No Pain no Gain? What Can We Learn From the Time Course of Muscle Damage After Eccentric Workouts. Plus: What's that Got to Do With Your Doctor Sending You to the ER

Concentration curls are among those exercises, where eccentrics can easily be incorporate. Plus. As the EMG Series shows, this increases the biceps activity by almost 50% compared to the regular barbell curl (learn more). But will it also make you grow faster?

Just let me get this straight right away: I am well aware that it is still debated if and if so to which extend skeletal muscle damage affects or even determines the training induced gains in strength and/or lean body mass and it is not my intention to rekindle this never-ending debate. At least in my humble opinion, it does yet appear that a certain degree of "damage" is necessary for "optimal" gains. Anything that passes this threshold is however, as Schoenfeld points out in what I believe is the most recent review of the literature, not going to "further augment muscle remodeling and may in fact interfere with the process" (Schoenfeld. 2013).

The potential of negative interference is obviously particularly pronounced, when the the potentially muscle damaging physical activity is performed during the recovery phase. But how long it going to take until the repair and restructuring processes are completed?

In other words: How long would be optimal rest interval for someone who trains really intense with a focus on eccentric overload? 
 
At first sight it seems as if the results of a recent study from the State University of Campinas should help us to bring light into the darkness, but as we are soon going to see, things are (once again) more complicated than common sense would tell us.

The main intension of the researchers was to (I quote) "observe the time course of muscle damage and inflammatory responses to resistance-training with EO [eccentric overload]" (Neme Ide. 2013). To this ends, they recruited 3 women and 5 men in their early twenties who had at least one year of previous strength training experience and had them perform a standardized workout program with the following parameters:

No idea how to schedule your workouts? Learn how to do that and much or in the Step By Step Guide to Your Own Workout Routine!

• total duration: 13 sessions (total) distributed evenly across 7 weeks; 2x full body workouts trained every Tuesday & Thursday

• set & rep scheme: 4 sets of 8 reps at 80% of the 1-RM max for eccentrics; since that's more than you can "lift", i.e. move concentrically, the researchers who supervised the sessions had to help the participants on the eccentric part of the movement

• exercises: classic full body workout consisting of bench presses, 45-degree leg presses and bent-over rows

The blood samples were taken 96h after training session 2, 7, 9, 11 and 13, respectively and the creatine kinase, CRP and various hematological parameters were measured to evaluate the impact the eccentric workouts had on ...

• muscle damage - indicated by the amount of creatine kinase (CK) that leaked from the musculature into the blood,

• overall inflammation - indicated by the change in C-reactive protein (CRP) levels, 

• hemtaological paramaters - including red blood cell count (RBC), hemoglobin concentration (Hb), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), erythrocyte distribution width (RDW), white blood cell (WBC) count, lymphocyte (LYNF) count, neutrophil (NEUTR) count, and platelet count (PLT).

The reasoning behind the constant monitoring of CK, CRP and blood parameters was that the scientists expected that there would be an attenuation of the damaging effects of the workouts as the participants bodies got accustomed to the bi-weekly torture.

Don't let your Dr send you to the ER without letting him know that you trained the day before you got your latest bloodwork done.

If you take a look at the creatine kinase (CK) data I plotted in figure 1 (left) there are two things you should take a mental note of. Firstly, the increase in creatine kinase is "exorbitant" and could - assuming your doctor either doesn't know you are strength training or has no clue about the effects a heavy workout can have on the amount of the enzyme that "recycles" creatine into pohosphocreatine (PCr) that's floating around in your blood stream - be enough to have your physician send you to the ER - misdiagnosis: rhabdomyolysis (please bear in mind that Kraemer et al. (2004) suggest a reference interval for physically active subject of 1,309U/L; that's almost 4x more than the regular lab range that usually says everything past 400U/L would be pathological)

Figure 1: Creatine kinase (CK) levels (left) and C-reactive protein (CRP) levels (right) at different timepoints of the 7-week exercise intervention (Neme Ide. 2013)

And secondly, this increase in creatine kinase is hard to predict and varies from subject to subject (the numbers in the upper line of the label of the horizontal axis are the subject numbers):

