Myostatin Limits Muscle Hypertrophy in Young, Physically Active Resistance Trainees on High, but Not Normal Protein Diet - Irrelevant Outlier or Crucial Revelation for Trainees?

Who says, resistance training and high protein diets make you bulky? The study at hand suggest they don't because after a couple of weeks your body will pull the myostatin break | img (c) fighterdiet.com

You're training like mad and consuming a ton of protein everyday and still don't see the results you deserve? Maybe increased myostatin levels are holding you back!?

While previous studies mostly suggested that the role of myostatin in the normal (muscle) growth response to exercise may have been overestimated, a recent study from the University of Padova,  the Italian Medicine and Fitness Federation, Euganea Medica, and the University of Palermo. Brings the "muscle-growth break" (high myostatin = slow muscle gains) back onto our radar. And that not just because researchers from said institutions observed a significant increase in myostatin in response to chronic resistance training, but rather because this response appears to have been triggered by high(er) protein intakes.

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If you have been reading SuppVersity articles for quite a while now, you may remember my previous post about how "Chronic Resistance Training Reduces the Anabolic Signaling in Response to Exercise - 12 Days of Detraining Restore It" (read more). The corresponding study by Ogasawara et al. (2013) was yet conducted on rodents. Therefore, the applicability of the results remains at least questionable.

In a more recent study with human subjects, Antonio Paoli and colleagues from Italy did yet observe a similar, but not identical effect. The researchers aim was to "investigate the influence of 2 months of resistance training (RT) and diets with different protein contents on plasma myostatin (MSTN), interleukin 1 beta (IL-1β), interleukin 6 (IL-6), tumor necrosis factor alpha (TNF-α), and insulin-like growth factor 1 (IGF-1).

Does an increase in protein intake increase myostatin, as well?

To this ends, they recruited 18 healthy, young, physically active volunteers who were then randomly divided in two groups; A high protein (HP) and normal protein (NP) groups. The diets contained 1.8 and 0.85 g of protein/kg body weight per day for the HP and NP diet, respectively.

In addition to the dietary intervention, all subjects were subjected to the same 8 weeks of standardized progressive resistance training. MSTN, IGF-1, IL-1β, IL-6, and TNF-α were analyzed before and after the first and the last training sessions. In addition, Paoli et al. measured the lean body mass, muscle mass, upper-limb muscle area, and strength.

Figure 1: Much to the surprise of the researchers, the muscle gains were identical, but the msucle gain reducing myostatin increase was significant only in the high protein group (Paoli. 2014)

Somewhat to the scientists surprise the plasma MSTN showed a significant increase (P<.001) after the last training in the HP group compared to both the normal protein (NP) group and the starting values. Surprisingly, these increases occurred in the absence of differences in IL-1β, IL-6, TNF-α, and strength and muscle mass or muscle area.

Protein blunts the exercise induced decrease in myostatin, but it increases the alleged myostatin blocker FLRG (Hulmi. 2008) - Result? A null or maybe even beneficial effect?

This is not an outlier study! Bad news, bros You cannot discuss the findings of the study at hand away. Previous studies by Hulmi (2008) found that the decrease in myostatin that would usually occur in response to resistance training in older male trainees was blunted, when the resistance training session was followed by the ingestion of 15g of whey protein. Needless to say that this does not necessarily mean that you'd gain less. In fact, the concomitant increase in folistatin related gene expression (FLRG), a gene which is thought of regulator off the myostatin inhibitor folistatin (Hill. 2002), may more then compensate the slight increase in myostatin (see Figure on the left) in the first 48h after a workout. If that's the same in the long run, will have to be tested in future studies.

If the muscle mass / area had been increased as well, it would have been easy to interpret the increase in myostatin as a reaction to an increase in muscle cell size and a corresponding increase in domain sizes. The way it is, though, it's difficult to explain the increase in myostatin and its correlate IGF-1 (correlate in this study, not in general).

Is this just a matter of domain sizes?

Figure 2: Domain sizes of EDL and soleus muscle fibers in wild-type control, myostatin negative and IGF1 over-expressing mice (data based on Qaisar. 2011)

As you will remember from previous articles, the latter would require the recruitment of additional muscle satellite cells that would form new myonuclei and thus help normalize the domain sizes and myostatin levels.

