Friday, December 7, 2012

Science Round-Up Seconds: PGC-1 Alpha 4 Unlocks Muscle Growth, Alpha Lipoic Acid & Dietary N-6 Overload, Aspirin & Other NSAIDs Your Liver & Overall Mortality

Myotubes under the microscope - vehicle (top, normal size), clenbuterol (+100% protein content, middle), clenbuterol + PGC1a4 inhibition (+50% protein content, bottom)
Actually I would hope that you have by now already listened to yesterday's installment of the SuppVersity Science Round-Up. If you did, you are one of a group of highly privileged trainees who already knows why not all PGC1-alpha is created equal and how the alpha-4 isoform does appear to be the missing link between myostatin, on the one hand, and IGF-1 on the other. If you have already listened to the show, you may also have noticed that I was pretty excited about the publication of the Ruas paper (Ruas. 2012). Firstly this study has almost everything you could expect from cutting edge science: A in-vitro tudy to elucidate the basic mechanisms, an in-vivo rodent study involving both wild-type and genetically modified mice and - much to my own surprise - an in-vivo exercise part. And secondly, the results provides the missing link I personally have been looking for, when I wrote the Intermittent Thoughts on Building Muscle Series (click here for the summary and overview of the individual parts) - the link between IGF-1 and myostatin and the reason working out will always make you stronger and bigger and not bigger and weaker, as it is the case in the poor myostatin-knockout mice. Ah... I almost forgot: Third- and lastly, the fact that the researchers induced their hypertrophy effects in a specific part of their study by administering clenbuterol, which then did what I have likewise written about before (see "The Clenbuterol Myostatin Connection"), which is decreasing the expression of myostatin and thus producing skeletal muscle hypertrophy, yet as we now know not directly, but rather in consequence to its PGC-1 a4 promoting effects (+400%!) and the respective downstream effects on myostatin, which were non-existent, when the scentsts blocked PGC-1 a4 expresson (see images on the right)... 

I guess, you need to be somewhat geeky to find that exciting, but anyway. If you don't I'd still recommend you take a listen to the show - it's well worth it, even for totally normal exercise enthusiasts ;-)

And now for the actual seconds

Since the Ruas study appeared on my "radar" quasi in the last minute. We did not get to talk about several of the things I have announced and just to make sure you are not going to be disappointed, once you have gone through the following findings, I will address the acidity / alkalinity issue in a separate post in the future. It requires some more detailed elaborations - but the wait is going to be worth it ;-)

ALA rescues the liver from toxic N-6 overload

Actually this item would have fitted in pretty neatly with the things I explained about the different isoforms of PGC-1 alpha and how they appear to be regulated by diet / energy energy intake and expenditure via AMPK, on the one hand, and MAPKs, i.e. 'switches' that are triggered by stress, as the wear and tear of exercise, for example would be one. Now, we have already talked about the latter aspect, so that I guess I can get right to the not so novel, but still intriguing insights a  group of scientists from the Cerrahpa┼ča Medical Faculty Medical Biology Department at the Istanbul University  bring to the table as far as the former pathway is concerned (Kaya-Dagistanli. 2012).


In their 8-week experiment, Kaya-Dagistanli and her colleagues confirmed two things, of which I don't even know what would be the more important result:
Figure 1: Fibrosis and fatty degeneration scores in the control group (normal diet) and the high omega-6 group w/ and w/out ALA Kaya-Dagistanli. 2012)
  1. The administration of a diet that contained 60% fat from safflower oil, 20% kcal carbohydrate and 20% kcal protein (51% of the fat from n-6, n-6:n-3 ratio of 15.4) did produce major changes not only in the GSH levels, a measure of the total antioxidant capacity in the livers of the 24 Wistar rats, the relatively short time span was even enough to increase the fibrosis and fatty degenration scores by ~10x (see figure 1) compared to the rodents on the low fat standard chow in the control group (only 12% fat total, 39.1% n-6, n-6 : n-3 ratio of 9.3).
  2. The addition of 35 mg/kg DL-alpha lipoic acid (human equivalent: 5.7mg/kg; ~500mg/day) from week 4 to week 8 reduced both the negative effects of the omega-6 overload on GSH and the pathological degeneration of the liver, but could not fully restore it to normal levels.
Not just in view of the fact that ALA could not totally blunt the detrimental effects of the n-6 diet, but also in view of the fact that rodents on the regular diet did not see any benefits (remember: if you are not fat and metabolically deranged ALA ain't necessary, probably counterproductive; "Lean & Muscular W/ alpha lipoic acid?"), I personally gravitate towards (1), as far as the more significant finding is concerned. After all, it goes to show you that you simply have to the absolute (and relative?) amount of omega-6 fatty acids in your diets and can go without any such supplements as high dose fish oil and/or alpha lipoic acid. Bottom line: Don't bang your head against the wall and you won't need a helmet ;-)