"CK and CRP presented significant changes at specific time points, but not for all subjects. Four subjects presented significant changes in CK activity at P2 (+1719%, +1250%, +1281%, and +312% resp.), and other two at P13 (+391% and +139%, resp.). For CRP six subjects presented significant changes at P2 (+1100%, +243%, +3800%, +2500%, +1400%, and +2400%, resp.), one at P4 (+567%), other at P9 (+3200%), three at P11 (+300%, +3400%, and +3900%, resp.), and other at P13 (+1500)." (Neme Ide. 2013)

Interestingly, there was no significant correlation between the changes in creatine kinase (CK) and C-reactive protein (CRP) as you would expect if muscle damage and systemic inflammation went hand in hand.

Accommodation? yes! Unequivocal results? No.

Despite the fact that the expected pronounced initial CK response was present only in four out of the eight individuals, the scientists are confirmed that the data they gathered does support their initial hypothesis that there would be an attenuation of muscle damage in the course of the 7-week study period and ascribe the latter to the repeated bout effect a term, scientists use to refer to the protective effects a single bout of eccentric exercise has on the muscle damage during subsequent bouts (Mc Hugh. 2003).

"The potential adaptations that explain the phenomena have been categorized as neural, mechanical, and cellular. Regarding the cellular adaptations there is evidence of longitudinal addition of sarcomeres and adaptations in the inflammatory response following an initial bout of eccentric exercise, limiting also the proliferation of damage." (Neme Ide. 2013)

While a similar trend was observed for the CRP levels, the initial increase of the latter was by far less pronounced than for the CK values, so that the levels remained within the physiological norm for active people (the average CK values, on the other hand, were 2x elevated over the already high reference interval for physically active individuals).

Changes in hematological parameters were the exception

In case your workout program looks anywhere like Adelfo's Overkill Program from April 2013, you better make sure to come up with a new one after no more than max. 3-4 weeks!

If we acknowledge the reasoning Plaisance and Grandjean present in their 2006 review of the literature and take the comparatively low exercise related increases in C-reactive protein levels (CRP) as an indicator of damage in non-skeletal muscle tissue, it is also not surprising that this unquestionably intense and obviously muscle damaging exercise regimen did not have more pronounced effects on the blood panel of the study participants.

Only two subjects presented significant changes in neutrophils with an unpredictable up and down for subject 7 and a significant 60% increase after the final session in subject 6. In view of the fact that subject 7 was also the only one with detoriations in almost all other blood parameters, it's yet pretty unlikely that this was a result of the workout protocol and not the result of some sort of infection or whatever.

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Ok, so what exactly have we learned now? This is actually a pretty good question. I guess one thing we have learned is that physically active individuals can actually shock their doctors with "exorbitantly" high (yet still normal) creatine kinase levels. This does not mean that you can simply ignore constantly elevated / abnormal CK values, but it's important to realize that the 400U/L range your lab report lists is probably not sufficient for your personal CK values if you get blood drawn in the vicinity of a hard workout (on a related note: especially when you are low-carbing and eating high amounts of protein the increase in CK usually goes hand in hand with increases in the "turn protein to energy" enzymes AST and ALT, which are in this case not necessarily indicative of "liver damage").

There is evidence that the expression of the local factions of IGF-1, MGF & Co., depends on the exercise induced wear and tear  (learn more), it would be stupid to assume that there was no turning point at which the beneficial damage turns against you.

What we unfortunately didn't learn (and I feel that the scientists really missed out on this opportunity) is what the underlying reasons of the differential CK response to the workout may have been. Would it really have been too difficult to ask the "non-responders" what kind of exercise protocol (including set + rep schemes, frequency, weights and exercises) they had been following before they enrolled in the study? I don't think so. In fact, I would rather argue that it would have been obligatory. For me, for example, the eccentrics would have been the only novel stimulus in this workout. I have however been training with a female friend of mine a couple of days ago who would certainly qualify as having been training for at least a year and following a training program consisting of 3–5 sets of 6–12 repetitions with 1-2-minute rest interval between sets, performed 4-5 times per week (these were the inclusion criteria for the study at hand), for whom all of the exercises would have constituted a whole new stimulus in and out of itself (she usually works out on those fancy machines).