Without myostatin, the domain sizes would keep increasing and the muscle would become as huge, but dysfunctional as it does in myostatin negative mice (see Figure 2, red | not the similar increase in domain size in IGF-1(+) mice which underlines the role both myostatin and IGF-1 play when it comes to controlling domain sizes and facilitating "Getting Big Beyond Temporary Physiological Limits" | learn more)

The way it is, the observations Paoli et al. made in their most recent study remain, as the authors themselves call it "paradoxical" and could in fact "explain the substantial overlapping of MM [muscle mass] increases in the two groups", no one of you would have expected, right? Well, it's a pitty we don't have data on the level of follistatin related gene expression as it was measured in the Hulmi study (see red box) - if that did not increase, or only to a small extend, it's actually no wonder, both groups gained the same amount of muscle mass.

How intense is "intense enough"? The training program Roth reused in their 2003 study and which reduced the myostatin expression sign. consisted of five sets of high-volume (55 total repetitions), heavy-resistive exercise performed 3 days/wk. The resistance for each set was based on the subject’s 5RM. After performing a first set of five repetitions at 50% of the original 1RM for a warm-up, the subject performed a second set of five repetitions at the 5RM resistance after a 30-s rest period. The third set consisted of 10 repetitions, with the first four or five repetitions at the current 5RM value, then the resistance was lowered just enough to complete one or two more repetitions before the subject reached fatigue. The process was repeated until a total of 10, 15, and 20 repetitions were completed for the third, fourth, and fifth sets, respectively. The third, fourth, and fifth sets were preceded by rest periods lasting a minimum of 90, 150, and 180 s, respectively. This protocol demanded a near-maximal effort on every repetition throughout each set.

Do we need myostatin blockers to maximize our gains? As far as I know, no scientifically proven myostatin inhibitor is yet available as an OTC supplement. Luckily, previous research by Roth (2003) and Willoughby (2004) suggests that these products may not even be necessary. In 2003 Roth et al. write in a "short communication" (something similar to a "mini paper") that really heavy resistance training with maximal effort on each set can (at least temporarily) reduce the myostatin levels (see box to the right for information on the exact protocol) - an effect that is unfortunately reduced with aging and almost non-existant in aging women (old men -37%, old women -11%, young men -56%, young women -46% | Kim. 2005), but could be buffered by concomitant increases in folistatin-related gene (FLRG) expression, as it was observed by Willoughby in his 2004 study.

Figure 3: Serum folistatin related gene expression in response to 12 week high intensity resistance training vs. control (Willoughby. 2004)

The key to actually making the gains you could make due to the increase in protein availability, could thus simply be to train harder to either facilitate greater reductions in myostatin or promote long-term increases in its "buffer" FLRG, as they were observed by Willoughby (see Figure 3).

In the long run, this does yet entail the risk of severe overtraining, which should remind you of the periodization techniques and the interplay of phases of maximal and sub-maximal exercise intensity in 4-6 week cycles. You have no idea how that works? Well, I suggest you take a look at the overview of previous SuppVersity articles on periodization - specifically this one: "Periodization Techniques Revisited: Improved Strength & Size Gains W/ 12-Week Undulatory vs. Linear Periodization" | Comment on Facebook.

References:

• Hill, Jennifer J., et al. "The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum." Journal of Biological Chemistry 277.43 (2002): 40735-40741.
• Hulmi, Juha J., et al. "The effects of whey protein on myostatin and cell cycle-related gene expression responses to a single heavy resistance exercise bout in trained older men." European journal of applied physiology 102.2 (2008): 205-213.
• Paoli, et al. "Protein Supplementation Increases Postexercise Plasma Myostatin Concentration After 8 Weeks of Resistance Training in Young Physically Active Subjects." J Med Food. Aug 18 (2014). Epub ahead of print.
• Qaisar, Rizwan, et al. "Is functional hypertrophy and specific force coupled with the addition of myonuclei at the single muscle fiber level?." The FASEB Journal 26.3 (2012): 1077-1085.
• Roth, Stephen M., et al. "Ultrastructural muscle damage in young vs. older men after high-volume, heavy-resistance strength training." Journal of Applied Physiology 86.6 (1999): 1833-1840.
• Roth, Stephen M., et al. "Myostatin gene expression is reduced in humans with heavy-resistance strength training: a brief communication." Experimental Biology and Medicine 228.6 (2003): 706-709.
• Willoughby, Darryn S. "Effects of heavy resistance training on myostatin mRNA and protein expression." Medicine and science in sports and exercise 36.4 (2004): 574-582.