NAC Lowers DOMS, Initially, but on Day 5-6 it Makes Things Worse | Plus: Putative Performance Benefit is Negligible

In the long run, choking the exercise-induced fire too much is going to negate all the cherishable benefits of working out.

As a SuppVersity reader, you know what hormesis is and are aware that the proinflammatory assault of exercise, is an essential stimulant to musculoskeletal adaptation - a number of human and dozens of animal experiments show: if you quell the production of pro-inflammatory reactive oxygen species with high doses of vitamin C and E the growth and health response to exercise will be impaired. And vitamin C + E are not the only radical scavengers with this side effect.

In 2013, I wrote about a study that clearly demonstrated how N-acetyl-l-cysteine aka NAC "Reduces Inflammation, Muscle Injury & Cytokine Expression, but Impairs Anabolic Signaling, Satellite Cell Activity and Recovery" (re-read it) - keep that in mind before getting overly excited.

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Hence, NAC supplements shouldn't be used chronically. To control the inflammatory response to a workout and be able to return to the grind earlier, however, many people still rely on its noticeable ability to reduce early onset of DOMS (deep onset muscle soreness - learn more).

Is taking NAC ever a good idea for athletes?

Well, the good news for NAC lovers is: When used during a short competition, sportsmen and -women can actually benefit from the anti-DOMS effects, a recent study from the University of Auckland (Rhodes 2018) confirmed when it investigated...

"whether NAC supplementation decreases muscle soreness and enhances performance in a semi-elite sport setting [as well as] adverse effects and the tolerability of oral NAC supplementation" (Rhodes 2018).

The bad news is that using NAC for that very purpose won't just impair long-term gains, it would also backfire in terms of the what one could call a delayed DOMS response (if DOMS wasn't already delayed onset muscle soreness, obviously) on day 5-6 of the recovery period.

Figure 1: Schematic overview of the experimental design. Preliminary YYIRT-L1 performance measures were taken during preseason training, and post-supplementation performance measures were performed on days 5 and 6 of supplementation (NAC or placebo). Side effects and subjective muscle soreness were monitored through a daily TXT message during the supplementation period. NAC = N-acetylcysteine (Rhodes 2018).

That's at least what Rhodes' et al's observation that the initial "likely protective effect" (−19% ± 27%) on subjective muscle soreness of the 28 semi-professional, semi-elite male rugby players (age = 20.4 ± 0.9 yrs, height = 182.3 ± 7.4 cm, weight = 103 ± 12 kg, Yo-Yo Intermittent Recovery Test Level 1 [YIRT-L1] = 17.14 ± 1.73 level) who participated in the study, turned out to be reversed after 5-6 days of supplementation with 1g of NAC to when the authors observed a "very likely harmful effect" (71% ± 59%).

Figure 2: Running times (lower = better) and subjectively measured muscle soreness before during and at the end of the 6-day intervention with 1g of NAC in 28 semi-professional, semi-elite male rugby players (Rhodes 2018).

The effects on the actual exercise performance during the shuttle-run, on the other hand, were negligible - yes, this means you can safely ignore them. Everbody can tell that by looking at the running times in Figure 2, ... and yes, I don't care that the results of the “sportsci” parallel group trial spreadsheet (Hopkins 2015) suggest a "likely beneficial performance effect on maximum shuttle sprint time (2.4%; 90% confidence limit ± 4.8%)".

Whether more helps more is not clear! What is clear, though, is that 2 and more grams of NAC are more prone produce side effects in form of diarrhea, nausea, vomiting, and headache. You should furthermore remember that hormesis is all about managing the exercise stress - not annihilating. If you're using NAC, using the lowest effective dose should thus always be your goal.

To be fair, I should point out that the authors refrain from claiming to have a found a practically relevant performance benefit, when they write that..."this study was unable to demonstrate a clear effect of 1 g NAC on total time to complete a broken bronco exercise protocol" - that this was due to the low dosage of NAC, which is what they claim right after the cited passage, though, sounds a bit biased; and that despite the quoted results from a 2011 study by Cobley et al. (Cobley 2011), who gave their participants a higher dose of 50 mg/kg/day and observed an increase in YYIRT-L1 performance over time, with the greatest performance enhancement seen on the last testing session (three sessions in total).

When it comes to choosing whether and at which dose to use NAC (or vitamin C and vitamin E) you must consider hormetic dose-response relationship between stress exposure (X-axis) and adaptational response (Y-axis). Stimulatory effects occur in the low-dose region at the left of the no-observed-effects-level (NOAEL), whereas adverse effects occur in the high-dose region at the right of the NOAEL - The higher your baseline stress the more likely you'll benefit from antioxidants by reducing the background noise and enhancing the signal:noise ratio (Agathokleous 2018)

Overall, we need more research before we can - with some confidence - advice athletes to consume (high dose) NAC supplements during phases of intense competition; and that is particularly true for the purported recovery- and performance-enhancing effects semi-elite athletes are supposed to experience during exercise sessions with a high turnaround rate.

Learn more about hormesis

Taking NAC right before or during a meet or competition may still make sense -- I wouldn't totally exclude that there is a dosage effect, though, accordingly higher dosages (5g vs. 1g) should be recommended to those who want to (ab-)use NAC strategically during what Rhodes et al. aptly describe as "periods of anticipated high energy turnover with limited recovery time, such as during tournaments, competitions, or back-to-back hard training sessions" (Rhodes 2018).

During the training/off-season, however, it would be madness to interfere with ROS formation and IL-6 release as they have been found to be the real drivers of the adaptive response you're training for... ah, and by the way: To write "I take my NAC away from my workout" in the comments, will only expose your lack of knowledge about the way(s) your body functions. It's not going to help you soothe your conscience and make you feel good about a habit (=taking your high-dose NAC supplements religiously) that's almost certainly going to impair your gains - if you actually know what you're doing, however, and want to use NAC strategically before/during a meet or a short tournament, go for it but mind the side effects (test your individual tolerance before ending up in bed with a headache or on the toilette with diarrhea during the competition) | Comment!

References:

• Agathokleous, Evgenios, Mitsutoshi Kitao, and Edward J. Calabrese. "Environmental hormesis and its fundamental biological basis: Rewriting the history of toxicology." Environmental research 165 (2018): 274-278.
• Cobley, James N., et al. "N-Acetylcysteine’s attenuation of fatigue after repeated bouts of intermittent exercise: practical implications for tournament situations." International journal of sport nutrition and exercise metabolism 21.6 (2011): 451-461.
• Rhodes, etal. "Acute Effect of Oral N-Acetylcysteine on Muscle Soreness and Exercise Performance in Semi-Elite Rugby Players". Journal of Dietary Supplements (2018).