Now this may be a pity, but int the end, the differential CK response could have been totally irrelevant anyway. The pertinent evidence from human studies may be more than scarce, but if we go by the few studies we have, it appears that even a 5x higher CK response to eccentric exercises as it was observed in the non-preconditioned group in a 2011 human study by Flann et al. does not result in significantly different increases in either muscle size, or strength (cf. figure 2).

Figure 2: Strength and hypertrophy (left) and creatine kinase (CK, right) response in pre-trained and naive individuals in the course of an 8-week eccentric training protocol (Flann. 2011)

The fact that Neme Ide et al. did not measure the strength and/or hypertrophy response, still baffles me. I do however believe that (most) scientists are not just clever, but also very rational beings and therefore I would suspect that there is soon going to be a follow-up paper with the respective data. Why's that? Well, in a scientific community, where the number of publications is unfortunately more important than their quality, tricks like these may eventually give you the edge over the competition on your next job application ;-/

References:

• Flann KL, LaStayo PC, McClain DA, Hazel M, Lindstedt SL. Muscle damage and muscle remodeling: no pain, no gain? J Exp Biol. 2011 Feb 15;214(Pt 4):674-9.
• Kraemer WJ, French DN, Paxton NJ, Häkkinen K, Volek JS, Sebastianelli WJ, Putukian M, Newton RU, Rubin MR, Gómez AL, Vescovi JD, Ratamess NA, Fleck SJ, Lynch JM, Knuttgen HG. Changes in exercise performance and hormonal concentrations over a big ten soccer season in starters and nonstarters. J Strength Cond Res. 2004 Feb;18(1):121-8.
• McHugh MP. Recent advances in the understanding of the repeated bout effect: the protective effect against muscle damage from a single bout of eccentric exercise. Scand J Med Sci Sports. 2003 Apr;13(2):88-97. R
• Neme Ide B, Alessandro Soares Nunes L, Brenzikofer R, Macedo DV. Time course of muscle damage and inflammatory responses to resistance training with eccentric overload in trained individuals. Mediators Inflamm. 2013;2013:204942.
• Schoenfeld BJ. Does exercise-induced muscle damage play a role in skeletal muscle hypertrophy? J Strength Cond Res. 2013 May;26(5):1441-53.

Science Round-Up Seconds: Cytokine Modulating Power Cakes, Endurance & Resistance for Maximal Cardiovascular Benefit, Gluten Degrading Bacteria and Cancer Fighting Green Tea + Levitra Combo. Plus: Sirt-3 & Protein Blends

Not sure if the "Power Cakes" in the Kerasioti study looked like these, but it would sure have been appropriate, after all the poor study participants had to cycle for 3h (in total) - makes you wonder if they are WADA approved, doesn't it?

Today's installment of the SuppVersity Science Round-Up Seconds has some delicious stuff for you in stock. We will start out with an interleukin 6 & 10 modulating CRP reducing cake from Greece as an appetizer, or pre-workout, whatever you like better. When we have finished that one, the table or gym talk will center around debunking the myth that only aerobic training was good for your cardiovascular system. When even the last i**** has gotten that, it's about time to devour the delicious anti-carcinogenic and gluten destroying bacteria stew with green tea and Levitra(R), I've been cooking for ya ;-)

Before you go for the cake, however, I want to apologize that I was somewhat out of it on yesterday's show (click here to listen to the podcast). As a compensation today's Seconds have - as you can see - become pretty "nutritious" at least on a quantitative level ;-)

Looking for the perfect peri-workout meal? What about some cake?

(Kerasioti. 2013) -- It may not really sound like "high performance fuel", but in fact the protein cake a group of Greek scientists fed to their nine physically active and pretty well-conditioned male subjects (age, 28 ± 2 yr; height, 184 ± 3 cm; body fat, 11 ± 2%; body mass index, 23 ± 1 kg/m²) turned out to be much more than just performance fuel after the 2 h of continuous cycling on cycle ergometer at an intensity corresponding to 60-65% of the subjects established VO2max.

