Intermittent Fasting And Fast Twitch Muscle Fiber Atrophy – Part II

Intermittent Fasting And Fast Twitch Muscle Fiber Atrophy – Part II

Why would any individual concerned with fitness, performance, appearance, and health voluntarily choose to not eat?  Obviously because by not eating they expect to be able to positively impact one or several of those dimensions ( fitness, appearance, health etc. ) without doing overt harm to the others.  Recently, however, several studies have been published linking short term starvation with increased autophagy in fast twitch muscle fibers.  If this is true, then it is of significant concern because fast twitch muscle fibers are the ones that exhibit the highest capacity for hypertrophy, as well as the fibers recruited when maximal force output is called for.  These studies are especially worrisome because they suggest that metabolically speaking, fast twitch muscle fibers seem to be considered highly expendable, even more so than their slow twitch brethren.  Let’s take a look at one such study, brought to my attention by reader Rachid, that makes precisely these claims to see what we can find out, because if these findings are accurate, then we would have to seriously reevaluate our rationale for fasting.


Ogata et al. Fasting-related autophagic response in slow- and fast-twitch skeletal muscle.
This study investigated regulation of autophagy in slow-twitch soleus and fast-twitch plantaris muscles in fasting-related atrophy.  Male Fischer-344 rats were subjected to fasting for 1, 2, or 3 days. Greater weight loss was observed in plantaris muscle than in soleus muscle in response to fasting.  . . .  These findings suggest that preferential atrophy of fast-twitch muscle is associated with induction of autophagy during fasting and that differences in autophagy regulation are attributable to differential signal regulation in soleus and plantaris muscle.


[dropcap style=”color: #336666;”]A[/dropcap]fter reading this abstract, I would not fault you if you came away with the impression that these researchers determined that rat metabolism sacrifices fast twitch muscle fiber in lieu of slow twitch fiber under fasting conditions.  After all, “preferential atrophy of fast-twitch muscle” is pretty difficult to misinterpret, and the word “atrophy” itself is ominous.  My dictionary tells me that atrophy means to waste away, typically due to degeneration of cells.  It sounds, on the face of it, like bad news all around.


[dropcap style=”color: #336666;”]B[/dropcap] y now, though, if you’ve read some of my previous posts, you should have come away with the realization that the devil is always in the details, and far more often than should be the case, paper abstracts are downright misleading.  So, let’s look at some of those details and see whether we can exorcise some devils.    Going straight to the meat of the matter,  the results section of the paper, here is what we find:


Ogata et al. Fasting-related autophagic response in slow- and fast-twitch skeletal muscle.
Body weight declined in a fasting duration-dependent manner, and F-3d rats were 31% lighter than control rats.  Compared with control muscle, absolute soleus muscle weight was not changed in the F-1d or F-2d groups, but it decreased significantly by 10% in the F-3d group. In contrast, notable plantaris muscle loss was observed with fasting. Weight loss was 11% in F-1d, 19% in F-2d, and 23% in F-3d rats relative to control rats. Total protein content was not changed by fasting in either muscle type.


[dropcap style=”color: #336666;”]B[/dropcap]y my count, there are two bombshells in that paragraph.  See if you can spot them.  I’ll wait … on the internet, we have infinite time.  Click on the bombshells below to reveal them when you are ready.


Bombshell One

F-3d rats were 31% lighter than control rats.  


[dropcap style=”color: #336666;”]O[/dropcap]nce you collect your jaw from the floor, ponder what in the world must have been going on in these rats to make them a full 1/3 lighter than their unfasted companions after a mere three days of food deprivation.  But, before you go down that speculation rabbit hole,  you might want to decide whether that really matters to you because, frankly, you do not need to know a single thing about metabolism in order to understand that this simply is not the way that things work in human beings.


[dropcap style=”color: #336666;”]I[/dropcap] will freely admit that the first time I read that number, I had to go to the results table because I fully expected that it was a typographical error that had slipped by the editors.  But, no, the computation is correct:



[dropcap style=”color: #336666;”]N[/dropcap]ote that the F-3d 31% weight loss computation is the result of taking the 98g post weight of these rats and comparing it to the control rats post weight of 142g.  If you actually compare the pre and post weights for all of the groups, the control group gained 4% body mass (!!), the 1 day fasted group lost 14%, the 2 day fasted group lost 24%, and lastly, the 3 day fasted animals lost 28% of their mass.