NSAIDs liver cancer, chronic liver disease and other nasty ways to die

It's quite a happy coincidence that the December issue of the Journal of the National Cancer Institute held yet another intriguing study on the potentially beneficial health effects of the use of NSAIDs, which had been addressed in August already, when Jacobs et al. have gotten quite some public attention with their paper on aspirin use and the decrease in all-cause mortality (Jacobs. 2012). The novel paper that's based on prospective data on 300,504 men and women aged 50 to 71 years who had participated in National Institutes of Health-AARP Diet and Health Study and has been written by a group of scientist who actually work at the National Cancer Institute (Sahasrabuddhe . 2012), did not deal with a slightly different research question, i.e. does the use of aspirin and other NSAIDs offer protection against liver cancer (hepatocellular carcinoma) and death due to chronic liver disease, it also offers a slightly more sophisticated analysis of the (a) the frequency of NSAID use and potential interactions. Still, I decided to summarize the main findings of both, also in view of the fact that we are dealing  wih different cohorts (study subjects in the Jacobs paper were 100,139 men and women with no history of cancer in the Cancer Prevention Study II Nutrition Cohort).
Figure 2: Main results (hazard ratios) of two of the latest epidemiological studies into the effects of aspirin and other NSAIDs on liver cancer, death due to chronic liver disease (left) and aspirin alone on all cause mortality (right; data based on Sahasrabuddha. 2012 & Jacobs. 2012)
With the "demarcation lines" being present at 1.0 (meaning normalized risk) it is pretty easy to see that at least with respect to liver health and all-cause-mortality and solely based on epidemiological evidence, aspirin appears to be one of those "miracle drugs" everyone can benefit from. We have to be cautious however, when we compare everyone with ourselves, after all - and pretty much stands out of question - the protective effects of aspirin and the slightly less unambiguous and as far as hepatic cancer goes, even detrimental effects of other NSAIDs are mediated by...
  • the modulation of inflammation via inhibition of the COX enzymatic pathways necessary for the synthesis of prostaglandins
  • the ensuing decreases in epithelial proliferation and angiogenesis, as well as an
  • increased apoptosis (regular cell death) and ameliorations in the inflammatory response and inflammatory cytokines via non-COX mediated pathways
Now, if you remember the previous study about ALA and how useful it can be if you are the kind of person who hammer his head... ah, I mean who still has not gotten the message that the formerly hailed omega-6 PUFAs from the "healthy corn and vegetable oils" are not a bit healthy, on the one hand, and how superfluous (if not detrimental) the same supplement is for someone who does not exhibit exuberant inflammation to begin with, this certainly does put the results into perspective.



Apropos perspective, I am not quite sure how you like the perspective that this is it, for today, but I would be pleased if you took that as an incentive to come back tomorrow and check out the next installment of SuppVersity On Short Notice and for the time being, I still have a couple of facebook news, I am sure you will enjoy:
  • Scientists from the UK and New Zealand do pretty damn good job pimping the sales of low fat products - learn what the press release does not tell you (read more)
  • German scientists find: Bisphenol A clogs calcium channels - don't know if you'd agree with them that the good news is that it appears to be reversible (read more)
  • Grazing is for fat cows, only  - women who want to be lean better eat like a human, i.e. three square meals not more that's it - this will also help with blood triglyceride management (read more
  • more, much more ;-) 
Any you know, facebook is a fast media, so expect more news to be posted even before the official next SuppVersity article will hit the main site ;-)