Figure 1: Interleukin 6, interleukin 10 and c-reactive protein (CRP) levels before and after the first 2h exercise bout with experimental (EXP) and placebo (PLA) cake; data expressed relative to baseline (Kerasioti. 2013).

As the data in figure 1 goes to show you, the cakes which contained a combination of 0.9g/kg carbohyrates and 0.26g/kg protein did in fact have surprisingly more beneficial effects on the rise and fall of the pro- and anti-inflammatory cytokines IL-6 and IL-10 (IL = interleukin) during the two counterbalanced trials, than the placebo, an identical cake with a different macro-nutrient ratio of 1.1g carbs and 0.1g protein per kg body weight.

Training twice a day? No problem with the power cake ;-)
 
Only four hours later the scientists shooed their subjects onto the bike again for another hour of medium intensity exercise and a 95% VO2max time-trial sprint at the end, "to determine if the cake administration affects performance" (Kerasioti. 2013). Sounds logical, right? What's confusing, though is that Kerasioti et al. don't even mention the performance effects they did or didn't observe in the second bout in the discussion of their results - so I suspect that (a) there were no differences or (b) Kerasioti et al. regard the cytokine response to the second trial as a "performance" marker and stick to that as their "effect on performance" (I don't know about you, bun in my humble opinion the latter would be an even greater flaw than leaving the non-significant information out).

Figure 2: IL-6, IL-10 and CRP response over the whole study period; expressed relative to baseline (Kerasioti. 2013)

If you add the cytokine expression in the steady state 2h trial from figure 1 to the data that was recorded after the completion of the 1h steady state + time trial cycling session four hours later and the 48h post levels of the inflammatory markers, the resulting graph exposes a very neat symmetry with an almost identical rise and fall in the expression of the short-lived cytokines and an eye-catching difference in the intermediate inflammatory response evidenced by the increase in CRP in the recovery phase of the placebo trial (just as a reminder: C-reactive protein aka CRP is the same stuff you will also see chronically elevated in diabesity and all sorts of inflammatory diseases).

A propos protein: We also talked about the benefits of protein blends with fast and slow proteins.Here is the SuppVersity article about the human study on the casein + whey combination I mentioned.

Bottom line: Compared to carbohydrates alone the combination of carbs + whey does not only offer a muscle building, but also an inflammatory edge, especially endurance athletes and anyone with a high training density will benefit from -- just like the 3g glutamine (1.5g pre, 1.5g post workout), Carl and I talked about during yesterday's installment of the SuppVersity Science Round-Up, by the way, with the only difference being that the effects of whey protein are probably mediated by it's glutathione (the master oxidant) repleting glutamylcysteine groups (Bounous. 1991), beta-lactoglobulin, lactoferrin and other anti-inflammatory compounds in whey proteins (Peng. 2009).

Cardio and weights: Your cardiovascular system loves both

(Spence. 2013) -- There is this longstanding and die hard myth that only aerobic training would be good for the heart. With the publication of a recent paper by a group of scientists from the University of Western Australia and the Liverpool John Moores University, you do now finally have something to print out, and tack it to every idiots forehead who still insists that only half-marathon running, but not resistance training could save you from cardiovascular infarction ;-)

For their 6-months experiment, the scientists recruited 23 27±5 year-old healthy male subjects who were then randomized to either either endurance (ET, n=10) or resistance training (RT, n=13) in order to evaluate the long-term effects of these training modalities on brachial, femoral and carotid artery diameter and wall thickness (IMT), as well as femoral and brachial flow-mediated (FMD) and glyceryl trinitrate (GTN) mediated dilation. Ha? Well, let's say they wanted to know how the different exercise protocols, the scientists desribe as follows,

For those of you who want to add something to their regimen that boosts the longevity sirtuin, sirt-3 Carl and I have talked about during yesterday's show, here is the HMB + Leucine study I mentioned.