Research Update: Do NSAIDs Augment or Impair Exercise Induced Hypertrophy & Strength Gains in Young and Old?

Are you young and healthy? Then, high-dose NSAIDs may ruin your quad-gainz.

If you browse the SuppVersity Archive, you will find that NSAIDs, i.e. Non-Steroid(=not based on cortisone)-Anti-inflammatory-Drugs like aspirin, celecoxib, diclofenac, ibuprofen, or indomethacin, are not as bad as the bros in the locker-room may have told you.

In fact, a relatively recent study by Mackey et al. (2016) observed beneficial effects on muscle repair in young men. And an even more positive image of NSAIDs emerges if you read Trappe et al.'s 2016 study in which they observed significant increases in muscle gains in older trainees.

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In Schoenfeld's 2012 meta-analysis the three human trials, investigating the effects of NSAIDs on skeletal muscle hypertrophy that were available at that time seem to confirm the notion that the use of the prostaglandin-blocking COX-enzyme inhibitors won't impair your gains: while two of the study produced a null result (Krentz 2008; Petersen 2011), the other one, once more a study by Trappe et al. (2011), recorded a significant increase in muscle hypertrophy in the elderly subjects of the study.

Figure 1: In their 2011 study, Trappe et al. observed significant (and in relative terms identical) increases in skeletal muscle hypertrophy when they examined the influence of acetaminophen (no NSAID) or ibuprofen (NSAID) consumption on muscle mass and strength during 12 wk of knee extensor progressive resistance exercise training in older adults.

You probably already noticed that I've italicized all attributes that describe the age of the subjects in my previous elaborations... well, that's not without reason: as pointed out in previous articles on NSAIDs the 2016 study by Mackey seems to be the exception to a rule that says "If you see benefits, you'll see them in older subjects".

What does the latest study on hypertrophy tell us?

If the previously phrased hypothesis (old = benefits, young = detriments) holds true, the result of the most recent investigation into the effects of NSAIDs on skeletal muscle hypertrophy which was conducted by Mats Lilja and colleagues from the Karolinska Institutet and the Swedish School of Sport and Health Sciences, in young, healthy men and women (aged 18-35 years) should yield a null or a negative result - and that's indeed what you can see in Figure 2.

Figure 2: The latest study by Lilja et al. observed a significant negative effect of high dose ibuprofen on hypertrophy.

When the scientists measured their subjects' muscle volume at the end of the 8-week training period, over the course of which subjects had ...

• consumed either ibuprofen (IBU; 1200 mg; n=15 - consumed in form of 3 separate 400mg doses at 8am, 2pm and 8pm) or a placebo, in this case acetylsalicylic acid aka aspirin (ASA; 75 mg; n=16 - consumed in the AM) at a dosage that was chosen low enough to assume that it won't mess with the study outcomes (if it did, it would only diminish the inter-group difference, so even if it did, the results of the study imply that NSAIDs impair muscle gains in young, healthy individuals), daily, and ...
• performed 20 leg workouts consisting of 4 × 7 maximal repetitions on a flywheel device (2 min rest) with one leg and 4 × 8–12 repetitions to failure a "weight stack" machine, of which I assume it was a leg extension device, with the other leg,

the scientists found similar increases in m. quadriceps volume with the flywheel and the leg-extension machine. What did differ, however, were the gains in the ASA = control and the treatment = IBU group: averaged across legs, the ASA (7.5%) group saw a significantly greater increase in muscle volume than the IBU (3.7%, group difference 34 cm³; P=0.029) group.

With a sign. lower dosing (1x400mg IBU only on workout days) Krentz et al. (2008) didn't observe ill effects on gains/strength in a six-week 5d/wk biceps training study.

Dosing matters - probably, only high dose IBU (more than 400mg/d) is detrimental: The results of the study at hand conflict with the observations Krentz et al.'s (2008) made in a counter-balanced, double-blind study in which they treated 12 men and 6 women, who participated in a standardized biceps training program five days a week (alternating left and right biceps) for 2x 6 weeks, with only 400 mg/d of ibuprofen on workout days. If you scrutinize the data in the figure to the left you will see that there was no effect strength or size and a significant effect on muscle soreness in week 2.

That's interesting because the subjects' strength gains didn't differ to the same extent. In fact, the leg extensions triggered (within the statistical margin of error) identical strength increases of 11-20% in both groups. The strength gains in response to the flywheel exercise, which allows for maximal voluntary force to be produced from the very first repetition, on the other hand, were "generally greater (interaction effects P<0.05) for ASA compared with IBU" (Lilja 2017).

A difference in training volume was observed neither in the study at hand nor in previous studies (where it was tested) - including those in older subjects that showed significant beneficial effects of NSAIDs on skeletal muscle hypertrophy such as Trappe et al. 2011 and 2016.

What's / what are the mechanism(s)? 

The problem about identifying the underlying mechanisms is that Lilja et al.'s extensive molecular analyses found only one statistically significant inter-group difference that could potentially explain the previously described detrimental effects of IBU on size and, to a lesser extent, strength gains: the sign. reduced mRNA expressions of IL-6 (P<0.0001) in response to high dose ibuprofen treatment.

Figure 3: Changes in IL-6 (left), COX1, COX2, PGF2-alpha, and p70S6K mRNA/protein expression (Lilja 2017).

That's a problem because it implies that the usual suspects, COX, prostaglandins, and the "protein synthesis trigger protein" p70S6K (all didn't change in the study at hand) cannot be blamed for the NSAID-induced reduction in skeletal muscle hypertrophy. In other words: it's (a) neither an inhibition of the pro-anabolic effects of PGF2α scientists as it has been observed repeatedly in the petri dish nor the previously observed in vivo reduction of p70S6K (downstream of mTOR) in the early hours following acute resistance exercise that would blunt the protein synthetic response.

There's clearly need for future research: While the hormesis theory seems to explain the fundamental difference between the hypertrophy response of young and aged muscle upon NSAID-and acetaminophen-administration (the non-NSAID painkiller has also been shown to suppress the age-induced increase in ROS | Kakarla 2010) in the previously referenced studies, it is necessary to confirm that its predictions hold true in overtrained subjects or people who suffer from diseases that result in chronic inflammation. At least the latter should benefit from NSAIDs, as well.

While Lilja et al. speculate that they may have missed relevant signaling proteins or potential effects on satellite cells (note: a previous study shows that IBU expedites satellite cell recruitment, so that's very unlikely), I believe it's better to focus on the previously mentioned reduction in IL-6 - a reduction I would like to interpret as evidence of an overall reduced inflammatory/stress response, which could (a) impair the hormetic response to exercise in young individuals and thus explain the reduced hypertrophy in the study at hand (see Figure 2, 'NSAIDs in young individual'), and (2) reduce the already chronically elevated levels of of inflammation in aged muscles (Roubenoff 2003) to a tolerable level within the adaptation zone (see Figure 4, 'NSAIDs in old individuals') and could thus explain the increased hypertrophy Trappe et al. (2011) observed in their study in older individuals.