References:
  • Jacobs EJ, Newton CC, Gapstur SM, Thun MJ. Daily aspirin use and cancer mortality in a large US cohort. J Natl Cancer Inst. 2012 Aug 22;104(16):1208-17.
  • Kaya-Dagistanli F, Tanriverdi G, Altinok A, Ozyazgan S, Ozturk M. The effects of alpha lipoic acid on liver cells damages and apoptosis induced by polyunsaturated fatty acids. Food Chem Toxicol. 2012 Nov 28.
  • Ruas et al. APGC-1aI soform Induced by Resistance Training Regulates Skeletal Muscle Hypertrophy. Cell, December 7, 2012; 151:1319–1331. 
  • Sahasrabuddhe VV, Gunja MZ, Graubard BI, Trabert B, Schwartz LM, Park Y, Hollenbeck AR, Freedman ND, McGlynn KA. Nonsteroidal Anti-inflammatory Drug Use, Chronic Liver Disease, and Hepatocellular Carcinoma. J Natl Cancer Inst. 2012 Dec 5;104(23):1808-14.

22 comments:

  1. Re: the first part.

    It seems that once training and diet are inside the relatively broad parameters of sanity, in terms of building muscle, actual results are based almost entirely on genetic factors. Until there's some kind of methodology that addresses the genetic aspect in a feasible way (i.e., drugs-that-won't-kill-ya), the individual appears to have a very limited ability to change the magnitude of hypertrophy.

    In other words, although training and proper nutrition are needed to effect a muscle-building response, the actual response (whether it be impressive on one end down to near-nothing on the other), is completely out of one's hands.

    That may seem a bit obvious, but it also nullifies (IMO) the need for all the different training routines, diet ideas and supplements. Once you get into a relatively sane diet and training path, the fine-tuning is of almost no consequence.

    JMO and of course I'm well-known to be often wrong.

    John

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    1. The idea that training stimulus needs to change constantly is just something personal trainers tell you so that they will keep getting hired. As long as "progressive overload" is met, muscle growth will continue (up to your genetic potential that is).

      With regard to natural muscle growth (key word being natural), one can expect a maximum of about .5lbs per week.

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    2. I disagree with the way you formulate that anonymous it's by now means "out of your hand", it's rather fully in the hands of 99% of those complaining about insufficient gains - they in 80% of the cases they overtrain and their diet sucks, in the other 20% only one of the two components sucks

      You are however right that it is more or less out of your hand if you gain the .5lbs on a weekly (which would be awesome and is unrealistic for someone with years of training experience, if we talk about lean mass), bi-weekly or monthly basis. Even if you did it on a monthly basis, 6kg of pure muscle are HIGHLY visible (on a ripped frame) and that's what you can gain in the course of one year

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    3. learning_to_lift_weightsDecember 8, 2012 at 12:16 PM

      ".... they in 80% of the cases they overtrain and their diet sucks ....."

      Prof., does it mean that a little under-training is better than over-training?

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    4. chronically, yes. You will still progress, if you "undertrain" (as long as this does not mean training totally irregularly or just lifting those plastic dumbbells; if you constantly train at 110% of the optimum stagnation is almost guaranteed. And not just in the gym, but also in other areas. It just takes a toll on your whole life.

      A short cycle of 2-3 weeks of overreaching with appropriate "underreaching" afterwards may in fact be productive - in a way that's similar to the hind-limb suspension in rodents. For the atrophied leg that's a major "overtraining", when the rodents start using it again; it's the "ups and downs" that induce the most change.

      Nevertheless any regular workout regimen must have some sort of build in progression, so if we assume you train at 90% of the threshold to overtrain those 90% would still increase from week to week, you would be able to lift more weight and make progress.

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    5. A good model to follow is train hard for 4-6 weeks followed by a 2 week sup-max run-up. Assuming you wanted to bulk/build strength, the "hard" weeks would be when you eat more calories and push yourself on the weights to increase your strength and stimulate MPS. The "easy" sub-max run-up you would then bring your calories back down to maintenance (or maybe slightly above) and bring your lifts down to maybe 80% the first week and then 90% the second week to allow for recovery.

      That is, assume when you finish your "hard" weeks you can bench 100lbs for 3 sets of 12. Week 1 of the sub-max you would bench 80lbs for 3x12, and then bench 90lbs for 3x12 in week 2. Then when you restart the hard phase you would start at your original 100lbs and try to put more weight on the bar.