"[...] the ET intervention consisted of a progressivelyoverloaded programme of walking, jogging and running, inclusive of specified training phases over the 24week period. The focus of the periodized RT programme was Olympic weightlifting with incorporated supplemental exercises (e.g. dead-lift, back squat, front squat, bench press and overhead press) to develop overall strength and technique. Relative intensities for the ET and RT interventions were monitored throughout the sessions, individualized and progressed to ensure that subjects were exercising at prescribed percentages of VO2peak and 1RM, respectively" (Spence. 2013)

would effects the structure and performance of the hearts of their subjects, who completed three 1h training sessions of the respective exercise type per week.

As even resistance training enthusiasts should have expected, the RT group did not see significant improvements in O2Peak (ET yielded +5% increase in this indicator of cardiovascular fitness). On the other hand, the endurance training had no effect on upper body strength, which increased by statistically highly significant +21% in the resistance training group. Both these improvements are yet not really newsworthy and the whole study would not have made it to the SuppVersity Science Round-Up, respectively the Seconds, if it had not been for the high-resolution ultrasound images of the heart, which revealed:

Figure 3: Changes in body composition
relative to pre values (Spence. 2013)

• Resistance training affects the brachial artery, increases brachial artery resting (+8%, P<0.05), peak FMD  and GTN-mediated (P<0.01) diameters
• Endurance training affects the femoral artery, increases resting (+3%, P<0.05), peak FMD femoral artery diameters, and improvements in the femoral FMD-to-GTN% ratio 
• Both forms of training had similar beneficial effects the carotid artery wall thickness

In summary: Despite the fact that the two training forms will have differential effects on your overall conditioning and strength, they both increase lean mass (see figure 3) and decrease the artery wall thickness of the artery which supplies your brain with oxygen (the carotid artery). And with their unique effects on the brachial artery in the upper arm (RT) and the femoral artery in the tigh (ET), they make a perfect team to protect you from cardiovascular disease and stroke.

"I'd like a Levitra(R) enhanced green tea with probiotics..." What?

The last two items from yesterday's list that did not make it into the show are actually not brand new studies. One is a comment from the Journal of Clinical Investigation and the other one is a study that has been around since 2011, already. I picked them up in the course of the week and found them news-worthy, although it is not really sure, a combination of green tea, viagra and rothia bacteria is going to prevent cancer and solve your problems with gluten or whether one or the other or a combination of all is going to kill you ;-) Anyways, here are the details:

• 

  Rothia has hitherto rather been known as a bad guy, which can, if it gets into the wrong places cause endocarditis (heart), meningitis (brain), peritonitis (an inflammation of the peritoneum, the thin tissue that lines the inner wall of the abdomen and covers most of the abdominal organs) and other infections (Photo by Nathan Reading)

  Rothia bacteria in the upper gastrointestinal tract degrade gluten (Zamakharchi. 2011) -- Back in 2011 already a group of researchers from the Boston University Henry M. Goldman School of Dental Medicine published a paper in which they describe the astonishing ability of a common gram positive bacteria called Rothia, which is also present in the oral cavity could degrade 50% of the glyiadin peptides the scientists had added to the petri dish before the they were incubated for 30min.
  
  In view of the fact that the immunogenic parts of the peptides, that cannot be cleaved by our natural digestive enzymes, it does appear like a too happy coincidence that our microbial subtenants from the oral and upper gastrointestinal tract possess the enzymatic machinery to degrade the harmful gluten peptides for us - don't you think so?
  
  One thing is for sure, the presence of a bacteria that deals with the stuff, we cannot deal with on our own in our oral cavity certainly does support what I said in the context of the "bulimia apparatus" - the digestive process with all it's downstream effects on your metabolism starts in the mouth:
  

  "During mastication (chewing) foods are mixed with whole saliva helping to accelerate the break-down by digestive enzymes during the residency time in the oral cavity. Oral microorganisms in the swallowed food bolus may or may not survive and/or continue to exert proteolytic activities during or after gastric passage. Our in vitro data with R. aeria show that its enzymes are not abolished at acidic pH values, and are optimally active under more basic pH conditions. In vivo, this could mean that during gastric passage the enzymes will neither be active nor destroyed, and that enzymatic reactivation would occur upon transfer to the duodenum." (Zamakharchi. 2011)

  Aside from the fact that they could make it into the large intestine, previous studies have already confirmed that R. mucilaginosa can even gain a foothold there (Ou. 2009), so that probiotic supplementation with Rothia mucilaginosa could in fact turn out to be a viable treatment / prevention strategy for celiac disease and other gluten related health problems.