Figure 4: Illustration of the ways inflammation may trigger both, adaptation (hypertrophy and strength gains) and failed adaptation (catabolism and sarcopenia), depending on whether and to which degree it hits or misses the organism and age-dependent optimal degree of inflammation. This theory can explain why reducing the inflammatory load with NSAIDs will (1) reduce the gains in young individuals, who will end up with too little inflammation, and (2) improve it in elderly individuals, by reducing the degree of age-related chronic inflammation and bringing them back to the adaptation zone.

If this hypothesis is correct, an allegedly simplistic model of the interaction of NSAIDs with exercise-induced strength and size gains would describe them as tools that may hinder (young and healthy) or help (old or sick) you achieve "optimal" = hormetic levels of inflammation.

The hormesis theory can explain why young, healthy individuals see reduced, while older individuals see increased gains on high doses of NSAIDs - that doesn't mean, however, that it's indeed accurate. Further studies to confirm the hypothesis that the effects of NSAIDs are mere results of their modulatory effect on baseline + exercise-induced inflammation are necessary.

Bottom line: The study at hand adds to the evidence that NSAIDs - at least at high doses, bordering the maximal allowable OTC dosage - will impair the beneficial effects of exercise on muscle size and, albeit to a lesser extent, strength. This is something they seem to have in common with high doses of ROS-scavenging antioxidants like Vitamin C + E, of which previous studies have shown that they can blunt the beneficial metabolic (insulin sensitivity) and training (hypertrophy) effects of exercise.

Even though the study at hand did not measure the concentration of reactive oxygen specimen (ROS), we know that NSAIDs in general, and IBU in particular, can reduce the formation of ROS in response to exercise (Pizza 1999). Furthermore, ROS has been shown to directly stimulate the release of IL-6 (Kosmidou 2002), of which we do know that it was significantly reduced with IBU in Lilja's most recent study.

Accordingly it seems logical to assume that a reduced ROS response is responsible for the reduced hypertrophy and strength adaptation - two auxiliary, but still important features of optimal health of which Ristow and Schmeisser (2014), in turn, have long been arguing that it has an inverse-U-shaped relationship with ROS / inflammatory processes as I've sketched it in Figure 4.

Warning: Do not take NSAIDs day in, day out, as if they were creatine. While the latter is often falsely portrayed as "dangerous steroid" in the media, the sides of aspirin, ibuprofen and co are hardly talked about and that despite the fact that they can, when taken chronically, severely damage the stomach lining, hurt the kidney, cause CNS-related side effects and allergies - in particular if they are taken at high dosages, as they are needed for the beneficial effects that were observed in the elderly. Short-term, i.e. to acutely treat pain (10 days or less), they do yet have a better safety profile than some non-evidence websites may try to tell you (Aminoshariae 2016).

In short: While young people risk ending up too far on the left-hand side of the "optimal ROS concentration" / "optimal level of inflammation" (Figure 4, green) when they consume high doses of NSAIDs on a daily basis (lower doses and less frequent administration may have correspondingly less pronounced effects), older people may benefit from the ability of NSAIDs to reduce the age-induced increase in inflammation (Figure 4, orange) and bring the inflammation levels closer to the dashed green line that represents the optimal degree of inflammation in Figure 4... ah, obviously this is just a hypothesis; unlike the differential effects in young and old subjects, by the way | Comment!

References:

• Aminoshariae, Anita, James C. Kulild, and Mark Donaldson. "Short-term use of nonsteroidal anti-inflammatory drugs and adverse effects: an updated systematic review." The Journal of the American Dental Association 147.2 (2016): 98-110.
• Diaz, Arturo, John Varga, and Sergio A. Jimenez. "Transforming growth factor-beta stimulation of lung fibroblast prostaglandin E2 production." Journal of Biological Chemistry 264.20 (1989): 11554-11557.
• Haddad, Fadia, et al. "IL-6-induced skeletal muscle atrophy." Journal of applied physiology 98.3 (2005): 911-917.
• Kakarla, Sunil K., et al. "Chronic acetaminophen attenuates age-associated increases in cardiac ROS and apoptosis in the Fischer Brown Norway rat." Basic research in cardiology 105.4 (2010): 535-544.
• Kosmidou, Ioanna, et al. "Production of interleukin-6 by skeletal myotubes: role of reactive oxygen species." American journal of respiratory cell and molecular biology 26.5 (2002): 587-593.
• Krentz, Joel R., et al. "The effects of ibuprofen on muscle hypertrophy, strength, and soreness during resistance training." Applied Physiology, Nutrition, and Metabolism 33.3 (2008): 470-475.
• Lilja, Mats, et al. "High‐doses of anti‐inflammatory drugs compromise muscle strength and hypertrophic adaptations to resistance training in young adults." Acta Physiologica (2017).
• Mackey, Abigail L., et al. "Activation of satellite cells and the regeneration of human skeletal muscle are expedited by ingestion of nonsteroidal anti-inflammatory medication." The FASEB Journal (2016): fj-201500198R.
• Pizza, F. X., et al. "Anti-inflammatory doses of ibuprofen: effect on neutrophils and exercise-induced muscle injury." International journal of sports medicine 20.02 (1999): 98-102.
• Ristow, Michael, and Kathrin Schmeisser. "Mitohormesis: promoting health and lifespan by increased levels of reactive oxygen species (ROS)." Dose-Response 12.2 (2014): dose-response.
• Roubenoff, Ronenn. "Catabolism of aging: is it an inflammatory process?." Current Opinion in Clinical Nutrition & Metabolic Care 6.3 (2003): 295-299.
• Steinbacher, Peter, and Peter Eckl. "Impact of oxidative stress on exercising skeletal muscle." Biomolecules 5.2 (2015): 356-377.
• Trappe, Todd A., et al. "Effect of ibuprofen and acetaminophen on postexercise muscle protein synthesis." American Journal of Physiology-Endocrinology and Metabolism 282.3 (2002): E551-E556.
• Trappe, Todd A., et al. "Influence of acetaminophen and ibuprofen on skeletal muscle adaptations to resistance exercise in older adults." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 300.3 (2011): R655-R662.
• Trappe, Todd A., and Sophia Z. Liu. "Effects of prostaglandins and COX-inhibiting drugs on skeletal muscle adaptations to exercise." Journal of Applied Physiology 115.6 (2013): 909-919.
• Trappe, Todd A., et al. "COX Inhibitor Influence on Skeletal Muscle Fiber Size and Metabolic Adaptations to Resistance Exercise in Older Adults." J Gerontol A Biol Sci Med Sci (2016): Advance Access publication January 27, 2016.