[dropcap style=”color: #336666;”]L[/dropcap]et’s suspend disbelief and assume that the above weight loss figures are accurate and representative of what we would observe in humans under equivalent conditions.  This would have several and immediate effects.  The principal effect would be the complete and utter collapse of the diet book, infomercial, supplement, and magazine industries.  You would never need to see another article entitled “How the celebrity flavour of the week lost 7 lbs. in 7 days” because the simple answer would always be … fast for one day and you will lose 14% of your body mass.   No need to suffer through eating only grapefruit for an entire week when you can simply get it over with in a mere 24 hours.  This alone makes me wish that things did work this way!  But, the fact of the matter remains that we are awash in all of these plagues … diet books, supplement pitches, and strident  magazine articles gushing about the latest diet fad.  We can surmise from this that fasting probably does not work quite like this for people.


[dropcap style=”color: #336666;”]D[/dropcap]o human beings ever experience weight loss that is this rapid?  Yes, we do, but only as a result of severe pathologies that are fatal unless immediately treated.  Think cholera, AIDS, and advanced cancer.  If you have ever fasted for 24 hours and wound up losing over 10% of your body mass, please contact me.  I would love to hear from you.  Oh, and by the way, just to appease the lawyers … I am in no way advocating cholera as a weight loss technique.


Bombshell Two

Total protein content was not changed by fasting in either muscle type.


[dropcap style=”color: #336666;”]W[/dropcap]ait, what?  Aren’t these the same researchers that lead off the discussion of their results with the following:


Ogata et al. Fasting-related autophagic response in slow- and fast-twitch skeletal muscle.
Skeletal muscle contains a large amount of protein that can serve as an energy source, and atrophy is induced under fasting conditions.  Interestingly, the degree of fasting-related atrophy is greater in fast-twitch muscle than in slow-twitch muscle. However, the reason for muscle type specificity in protein degradation with fasting is unknown.


[dropcap style=”color: #336666;”]A[/dropcap]ll my life I have been told that you cannot have your cake and eat it too.  My understanding of  this idiom was that certain states of reality are mutually exclusive, and one must choose one or the other, but not both.  You either possess your cake, “have it”, or you do not, because you have eaten it.  It turns out that this was all a pack of lies because Ogata et al seem to have discovered a new phenomenon whereby at the cellular level, you can both have your protein and also use it as an energy source.  I’m sure that it is only a matter of time before this principle is demonstrated at a macroscopic level, and when that happens, I’m going to give my parents an earful!  I also plan to retroactively demand to have all the cake that I have eaten since I was three.  Revenge will be cloyingly sweet!


[dropcap style=”color: #336666;”]O[/dropcap]n some level, though, you need to take a step back and applaud the judo like mastery of that paragraph.  Everything it says is absolutely true … skeletal muscle does contain large amounts of protein, protein can be used as an energy source, and they did observe atrophy in their experiment.  The implication is left up to the brain of the reader … that the atrophy was caused by the use of skeletal muscle protein as an energy source leading to “muscle type specificity in protein degradation”.


[dropcap style=”color: #336666;”]T[/dropcap]his implication is completely false and a direct contradiction of their actual results, but they carefully word the paper so as to never make this provably false assertion.  Once the seed  of the implication has been planted in the mind of the reader, the issue of no change in the muscle protein content after fasting is never touched upon again.  Instead, the remainder of the discussion centers solely on the increased rates of authophagy observed in fast twitch fibers relative to slow twitch and the arcane details of autophagy regulation.


[dropcap style=”color: #336666;”]W[/dropcap]hen all is said and done, it is left entirely up to us to explain the increased autophagy activity that was observed coupled with the pronounced weight loss.  We certainly cannot rely on Ogata et al at all, because they seemingly have a different agenda than furthering our understanding.  If you will indulge me, I would like to take stab at it.


[dropcap style=”color: #336666;”]W[/dropcap]hy would fast twitch muscle fibers exhibit different autophagy rates under fasting conditions than slow twitch fibers?  Clearly because the different muscle fiber types have different energy requirements and different metabolic machinery to address their specific needs.  It is well known that fast twitch muscle fibers are predominantly anaerobic and glycolitic, whereas slow twitch are predominantly aerobic.  This difference in respiratory pathways speaks directly to the energy consumption patterns of the muscle under consideration … anaerobic respiration produces modest amounts of energy, but very very quickly, whereas aerobic respiration produces much more energy but at a much slower pace.


[dropcap style=”color: #336666;”]P[/dropcap]ractically speaking, the aerobic vs. anaerobic respiratory pathway dichotomy is going to manifest as differences in oxygen carrier proteins ( myoglobin ), and the mitochondria that use this oxygen in aerobic respiration ( the TCA / Krebs cycle ).  Slow twitch oxidative fibers will have much more of both, relative to fast twitch fibers.  Moreover, when it comes to rodents, the dominant fast twitch fiber type is type IIb, which is the most anaerobic, “white” muscle that exists.  As a consequence, type IIb muscle fibers are the least dense in mitochondria and myoglobin.