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  2. Dr. Andro,

    To get the response of the PGC-1 a4 how much cardio before training is needed would a 10 general warm-up be enough or does the full 30mins you mentioned on superhuman radio need to be done to see the increase?

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    1. I don't know. I guess one thing you have to consider is that they tested 48h after the last workout - I suspect that that's the reason why only the combination training still had IGF-1 up (more stress) - so if "more stress" is the actual mechanism, or as I likewise said the "training depleted", 30 min would probably make a difference (=be superior); on the other hand you could argue that training fasted for example could add a similar stimulus within 10 min. We will have to see what future studies hold. Up to then, I may remind you of my previous posts on the matter, e.g. suppversity.blogspot.de/2012/10/cardio-weights-mutual-exclusives-or.html

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    2. It could be wise to note that IGF-1 is not indicative of muscle growth. IGF-1 levels are about twice as high in oxidative (smaller) fiber than in glycolytic fiber (Van Wessel et al, 2010). The same applies to myonucleair density and a ton of other factors one associates with "hypertrophy" but are in effect just factors of protein synthesis, which is infinitely greater in oxidative or injured fiber than in glycolytic fiber. I think the key problem is that people still think there is a dose response relationship between muscle damage and growth, whereas when one looks at muscle damage with the proper objective parameters as Paulsen et al. (2012) did that you get a clear picture of damage being greater in injury > endurance exercise > resistance exercise, and that nearly all factors associated with muscle damage lead to fast to slow fiber type switching (which preserves more overall mass) and if severe enough to apoptosis and atrophy. The primary signals seems to be calcium related. Which is obvious since endurance training leads to prolonged sustained calcium levels (leading to increased calcineurin and CaMMK, negative regulators of mass) and even more severe damage is linked to calcium leakage which induces calpains etc.(modulators or apoptosis).

      So I think the whole assumption of more IGF-1 = more hypertrophy is faulty to begin with.

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    3. I don't disagree, if it comes to systemic IGF-1 responses I would even go so far as to say that it is 100% irrelevant. If we are talking about the intra-muscular expression of IGF-1 and its splice variants I tend to disagree. In as much, by the way, as I disagree with the faulty identification of inflammation and muscle damage, if you look at the heat shock protein expression in the Febraio study I cite in today's blogpost, for example ( http://suppversity.blogspot.de/2012/12/the-igf-1-promoting-myostatin-reducing.html) you will see that this happened in the absence of muscle damage and was not even measurable in circulation. So if we are talking about localized processes relying on systemic measures or muscle stiffness or changes in functionality miss as Paulson is bringing them forward are don't contradict the general idea that a certain degree of exercise stress is not just necessary, but actually the driving force of the exercise induced adaptations

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  3. I'd love to hear a further discussion on SHR (with Adel and the guy who did the NASA studies) and/or see a dedicated post here with respect to enhancing the beneficial effects of this PGC-1a4 springboard by way of supplement timing.

    If I were to do this protocol, it seems like I should just drink water instead of my usual "pick-me-up" pre-workout so that I enhance the depletion part during the cardio. Then, after the cardio and resistance, stock up on a small bit of fast carbs, essential amino acids, creatine, and, perhaps, PQQ?

    Kind of along Daron's question - how was the 30 minute cardio intensity defined? I'd certainly love it if walking my dog for 2 miles at 3-4 mph would cut it, but I doubt that's the case. I'd love to do 10-15 minutes of HIIT instead, with my stationary bike.

    Lastly - I know Carl alluded to this on the show, based on an interview with a previous guest and I was curious to get an opinion:

    Is the effect of the study's cardio work systemic, or is it just providing benefit to the involved muscles? Carl mentioned a hand ergometer, and I recently picked up this interesting device called a "Burn Machine", which one can simulate the motion of using a speed bag, but it's basically a cycle for one's arms/hands.

    My hypothesis is that it'd be best to handle it this way: on the lower body day, do HIIT beforehand on the bike, and on upper body day, do HIIT beforehand with the burn machine.

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    1. Training in a (semi-)fasted state (aka no carbs, BCAAs *might* help prevent catabolism, but I doubt to any significant degree, if you perform cardio beforehand since you will end up oxidizing them for energy) will enhance the post-workout anabolic window.

      With regard to your last part, that is correct. You must perform the aerobic work in the muscles that you will be resistance training that day.