Each +30 Min/d of Physical Activity Reduce HbA1c by 11%, Protein + CHO Maintain Bone Mass, Overlooked Benefits of BFR, New Marker of Overtraining - Jan '17 Science Update

  This is what the Jan '17 Science Update has to offer? -11% HbA1c reduction per 30 minutes activity, new benefits of blood flow restricted tr., the bone protective effect of immediate post-workout whey plus carb ingestion, and a new overtraining gauge...

It's almost, February... almost and that's why today's SuppVersity article still qualifies as a January '17 research update. One that is based on the latest (ahead of print) papers from the peer-reviewed journal "Medicine & Science in Sports & Exercise" - papers about the large impact of short bouts of moderate-to-vigorous physical activity (MVPA) on the messed up glucose management of people with an increased T2DM risk, the bone-preserving effects of a mix of whey and dextrose and how this effect depends on timing, the belated and thus overlooked beneficial effects of blood flow restriction on muscular rapid force development and, last but not least, a potential new marker of overreaching and -training that could also explain the dichotomous role of IL-6 in the adaptive and maladaptive response to exercise.

Learn more about blood flow restriction at the SuppVersity

BFR for VO2 & Strength Gains

Using BFR in Periodization

BFR Precondi-tioning = Useless

Benefits of Cuffs After sets?!

No Extra-Gains W/ BFR vs. HIT

Hormonal Re-sponse to BFR

• Scientists find new marker of overreaching and potentially -training: You know that exercise will increase the levels of the allegedly "bad" cytokine IL-6. Now, as a SuppVersity reader, you will yet also know that this "cytokine" is, in fact, a "myokine" if it is released in response to muscle contractions and that it appears to figure in the hormetic response to exercise stress... or, in other words, without it, you're not going to get the adaptational response in form of strength and size gains you're training for. With that being said, studies also show that significantly elevated levels of IL-6 can also occur with overtraining and are - in this situation - a sign of dysfunctional adaptation.
  
  Recent research does now suggest that the "dichotomous nature of IL-6 signalling appears to be determined by the respective concentration of its receptors (both membrane-bound (IL-6R) and soluble (sIL-6R) forms)" (Cullen. 2017) - measuring these concentrations could thus provide important information about whether the circulating IL-6 is going to trigger a hormetic response or not. Accordingly, Cullen et al. conducted a study that investigated the response of sIL-6R to long-term training, and the relationship between sIL-6R, self-reported measures of wellbeing, and upper respiratory illness symptoms (URS) in highly-trained endurance athletes.
  

  

  Figure 1: Unlike cortisol, which has a long history as a suspected, but rarely useful overtraining gauge, sIL-6R doesn't have a circadian rhythm (see explanation in green box). This doesn't mean it's an accurate marker of overtraining, but it does mean that it is less complicated and more convenient to use, because with overtraining the circadian rhythm can be so messed up that simply measuring at the same time won't suffice to get comparable and thus useful results to gauge your training status.

  Their results are quite conclusive: Firstly, they confirmed that sIL-6R is responsive to prolonged periods of exercise training. And second- and more importantly, the subjects' sIL-6R levels varied according to the individual training volume and could be linked to common symptoms of overreaching such as high levels of stress, and/or depressed mood.
  
  This is obviously not enough to use sIL-6R as an overtraining gauge. With future studies that determine the level of sIL-6R in overreaching and overtraining athletes, it may thus be possible to distinguish between these states (and regular training) and to use this information to optimize athletes and gymrats workout routines. 
• Rapid Force Capacity (RFC) increases sign. with blood flow restriction, but study shows: Adaptation takes time: This observation Nielsen, et al. (2017) made in their recent study is an important one, because it implies that previous studies on the effects of blood flow restriction + low-intensity training may simply have missed the beneficial effects when they measured (just as Nielsen, et al. did it, too), the adaptational response only 5 days after having subjects participate in a series of standardized workouts.
  
  In the study at hand, this series constituted of twenty-three training sessions which were performed within 19 days. In all 10 male subjects (22.8+/-2.3 years) who performed four sets of knee extensor exercise (20%1RM) to concentric failure during concurrent BFR of the thigh (100mmHg), and the eight work-matched controls (21.9+/-3.0 years) who trained without BFR (CON), the scientists tested the maximal slow and fast knee joint velocity muscle strength and rapid force capacity (e.g. RTD) as well as evoked twitch contractile parameters before and after the study.
  

  

  Figure 2: Changes in rate of force development (left) and mean muscle fibre area (right | Nielsen. 2017).

  Now, that's nothing new. What was new, however, is that they tested before (Pre) and 5 and 12 days after training (Post5, Post12). In conjunction with the data from the biopsies, Nielsen et al. were thus able to detect the improved rate of torque development for the first time. The sign. difference in muscle fiber area (Figure 2, right), on the other hand, is - interesting as it may be - no news: after all, we're comparing light load with BFR to light load w/out BFR and not, as many other studies did, light load BFR to regular high load training, where time and again the regular training group saw the greater muscle increases.
• Each extra 30 minutes of daily moderate to vigorous physical activity improve HbA1c of subjects at increased T2DM risk by 11%: MVPA aka "moderate to vigorous physical activity" is the buzzword of the fitness tracker generation. Now, a three-year study confirms what the medals your fitness tracker software will award to you already suggested: each minute spend moving at moderate to vigorous intensity is an investment into your health and well-being.
  
  

  

  How Accurate Are Activity Trackers? EE Data From Omron, Fitbit, Jawbone & Other Devices Reveals 10% Error & More | read the full SV article

  The above is the result of a recent study that correlated longitudinal (three-year follow-up) activity tracker data with changes of the long-term glucose marker HbA1c in a sample of 489 men and women at high risk of developing type II diabetes, participants (mean age 64.2 +/- 7.3 years, BMI 31.7 +/- 5.1, 63.4% male). And it's a result based on which the authors, Mathew McCarthy, and colleagues, rightly conclude that "[i]ncreases in MVPA and body weight were associated with a reduction and increase in HbA1c respectively, particularly in those with dysglycemia" (McCarthy. 2017).
• Immediate Protein + CHO post-workout nutrition protect your bone from the bone resorption in the hours after exhaustive running: Next to its important result, there are two things which make a recent study by Rebecca Townsend et al. particularly interesting. Firstly: The subjects were young, healthy men, not post-menopausal women as in so many other bone health studies; and second- and not less importantly, the study tested both the efficacy of a mix of 1.5g/kg dextrose + 0.5g/kg whey as a means to reduce bone resorption (=calcium leeching) markers and the effects of timing.
  

