained, young, healthy, male subjects (Vissing. 2011). In conjunction with the results of Burd et al. (Burd. 2011), who found that the beneficial effects of strength training on the subsequent response to protein feeding depend on exercise intensity and volume and last for >24h, these results further underline the synergistic effects the fasting, training, feeding cycle of classical intermittent fasting regimens had and still has on the health and physiqueof its practitioners.

Unfortunately, both the concept of "fat loss", as well as that of "muscle gain" are still largely associated with notion of what is commonly referred to as "energy balance". If you read my recent blogpost on the  "High(er) Reps for Fat Loss"-Myth, you will be aware of the fallacy behind the idea of "going to the gym to burn fat". And while more and more trainees (also thanks to the educational work of BodyRX Radio ;-) are getting the idea that you have already lost the fight against your love handles, when you go to the gym solely "to burn calories", the notion that you go to the gym to either "pump up" or "totally exhaust", "damage" and "break down" muscle tissue is similarly illusive. Contrary to what the more is more mentality of the western society may suggest, simple linear causality is nothing you will ever see as the underlying "reason" for the success of a given exercise regimen.

Gain muscle or lose fat? AMPK vs. mTOR and the unique effect of exercise
 

Image 2: "Immunocytochemistry/ Immunofluorescence - AMPK alpha 1 + AMPK alpha 2 (phospho S485 + S491) antibody (ab39400)" ... and if you do not understand this lingo, what you see here is nothing else but one of the unspecific markers for both isoforms of AMPK that is used in most of the studies (img abcam)

Regardless of whether you intend to lose fat, to build muscle or strength, the previous installments should have made it pretty clear that you will always be dealing with two-way processes, or I should say cycles. Now, interestingly enough, exercise, contrary to dieting or overeating, appears to have the unique quality of driving both at the same time - fat loss and protein synthesis, AMPK and mTOR. This works, and this is going to be the main message of this concise piece of the Intermittent Thoughts series, because the exercise induced muscular(!) AMPK-response differs from the one your brain and many other organs will exhibit, when you starve yourself during a diet. Actually we have been knowing for quite some time that the predominant isoform of AMPK that is expressed during exercise is AMPK-alpha2. Back in 2000, already, Wojtaszewski et al. found that "high" (in this case >70% of the individual VO2max) intensity exercise for 60min selectively increased AMPK-alpha2 activity almost threefold (Wojtaszewski 2011). Similar to the results of previously discussed studies, the increased AMPK levels returned to baseline within 3h after exercise-cessation.

Unfortunately, only few of the subsequent studies, which investigated the effects of different exercise regimen, used iso-form specific tests to determine which of the two AMPK isoforms was expressed consequent to the respective training protocols. According to the ground-laying work of Stapleton et al. (Stapleton. 1996) and supported by a study by Stephens et al., it is yet likely that the relative exercise-induced expression of AMPK-a1 in human muscle tissue is negligable.

Figure 2: AMPK-a2 expression (arbitrary units measured in the absence of AMP) and fat oxidation in g/min in 7 healthy individuals during 30 minutes cycling at 62.8% of VO2Max (data adapted from Stephens. 2002).

Moreover, the results of Stephens et al. underline that the exercise-induced increase in AMPK-alpha2 does not only increases fatty acid oxidation, but that both exhibit an excellent correlation with exercise induced glucose depletion (Stephens. 2002).

Figure 2: Glycogen content (mmol/kg) and phosphorylation of AMPK (arbitrary units) in human vastus lateralis muscle before (0 min) and at the cessation of 120 min of one-legged knee-extensor exercise, while consuming either a glucose containing drink or a placebo drink.  (data adapted from Thorbjorn. 2006)

It is thus not surprising that Thorbjorn et al. were able to show that the ingestion of 0.7 g of glucose/kg of body weight/hour did not only blunt the exercise induced AMPK-a2 response but also reduces its beneficial effects on fat oxidation by -47% (cf. figure 2)!

The results of older studies sometimes begin to shine in the light of novel findings 

Now, you probably knew all that before - after all we have been talking about this effect, its beneficial effects on fatty acid oxidation and glucose uptake, as well as its supposedly negative impact on protein synthesis in previous installments of this series. And in fact, these results begin to shine only, in the light of the results of a a recently published study by Mounier et al., who were able to show that only the increased expression of the alpha1 isoform of AMPK, but not AMPK-alpha2 does impair mTOR signalling. Against that background, the systemic antagonism of AMPK-alpha1 (expressed in liver, brain, and other organs) and mTORc1 mediated protein synthesis stands in stark contrast to the metabolically highly beneficial synergism of concomittant exercise-induced AMPK-alpha2 and mTORc1 expression.

To make a long story short: Exercise is unique in its ability to help you shed fat and build muscle "at the same time", because it activates a specific isoform of the "starvation sensor" AMPK, which does not block the concomitant increase in protein synthesis subsequent to the (likewise) exercise-induced increase in mTOR phosphorylation. On that note, my schedule forces me to end this abbreviated version of the Intermittent Thoughts, yet not without the promise that I am finally going to tie all the knots together in the next installments of this series.