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    2. Following my interpretation of the SHR conversation, it seems one shouldn't want anything else in their system that could provide the cardio exercised muscles any excess energy. Therefore, it seems I should just take in water (fasted) instead of either PES Alphamine or DS Craze, both of which I really like using.

      The aftermath of the protocol should ease any fear of catabolism. This supercompensation effect that it causes - well, I want to supplement it to get the most out of it.

      I guess I'm just gonna have to conduct my own experiment... and, listen to the SHR episode a few more times to make sure I have everything down.

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    3. It is not difficult. I suggest you read the SuppVersity Intermittent fasting series as it goes into much detail on this topic. Basically, the less glycogen you start with, the greater the anabolic rebound when you refeed post-workout.

      To apply the benefits of cardio on MPS, you must work the muscles that will be lifting beforehand.

      Thus, in a fasted state do 10-20 minutes of LISS with the muscles that will be trained, then do your lifting session. Afterwards ingest some carbs and protein and have a great day.

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    4. damn, I just closed this tab and the lengthy comment I wrote disappeared... well again (in short)... I already broached the issue of how much cardio in a previous comment further up, so please read that as well. When you are done, keep in mind that the involvement of glycogen depletion is more or less hypothetical and not necessary the key factor as both groups will have worked out for about the same time, since the strength only group had a higher training volume (more exercises), so that overall depletion could have been identical.

      That said, it could well be that there is a residual effect, but probably no direct effect via AMPK increases during the initial cardio session which would increase the production of the "classic" PGC-1 a. With the a-4 variant being more readily produced, once you the whole machinery is already set in gear. Whatever the role of glycogen may be it is overall more likely that this is triggered by MAPKs, meaning reactions to the expression of myokines like IL-6, HSPs etc. - in both cases, i.e. glycogen => more myokines or additional wear and tear => more myokines, you could argue that chances are that a 10-15min HIIT session would get the job done just as well... however, NOT with any form of glycogen repletion before you start working out. Wrt to stims and BCAAs, I don't really see how they should hamper the process. BCAAs won't be used for glycogen repletion mTOR is NOT a direct antagonist of AMPK (alpha-2, the muscle / exercise specififc variant that is; cf. http://suppversity.blogspot.de/2011/10/intermittent-thoughts-on-intermittent_30.html) in the absence of restored ATP (and that would NEED carbs)

      by the way: I sniff this is of so much interest that it would be appreciated if I did a whole post on the study on Sunday, hah?

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    5. With regard to the last part of your comment, that one is up to you! It would be a very interesting post do to all the conventional wisdom about gaining muscle and limiting cardio, etc.

      But then again, I am still waiting on that artificial sweetener post ;)

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    6. learning_to_lift_weightsDecember 8, 2012 at 12:25 PM

      Waiting for Sunday post! :-)

      ... want to hear more on glycogen & cortisol connection with PGC-1 a 4 iso.

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    7. learning_to_lift_weightsDecember 8, 2012 at 12:30 PM

      Like Primalkid, I do hope, probably a series on "intermittent thoughts on artificial sweetener". ;-)

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  4. A post dedicated to the study would be appreciated. Please and thank you.

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  5. I think a post about the study, connecting cardio with hypertrophy with some aplicable conclusions would be alot more consusive than the artificial sweeteners post. You just need to have a whole food diet and ditch the fucking (diet)soda's. Maybe use some stevia if you want but there shouldn't be a reason aspartame etc containing foods become a staple... And don't be dogmatic and NEVER consume them, just moderation... That will propably be the conclusion of the artificial sweenters post anyway... So I say discuss the cardio <-> glycogen <-> hypertrophy if possible :-)

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    1. I agree that a study connecting cardio with hypertrophy would be more prudent then one about artificial sweeteners. However, the reason I am so interested in them is not do a possible conclusion about their use. I personally only use stevia and erythritol, but I think a place that summarizes all the main artificial sweeteners (and maybe some sugar alcohols) would be very enlightening. In other words, I would simply like to further my knowledge about them and have a reference point whenever discussing them with friends and family. Knowing why each is sweet, the toxicity levels needs to do harm, if they effect insulin secretion, maybe some other surprises the studies reveal, etc.

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    2. there is something else that's intersting about sweeteners. Understanding them would probably entail understanding real glucose signaling and the effects of "just sweet" individually.

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