  

  Figure 3: Overview of the study design, note that active treatment or PLA were administered at three different time points with two servings of placebo ensuring that the subjects could not differentiate between the immediate supplementation, the 2h-post and 4h-post supplementation trial (Townsend. 2017).

  And guess what. The study, in the course of which the dextrose + whey drinks were administered either before or after a placebo drink immediately or 2h after the run (see Figure 3) did not just confirm that the nutrient mix can ameliorate and shorten the exercise-induced (75% VO2Max run to exhaustion) increase in the bone resorption markers β-CTX and P1NP, it also found that this effect is time-dependent with the administration of the dextrose + whey mix right after the workout having more beneficial effects than taking it 2h post. With the immediate consumption reducing the levels below pre-exercise levels (-22% to -61%) within 1h, while it remained elevated with the placebo drink and/or in the DF group in which the supplement was consumed 2h after the workout. Now all that could well be a mere time-shift in the bone anabolic response. The scientists' observation that "[t]he overall β-CTX response was significantly lower in the IF trial than the DF trial (P=0.019, d=0.37) and the PLA trial (P≤0.001, d=0.84)" (Townsend. 2017) does however clearly suggest a definite benefit of immediate (IF) vs. postponed (DF and PLA) nutrient consumption after exhaustive workouts.
  
  In this context, however, it is important to realize that that, eventually, i.e. 3-4h after the run, the level of β-CTX decreased to similar below pre-test levels in all groups. Practically speaking this means that the net effect of a single session of exhaustive exercise on the young men's bone was almost certainly positive, irrespective of whether and when they ingested the supplement.

What's the take away of the studies in this Science Update: For me personally, the most important lesson comes from the MVPA study by McCarthy et al. (2017). A mere 30 minutes of "exercise" (even fast walking would qualify) is after all an easily manageable workload of that will contribute to statistically and, more importantly, clinically significant improvements in blood glucose management.

Drop the weights, grab the shake! Timing matters for advanced trainees.

Sort of surprising was the time-dependence of the beneficial effects of a dextrose + whey mix on bone resorption after exhaustive running in young male subjects. As I hinted at in the discussion of the study, however, we got to be careful not to mistake a timeshift in the response for an actual improvement.

Imho, future (best longitudinal studies) should investigate the net effect on bone mass to avoid a similar confusion as we've had them for protein supplements of which the majority of studies refutes that their ingestion in the immediate vicinity of the workout would improve your gains.

Last but not least, there's Nielsen's BFR study, which doesn't just prove another hitherto overlooked benefit of blood flow restricted low-intensity training, but also constitutes a lesson in study design, which reminds us that the timing of a retest will often determine if you find an effect or not. Apropos timing, while the latter may matter less for sIL-6R data than it does for cortisol, there's still a lot of research necessary to confirm the validity of this new marker of overreaching and -training and develop reliable tests for athletes and gymrats | Comment on Facebook!

References:

• Cullen, Tom; Thomas, Andrew W.; Webb, Richard; Phillips, Thom; Hughes, Michael G. "sIL-6R Is Related to Weekly Training Mileage and Psychological Well-being in Athletes." Medicine & Science in Sports & Exercise: Post Acceptance: January 24, 2017.
• McCarthy, Matthew; Edwardson, Charlotte L; Davies, Melanie J; Henson, Joseph; Gray, Laura; Khunti, Kamlesh; Yates, Thomas. "Change in Sedentary Time, Physical Activity, Bodyweight, and Hba1c in High-Risk Adults." Medicine & Science in Sports & Exercise: Post Acceptance: January 24, 2017.
• Nielsen, Jakob Lindberg; Frandsen, Ulrik; Prokhorova, Tatyana; Bech, Rune Dueholm; Nygaard, Tobias; Suetta, Charlotte; Aagaard, Per. "Delayed Effect of Blood-Flow-Restricted Resistance Training on Rapid Force Capacity." Medicine & Science in Sports & Exercise: Post Acceptance: January 23, 2017. 
• Townsend, Rebecca; Elliott-Sale, Kirsty J.; Currell, Kevin; Tang, Jonathan; Fraser, William D.; Sale, Craig. "The Effect of Postexercise Carbohydrate and Protein Ingestion on Bone Metabolism." Medicine & Science in Sports & Exercise: Post Acceptance: January 24, 2017.

Overtrained or in the Zone? Tests & Analyses of Samples of Athletes' Saliva Shall Help Determine Objective Criteria

Could something as simple as a saliva test tell you if you or your clients are overtraining? I mean, common sense would dictate that cortisol, free T and IL-6 should tell us something.

Salivary testosterone, cortisol, and interleukin-6, those are the three parameters Travis Anderson and colleagues had on their list of candidates when they conducted their latest study at the University of North Carolina (Anderson. 2016).

As you will remember from previous articles I wrote about overtraining. The only decently reliable method of seeing it coming is to assess you heart rate variability. On the other hand, athletes who are complaining of general fatigue and decreasing performances in the latter phase of their overtraining, when the symptoms become often almost unbearable, will also show high cortisol, low free testosterone and increased IL-6 levels.

If you want to mess with your cortisol rhythm overtraining is exactly what you "need"!

Heart Rate Variability (HRV)

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It is thus only logical that the scientists assumed that it would be possible to evaluate the (overtraining) response of 20 moderate-to-highly trained young men to a standardized 6-week pre-season workout by the means of the said three parameters.

For this purpose, each subject was assessed at six separate sessions, next to their body composition, the scientists also measured the subjects' individual Recovery-Stress by the means of the standardized Recovery-Stress Questionnaire. In conjunction with the orally administered hormone / cytokine tests (always at 15:00-17:00 h) and the independently recorded training intensities and volumes (that was done by the researchers, not the subjects) on the bench, the back squat and the Olympic-style clean (+ auxiliary movements, see Table 1 | total session length including warm-up 45-60 minutes) these measurements were the basis for the scientists analysis.

Table 1: Overview of the primary and auxiliary exercises in the std. RT protocol (Anderson. 2016).

To make the subjects more overtraining-prone, the scientists kept gradually increasing the training load and began adding in conditioning runs to the workouts from week two on. The latter were done immediately after the RT workouts and consisted of 100 or 300m runs, of which the latter were replaced in week five with a speed/agility circuit that lasted another whopping 45 minutes.

Figure 1: Cortisol, IL-6 and free testosterone (left axes) and body weight (blue, right axis) development (Anderson. 2016).