[dropcap style=”color: #336666;”]B[/dropcap]ut if these fast twitch muscle cells do not contain much in the way of myoglobin and mitochondria, what do they contain?  It’s a safe bet that to a large extent, type IIb fibers fill the additional space in the cell with their preferred energy substrate, glycogen.  Keep this in mind, it will be critical shortly.


[dropcap style=”color: #336666;”]S[/dropcap]o, on an otherwise unremarkable day, our fast and slow twitch muscle cells determine via various signaling pathways that their external energy sources are not meeting their energy demands.  Within short order, the cells begin to reconfigure themselves to accommodate their new reality.  Cellular machinery that was dedicated to nutrient absorption and storage begins to be dismantled in order to be repurposed as machinery for the mobilization and utilization of previously stored energy.  The rate at which this will happen will depend on the energy requirements of the particular cell, with those cells that have higher energy needs exhibiting a higher rate of this reconfiguration.  I’ll let you come to your own conclusion as to which of the fiber types has the higher energy requirements.


[dropcap style=”color: #336666;”]A[/dropcap]s a concrete example of this process, consider that most muscle cells depend on glycogen synthase to take up freely available glucose during times of surplus and join them together to form long strands of the glycogen storage polymer.  In circumstances where there is a lack of free glucose as a substrate, it makes little sense to keep large quantities of glycogen synthase around, especially if the lack of free glucose occurs in conjunction with a lack of free amino acids.  Under such circumstances, it is perfectly sensible to break down glycogen synthase via autophagy into its constituent amino acids.  These amino acids are then recycled and used to synthesize additional glycogen phosphorylase, the enzyme that cleaves a glucose molecule from the end of a glycogen polymer to make it available for glycolysis and cellular energy generation.  Without the critical first step of autophagy, none of this is possible and the cell would quickly die in such a nutrient restricted environment.


[dropcap style=”color: #336666;”]F[/dropcap]rom the above, it should be readily apparent that high rates of autophagy may be entirely indicative of a massive cellular reconfiguration, without involving any use of the proceeds of autophagy ( free amino acids ) as an energy substrate.  It is this realization that explains why the massive weight loss observed occurred with no loss of cellular protein, even in the face of high rates of autophagy.  The cells were apparently relying on other sources of energy, either glycogen or fats.  The high rate of autophagy was the result of cellular reorganization to make these sources of energy more readily available.


[dropcap style=”color: #336666;”]S[/dropcap]let’s come back to glycogen as an energy substrate.  Why all the fuss?  Because unlike fat, glycogen must be stored associated with fluid, which means that every gram of stored glycogen comes with an associated 2 to 3 additional grams of water.  It is precisely for this reason that the body stores the vast majority of its excess energy as fat.  However, as glycogen is consumed, the cell no longer needs to retain the additional water so it will excrete it, and in so doing it will get lighter … much lighter, as it turns out.


[dropcap style=”color: #336666;”]A[/dropcap]rmed with this information, we can make a prediction … those cells with a higher proportion of their energy derived from glycogen ( the predominantly anaerobically respirating ones ) will experience the highest level of weight loss / atrophy during times of starvation as they excrete significant amounts of excess water.  We are extremely fortunate that we have the work of Ogata and colleagues to confirm this prediction, at least with respect to rat plantaris and soleus muscle cells.


[dropcap style=”color: #336666;”]W[/dropcap]e can actually go further with the above analytical framework.  Since three days of fasting had no effect on the protein content of muscle cells, reversing the so-called atrophy is merely a question of restoring glycogen levels, thereby essentially rehydrating the cells!  Sounds suspiciously close to a carb re-feed …


[dropcap style=”color: #336666;”]I[/dropcap]n the end, I actually really like this paper by Ogata et al., but for reasons quite apart from what the original authors most likely intended.  This paper unequivocally demonstrates that autophagy is highly conservative when it comes to protein.  There was no net protein loss in either fast or slow twitch muscles over a period of three days of fasting, despite the fact that significant loss of mass occurred, and despite massive increases in marker proteins (LC3-II) for increased autophagy.  Going forward, this information will be invaluable in assessing other similar scholarly articles pertaining to autophagy.  Those studies that do not attempt to measure and quantify the nature of the mass that was lost will be immediately suspect.



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  • jay

    Just coming in to read some of your posts, and I will be back! Enjoy the articles thus far.

  • Sam

    This is a great article. Thanks!

  • VachCon

    Well done.

  • Duncan Jones

    Well done. I love your blog–it’s sort of McDonaldan or Berkhanian in its evidence-based approach, though better written, more scholarly and with fewer arguably gratuitous insults of the audience. Keep it up!

    • Pablo Klopper

      Thank you … although, arguably? 😉