• EGCG + PDE-5 = cancer killer (Yang. 2013) -- Cancer is like the Learnean Hydra from ancient Greek mythology (see image on the right). Whenever you cut off one of its heads it'll grow two new ones... well, i must admit the analogy isn't perfect, but it's still useful to understand why the PDE-5 inhibitor vardenafil worked wonders when it was co-administered with the green tea catechin EGCG.
  
  

  

  You really have to wonder why these ancient heroes who had the cunning to kill the Hydra did not even wear a pair of speedos, when they entered into it's watery realms ;-)

  Just like the many Greek warriors who died in their battle with the Hydra before it was finally slain by Heracles, EGCG is well capable of doing major harm to the cancer cells. Just like the snake-like beast the cancer cells have yet found a way to resist the onslaught. Obviously not by growing new heads, though, but rather by over-expressing PDE-5 in order to repress the EGCG increased cGMP activity that would otherwise initiate apoptosis, i.e. the natural self-destruction mechanism of a cell.
  
  So what could be more straight forward than using a PDE-5 inhibitor just like Iolaus, Heracles cousin, used a firebrand to scorch the neck stumps of the Hydra after each decapitation. Clever and effective, don't you think so?
  
  Well, there still is one downside: Just like the story about the Hydra is nothing but a myth, the studies Yang and Wang reference in their commentary in the latest edition of the Journal of Clinical Investigation are only in-vitro studies and whether drinking green tea and popping one of Bayer's Levitra(R) pills after the other, is going to prevent, let alone kill existing cancer, will still have to be elucidated.

That's if for today! And since I am a bit in a hurry, I will leave it up to you to check out the latest really short news on the SuppVersity Facebook wall. Contrary to the green tea + Levitra treated cancer cells, the facebook news are guaranteed to proliferate even before the official Saturday installment of On Short Notice is going to be posted in ~24h (in fact, it will first have to researched and written ;-)

References:

• Bounous G, Gold P. The biological activity of undenatured dietary whey proteins: role of glutathione. Clin Invest Med. 1991 Aug;14(4):296-309.
• Kerasioti E, Stagos D, Jamurtas A, Kiskini A, Koutedakis Y, Goutzourelas N, Pournaras S, Tsatsakis AM, Kouretas D. Anti-inflammatory effects of a special carbohydrate-whey protein cake after exhaustive cycling in humans. Food Chem Toxicol. 2013 Jan 26.  [epub ahead of print] 
• Ou G, Hedberg M, Horstedt P, Baranov V, Forsberg G, et al. Proximal small intestinal microbiota and identification of rod-shaped bacteria associated with childhood celiac disease. Am J Gastroenterol. 2009;104:3058–3067.
• Peng X, Xiong YL, Kong B. Antioxidant activity of peptide fractions from whey protein hydrolysates as measured by electron spin resonance. Food Chemistry. 2009; 113(1):196–201. 
• Spence AL, Carter HH, Naylor LH, Green D. A prospective randomised longitudinal study involving 6-months of endurance or resistance exercise on conduit artery adaptation in humans. J Physiol. 2013 Jan 28. [Epub ahead of print] 
• Yang CS, Wang H. Cancer therapy combination: green tea and a phosphodiesterase 5 inhibitor? J Clin Invest. 2013 Jan 25:1-3. [Epub ahead of print]
• Zamakhchari M, Wei G, Dewhirst F, Lee J, Schuppan D, Oppenheim FG, Helmerhorst EJ. Identification of Rothia bacteria as gluten-degrading natural colonizers of the upper gastro-intestinal tract. PLoS One. 2011;6(9):e24455.