As you may see with some surprise, the subjects' weight knew only one direction. Unfortunately, the body fat and lean muscle data was either only measured at baseline or simply omitted from the respective table, which holds nothing but the weight information.

Since the subjects' performance on all the prime movers increased significantly, though, we can assume that at least some of these gains were muscle - and that in spite of the significant reduction of the free testosterone / cortisol ratio and the skyrocketing IL-6 levels.

Table 2: REST-Q score by affective category (Anderson. 2016); * denotes sign. difference from baseline (p < 0.05); values for the score range from 1 = low anger, depression, etc. to 5 = high anger, depression, etc.

For the latter, it is, by the way, easy to see that the thing that "hurt" the trainees the most was the late addition of the agility work (another 45 minutes of intense aerobic workouts | -20% free T, +110% cortisol, +600% IL-6 |  note: this is in line with previous studies showing that aerobic exercise is more likely to result in overtraining than anaerobic training). Strength training alone (week 1) and combined with the sprints (weeks 2-4), on the other hand, didn't affect the alleged anabolism gauge, the testosterone / cortisol ratio, significantly.

Based on both the accepted physiological (weight, performance) and psychological (REST-Q) the subjects were, as the authors rightly point out "not symptomatic of overtraining". A conclusion that leaves us with the question...

No overtraining and still sign. markers of overtraining in the saliva? As the authors point out, there's little doubt (based on previous studies) that their workout routines should have brought the subjects - even though they were experienced weight with the performance of elite American Football athletes - to the verge of overtraining. Moreover, the hormonal changes and sign. cytokine increases in weeks 5-6, clearly indicate that the exercise regimen was taxing.

Hormonal Response to Exercise, Revisited: A Consequence, not a Determinant of Your Mood, Effort & Performance | more

The fact that the typical signs of overtraining still didn't occur (unless you count the psychological effects, which appear to be generally emotionally suppressive as signi-ficant symptoms of overtraining), is difficult to interpret. Anderson et al., however, still believe that they were on the right track. At least with IL-6, of which previous studies such as Robson-Ansley (2007) indicate(d) that it, or rather, the overall cytokine response will be sign. elevated in overtrained athletes, the scientists still believe that they've backed the right horse - albeit without knowing the magic numbers, i.e. how much does IL-6 end up over baseline to serve as a viable predictor of overtraining. Testosterone and cortisol, on the other hand, turn out to be rather useless alleged markers of anabolism and I would love if the bros would finally acknowledge that | Comment!

References:

• Anderson, Travis, Et Al. "Changes in Resting Salivary Testosterone, Cortisol and Interleukin-6 as Biomarkers of Overtraining." Sport And Health (2016): 2.
• Robson-Ansley, Paula J., Andrew Blannin, and Michael Gleeson. "Elevated plasma interleukin-6 levels in trained male triathletes following an acute period of intense interval training." European journal of applied physiology 99.4 (2007): 353-360.

DOMS - Delayed Onset Muscle Soreness: No Pain, No Gain? Is DOMS Necessary to Build Muscle?

Are stretch, tear and DOMS what makes concentration curls an effective biceps builder? Can we use the soreness as a gauge for the efficiency of our training?

An article by Alex Leaf (CPT)

In last Sunday's first installment of our discussion on delayed onset muscle soreness (DOMS), we looked at what causes DOMS as well as treatment methods and supplements for relieving its symptoms. This led us to today’s big question:  Is DOMS necessary for muscular adaptations to exercise? No pain, no gain, right?

Before we can discern whether DOMS may benefit muscle growth, we need to look at what muscle growth is and what causes it, so that we may see if DOMS is in fact a piece of the puzzle.

Taking a Second Look at Muscular Hypertrophy

During muscle fiber hypertrophy, contractile proteins proliferate, and the muscle fibers enlarge to support this growth (Vierck. 2000). While there are many factors regulating this process, from gene expression to hormones and other growth factors, the two necessities for hypertrophy are some form of increased muscular tension, damage, or stress (Goldberg. 1975), and a positive net protein synthetic response with adequate energy availability (Miyazaki & Esser. 2009).

Beware of too much "good" ROS scavengers. NAC will effectively block the recruitment of new satellite cells | learn more

Through exercise, the former is accomplished and paves the way for the repair processes that require the latter to occur. In other words, without a need to increase muscle size and strength, hypertrophy will not happen. Likewise, even if there is a need, without proper nourishment hypertrophy simply cannot happen.

So with exercise being the trigger and nutrition the ammo, what is left to play the gun? Skeletal muscle does not undergo significant cell replacement once mature (Chargé & Rudnicki. 2004), and thus a repair mechanism for any microtrauma is essential.

This medic is the satellite cell, a type of stem cell found only within mature muscle tissue. After microtrauma, satellite cells activate, proliferate, and ultimately fuse to one another and existing muscle fibers to form new myofibrils (Toigo & Boutellier. 2006).

All parts of this regenerative weapon rely on one another. The satellite cells mediate the hypertrophic process, but without a need (the exercise) they will not start, and without the nourishment (energy availability) they cannot function. All else that impacts the accuracy of the gun can be thought of as the factors influencing satellite cell efficiency. Hormones could be wind speed, gene expression the user’s accuracy, and perhaps DOMS is the distance to the target (or not ;-).

Muscle Damage

Suggested Read: "Understanding Muscle Hypertrophy - Study Sheds More Light on Process of Satellite Cell Recruitment" | read more

The hypertrophy process begins with microtrauma and an ensuing accumulation of calcium within the damaged muscles (Sorichter. 1999). This is shortly followed by a rapid stimulation of satellite cells via hepatocyte growth factor (HGF) and nitric oxide (NO), both of which rely on the changes in calcium levels within the muscle tissue (Tatsumi, 2010), and satellite cells may even be activated by the calcium flux itself (Hara, et al., 2012).

Furthermore, HGF secretion is proportional to the extent of the muscle damage (Tatsumi, et al., 1998). Therefore, it seems plausible that greater muscle damage leads to greater satellite cell recruitment, especially since the activation of satellite cells is exclusive to the fiber that has become damaged and satellite cells of one muscle fiber will not respond to injury of adjacent muscle fibers (Chargé & Rudnicki, 2004).

As it just so happens, DOMS inducing eccentric contractions disrupts muscle integrity more so than concentric or isometric contractions (Faulkner, 1993).  What may seem odd, however, is that EMG activity has been shown to be lower in eccentric loading compared to concentric loading (Westing. 1991), suggesting less fiber recruitment.

Part I	Part II

Just a reminder: This is a twp-part series on Delayed Onset Muscle Soreness. You can switch back and forth between part I "What Is DOMS & How Can It Be Managed? Science, Strategies, Supplements" & part II "No Pain, No Gain? Is DOMS Necessary to Build Muscle?" by clicking on the images to the left.

In their study, (Westing. 1991) measured the torque and EMG activity of the quadriceps muscle at different movement speeds between a knee angle of 30° and 70° on the leg extension for both the concentric and eccentric portions of the exercise. The participants were 14 highly trained athletes that were accustomed to performing maximally during training. As you can see in Figure 1, average torque of the eccentric activity was significantly greater than that of the concentric activity across all movement speeds, but the EMG activity was significantly lower and continued to lower as movement speed increased. The fact that the EMG values of the eccentric activity are below 100% shows that the activation during the concentric phase was higher, even at lower speeds and despite “maximal” effort.

Figure 1: Exemplary data from Westing (1991) showing the mean and SEM torque- and EMG-velocity relationships during the eccentric (open symbols) and concentric (filled symbols) tests.

Actually, this gives support the idea that eccentric exercise is more damaging. It is hypothesized that neural drive to the working muscle is reduced under conditions of extreme muscle tension (i.e. less EMG but more torque) to protect the muscle from injury that could result if it became fully activated (Moore. 1984). Regardless, single bouts of eccentric contractions have been shown to increase the satellite cell content and activation status in Type II muscle fibers (Cermak. 2013).

Inflammation - Friend or Foe of Muscle Growth?

Learn more about eccentric training and satellite cell recruitment and how even fat cells can become muscle.

Once the damage has been done, the repair process may begin. As mentioned in "DOMS - Delayed Onset Muscle Soreness: What Is DOMS & How Can It Be Managed? Science, Strategies, Supplements" (read article), an acute inflammatory response follows microtrauma.

This is also the time that DOMS normally makes it move. During this time, the damaged muscle releases several cytokines, while white blood cells such as neutrophils and macrophages invade the damaged tissue and release several growth factors, all of which may regulate satellite cell activity (Toigo & Boutellier. 2006). Creatine kinase, for example, is a standard indirect measurement of muscle damage (Banfi. 2012).

As stated above, several cytokines and growth factors are involved in the anabolic response to muscle damaging exercise. The list is quite extensive but a few notable players are:

• The cytokine interleukin-6 (IL-6) appears to be an essential regulator of satellite cell mediated hypertrophy, and genetic loss of IL-6 blunts the hypertrophic response (Serrano, et al. 2008). There also appears to be a close association between cytokine concentrations and muscle damage (Pedersen, Ostrowski, et al. 1998), with (Bruunsgaard, et al. 1997) showing that IL-6 concentration is higher after eccentric cycling compared with concentric cycling.  Likewise, interleukin-15 (IL-15) is another highly anabolic player in the inflammatory response to muscle damage (Furmanczyk and Quinn 2003), and is elevated following resistance exercise but not treadmill running, suggesting a need for microtrauma in its stimulation (Pedersen, Akerström, et al. 2007).

• 

  Learn more about the different splice variants of IGF-1 and how they figure in the process of muscle hypertrophy and why systemic measures may mislead us.

  Insulin-like growth factor 1 (IGF-1) has also received much attention due to its ability to increase muscle mass via muscle protein and DNA augmentation (Chakravarthy, Davis and Booth 2000). These effects are at least in part attributed to the activation of satellite cells and increased protein synthesis within the muscle fibers (Barton-Davis, Shoturma and Sweeney 1999). And guess what? Damaging exercise increases IGF-1. A study by (Bamman, et al. 2001), for example, showed that eccentric exercise increased IGF-1 gene expression by 62% while decreasing inhibitory genes by 57%. Oh, and concentric exercise produced non-significant changes in the above markers, suggesting that it was indeed the structural damage responsible for the IGF-1 expression.
• Lastly, the aforementioned HGF acts as a chemo-attractant for satellite cells (Bischoff 1997), effectively stimulating satellite cells to migrate to the place of injury, where it then has a direct effect on satellite cell proliferation and differentiation (Vierck, et al. 2000). Oddly enough, abnormally elevated concentrations of HGF actually inhibit muscle regeneration via up-regulation of myostatin (Yamada, et al. 2010). Since HGF is secreted by regenerating muscles for the first three days following injury (Jennische, Ekberg and Matejka 1993), its accumulation could act as a regulatory “stop” mechanism that marks the end of muscle repair via satellite cells (Chazaud 2010).

A final indirect notion of the importance of DOMS is the idea that NSAIDs – a common treatment method – reduce the hypertrophic response. Recall that both NO and HGF are responsible for activating satellite cells in the early stages of the repair process. This process appears to be partially regulated by the cyclooxygenase (COX)-2 pathway, which releases various prostaglandins known to stimulate satellite cells (Bondesen, et al. 2004). The problem is that NSAIDs inhibit this pathway and thus may impair the hypertrophic response (Schoenfeld 2012). Indeed, studies have shown NSAID usage following eccentric exercise reduced satellite cell activity for up to eight days (Mikkelsen, et al. 2009).

Summary: Hypertrophy involves a complex array of anabolic and catabolic processes working in a downstream manner to favor protein synthesis over degradation. DOMS is not necessary,  may however present itself during the early stages of exercise. What is necessary is a mechanical overload of the muscle resulting in microtrauma. So train hard, train smart, and may the growth be with you.

So is DOMS necessary? DOMS can be thought of as a sign of muscle damage, but it is the damage itself and the subsequent inflammatory response that are responsible for hypertrophy. DOMS is actually a rather poor indicator of muscle damage and will not always reflect the magnitude of the damage (Nosaka, et al., 2002). Nor will it always be present.

Studies have shown that even a single bout of eccentric exercise reduces and may negate DOMS in subsequent bouts (Nosaka. 2001), and these effects persist for at least several weeks (Clarkson. 1992). This would explain why soreness is common in the beginning of a new routine full of unaccustomed damaging exercise, but fades as time progresses. And in fact Flann (2011) showed that using a three week acclimation protocol prior to beginning an eight week eccentrically loaded leg press protocol significantly reduced DOMS and markers of muscle damage compared to beginning the routine cold turkey.

References

• Bamman, M M, et al. "Mechanical load increases muscle IGF-I and androgen receptor mRNA concentrations in humans." American Journal of Physiology - Endocrinology and Metabolism 280, no. 3 (2001): E383-E390.
• Banfi, G, A Colombini, G Lombardi, and A Lubkowska. "Metabolic markers in sports medicine." Advances in Clinical Chemistry 56 (2012): 1-54.
• Barton-Davis, E R, D I Shoturma, and H L Sweeney. "Contribution of satellite cells to IGF-I induced hypertrophy of skeletal muscle." Acta Physiologica Scandinavica 167, no. 4 (1999): 301-305.
• Bischoff, R. "Chemotaxis of skeletal muscle satellite cells." Developmental Dynamics 208, no. 4 (1997): 505-515.
• Bondesen, B A, S T Mills, K M Kegley, and G K Pavlath. "The COX-2 pathway is essential during early stages of skeletal muscle regeneration." American Journal of Physiology - Cell Physiology 287, no. 2 (2004): C475-C483 .
• Bruunsgaard, H, H Galbo, J Halkjaer-Kristensen, T L Johansen, D A MacLean, and B K Pedersen. "Exercise-induced increase in serum interleukin-6 in humans is related to muscle damage." The Journal of Physiology 499, no. Pt 3 (1997): 833-841.
• Cermak, N M, et al. "Eccentric exercise increases satellite cell content in type II muscle fibers." Medicine and Science in Sports and Exercise 45, no. 2 (2013): 230-237.
• Chakravarthy, M V, B S Davis, and F W Booth. "IGF-I restores satellite cell proliferative potential in immobilized old skeletal muscle." Journal of Applied Physiology 89, no. 4 (2000): 1365-1379.
• Chargé, S B, and M A Rudnicki. "Cellular and molecular regulation of muscle regeneration." Physiological Reviews 84, no. 1 (2004): 209-238.
• Chazaud, B. "Dual effect of HGF on satellite/myogenic cell quiescence." American Journal of Physiology - Cell Physiology 298, no. 3 (2010): C448-C449.
• Clarkson, P M, K Nosaka, and B Braun. "Muscle function after exercise-induced muscle damage and rapid adaptation." Medicine and Science in Sports and Exercise 24, no. 5 (1992): 512-520.
• Faulkner, J A, S V Brooks, and J A Opiteck. "Injury to Skeletal Muscle Fibers During Contractions: Conditions of Occurrence and Prevention." Physical Therapy 73 (1993): 911-921.
• Flann, K L, P C LaStayo, D A McClain, M Hazel, and S L Lindstedt. "Muscle damage and muscle remodeling: no pain, no gain?" The Journal of Experimental Biology 214 (2011): 674-679.
• Furmanczyk, P, and L S Quinn. "Interleukin-15 increases myosin accretion in human skeletal myogenic cultures." Cell Biology International 27, no. 10 (2003): 845-851.
• Goldberg, A L, J D Etlinger, D F Goldspink, and C Jablecki. "Mechanism of work-induced hypertrophy of skeletal muscle." Medicine and Science in Sports 7, no. 3 (1975): 185-198.
• Hara, M, et al. "Calcium influx through a possible coupling of cation channels impacts skeletal muscle satellite cell activation in response to mechanical stretch." American Journal of Physiology - Cell Physiology 302, no. 12 (2012): C1741-C1750.
• Jennische, E, S Ekberg, and G L Matejka. "Expression of hepatocyte growth factor in growing and regenerating rat skeletal muscle." The American Journal of Physiology 265, no. 1 Pt 1 (1993): C122-C128.
• Mikkelsen, U R, et al. "Local NSAID infusion inhibits satellite cell proliferation in human skeletal muscle after eccentric exercise." Journal of Applied Physiology 107, no. 5 (2009): 1600-1611.
• Miyazaki, M, and K A Esser. "Cellular mechanisms regulating protein synthesis and skeletal muscle hypertrophy in animals." Journal of Applied Physiology 106, no. 4 (2009): 1367-1373.
• Moore, J C. "The Golgi tendon organ: a review and update." American Journal of Occupational Therapy 38, no. 4 (1984): 227-236.
• Nosaka, K, K Sakamoto, M Newton, and P Sacco. "The repeated bout effect of reduced-load eccentric exercise on elbow flexor muscle damage." European Journal of Applied Physiology 85, no. 1-2 (2001): 34-40.
• Nosaka, K, M Newton, and P Sacco. "Delayed-onset muscle soreness does not reflect the magnitude of eccentric exercise-induced muscle damage." Scandinavian Journal of Medicine & Science in Sports 12, no. 6 (2002): 337-346.
• Pedersen, B K, K Ostrowski, T Rohde, and H Bruunsgaard. "The cytokine response to strenuous exercise." Canadian Journal of Physiology and Pharmacology 76, no. 5 (1998): 505-511.
• Pedersen, B K, T C Akerström, A R Nielsen, and C P Fischer. "Role of myokines in exercise and metabolism." Journal of Applied Physiology, 2007: 1093-1098.
• Schoenfeld, B J. "Does exercise-induced muscle damage play a role in skeletal muscle hypertrophy?" Journal of Strength and Conditioning Research 26, no. 5 (2012): 1441-1453.
• Schoenfeld, B J. "The use of nonsteroidal anti-inflammatory drugs for exercise-induced muscle damage: implications for skeletal muscle development." Sports Medicine 42, no. 12 (2012): 1017-1028.
• Serrano, A L, B Baeza-Raja, E Perdiguero, M Jardí, and P Muñoz-Cánoves. "Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy." Cell Metabolism 7, no. 1 (2008): 33-44.
• Sorichter, S, B Puschendorf, and J Mair. "Skeletal muscle injury induced by eccentric muscle action: muscle proteins as markers of muscle fiber injury." Exercise Immunology Review 5 (1999): 5-21.
• Tatsumi, R. "Mechano-biology of skeletal muscle hypertrophy and regeneration: possible mechanism of stretch-induced activation of resident myogenic stem cells." Animal Science Journal 81, no. 1 (2010): 11-20.
• Tatsumi, R, J E Anderson, C J Nevoret, O Halevy, and R E Allen. "HGF/SF is present in normal adult skeletal muscle and is capable of activating satellite cells." Developmental Biology 194, no. 1 (1998): 114-128.
• Toigo, M, and U Boutellier. "New fundamental resistance exercise determinants of molecular and cellular muscle adaptations." European Journal of Applied Physiology 97, no. 6 (August 2006): 643-663.
• Vierck, J, et al. "Satellite Cell Regulation Following Myotrauma caused by Resitance Exercise." Cell Biology International 24, no. 5 (2000): 263-272.
• Westing, S H, A G Cresswell, and A Thorstensson. "Muscle activation during maximal voluntary eccentric and concentric knee extension." European Journal of Applied Physiology and Occupational Physiology 62, no. 2 (1991): 104-108.
• Yamada, M, et al. "High concentrations of HGF inhibit skeletal muscle satellite cell proliferation in vitro by inducing expression of myostatin: a possible mechanism for reestablishing satellite cell quiescence in vivo." American Journal of Physiology - Cell Physiology 298, no. 3 (2010): C465-C476.