Hypertrophy - Supplements HMB-FA, ATP vs. 600mg of Testosterone, and Hyper-responders

Is it possible to gain large amounts of muscle mass and lean body mass in a relatively short period of time (5-12weeks)? Recent and controversial publications show tremendous increases in lean body mass in 12 weeks, which most find too good to be true, but such reports are not unprecedented in the literature.

HMB/aminoacid supplementation

In 2009 Kraemer et al. (1) examined the effects of an essential amino acid-based formula containing HMB on hormonal and muscle damage markers in response to 12 weeks of resistance exercise.

More precisely one group received an MA supplement containing 1.5 g of calcium HMB, 7 g of arginine, 7 g of glutamine, 3 g of taurine, and 5.824 g of dextrose, and another group received a supplement containing or an isocaloric, isonitrogenous control containing nonessential amino acids (10 g of glycine, 11.5 g of alanine, 1.5 g of glutamic acid, and 1.5 g of serine) as well as calcium citrate (200 mg of calcium).

Subjects were 17 healthy men recreationally active. Training consisted of a non-linear undulating periodization non-linear undulating periodization split into ‘‘light,’’ ‘‘moderate,’’ and ‘‘heavy’’ days. 

The exercise program stressed all major muscle groups and included the following exercises (or variations of) in each session: bench presses, squats, lunges, shoulder presses, arm curls, stiff-leg dead lifts, lat pull downs, seated rows, calf raises, and sit-ups.

Whole body composition was assessed by DEXA. After 12 weeks total and lean body mass increased and percent body fat decreased in both groups, with greater improvements in body composition potentiated by MA supplementation. Precise numbers were not given, but from the graphic it appears to be an increase of around 9kg of LBM and a decrease in fat percentage of 5% for the MA group.

Both groups showed increased circumferences of the biceps, thigh, and chest; however, no change in waist circumference occurred. Subjects in the MA group had greater thigh and chest circumference than the CON group after training.

The greater results for the MA group were likely to the “anticatabolic properties of its ingredients: exercise-induced proteolysis is reduced by HMB, arginine and glutamine”.

Trained subjects

In 2013 started a series of studies with impressive results in trained subjects from the same group of researchers at the University of Tampa by Wilson et al. (2,3,4). 

ATP supplementation

The first one (randomized, double-blind, placebo- and diet-controlled, parallel groups) examined the effects of 400 mg per day of oral adenosine-5-triphosphate (ATP) supplementation utilizing a long-term, periodized resistance-training program (RT) for 12 weeks (2). 

The training program was divided into three phases:
- Phase one consisted of a three times per week non-linear periodized RT program for weeks 18, modified from the previous study by Kraemer et al. (1).
- Phase two consisted of a two-week overreaching cycle during weeks 9 and 10. 
- Finally, phase three consisted of participants tapering for weeks 11 and 12. 

Two weeks prior to and throughout the study, participants were placed on a diet consisting of 25% protein, 50% carbohydrates, and 25% fat by a registered dietician who specialized in sport nutrition. Participants met as a group with the dietitian, and they were given individual meal plans two weeks prior to the onset of the study. Diet counseling was continued on an individual basis throughout the study.

Body composition (lean body mass, fat mass, and total mass) was determined by DEXA, and skeletal muscle hypertrophy was determined via the combined changes in ultrasonography-determined muscle thickness of the vastus lateralis (VL) and vastus intermedius (VI) muscles.

Lean body mass increased by 4kg and body fat percentage decreased by 3.5% after 12weeks (2). 

HMB-FA supplementation

The next study investigated the effects of 12 weeks of HMB free acid supplementation on muscle mass, strength, and power in resistance-trained individuals using the same resistance training program as before (3). 

They got the same deal as before: 25% protein, 50% carbohydrates, and 25% fat, individual meal plans and diet counseling was continued on an individual basis throughout the study. 

In addition they had this time an assessment of 3-day food records taken at the beginning, mid, and last week of the study that revealed that diets consisted of 22 % protein, 45 % carbohydrates, and 33 % fat, with no differences between groups. Compliance of supplementation was assessed by having the participants hand their empty packets to a researcher at the beginning of each training day. Compliance was over 98 % for supplementation.

Supplementation with HMB-FA resulted in a significant increase in body mass and LBM.

LBM increase was about 7.5kg and body fat decrease was about 5.4 kg.

Supplementation with HMB-FA also resulted in significantly greater quadriceps thickness compared to the placebo group.

By 4 weeks the HMB-FA group already had an advantage of +2.1kg LBM over the placebo group, and it kept going until the end.

If you look closely by 8 weeks the placebo group gained 2.9kg, it was possible that if it wasn’t for the overreaching cycle they would have kept making progress rather than decreasing their gains. 

Looking at the muscle damage data in the placebo group it was higher than the previous 8 weeks, and twice the muscle damage of the HMB-FA group during the overreaching cycle.

The increased muscle damage and the increased LBM loss suggests the over-reaching was too much for the placebo group, and that if they had followed the first phase until the end LBM would most likely continue to increase, again at 8 weeks it was 2.9kg.

HMB-FA/ATP supplementation

The latest study combined the effects of HMB-FA and ATP supplementation, with the same exercise program (4). 

Again, the same deal as before: 25% protein, 50% carbohydrates, and 25% fat, individual meal plans and diet counseling was continued on an individual basis throughout the study.

Lean body mass was increased by a combination of HMB-FA/ATP by 12.7% or by 8.5 kg, and fat percentage decreased by 8.5% in the HMB-FA/ATP supplemented group after 12weeks.

For the placebo group we can see the same trend as before, with subjects gaining apparently 4% LBM from the graph (2.8kg) after 8 weeks and then dropping 1.9% from that to apparently 3% or “2.1 kg” LBM after 12 weeks.

Similarly, fat percentage decreased by 2.4 and 8.5 % in the placebo and HMB-FA/ATP supplemented group, respectively.

600mg of Testosterone

Bhasin et al. did a series of studies investigating the effects exogenous Testosterone administration (5,6,7,8). Of particular interest is the first one from 1996 in which they had a group which also combined 600mg of Testosterone enanthate and training (5). The other groups either received testosterone alone with no training, placebo, or just training alone. All the other studies investigated only the administration with increasing doses of testosterone (no training).

Briefly, what is perfectly clear from this set of classical studies is that Testosterone alone with no training can produce significant increases in total body lean mass and hypertrophy of skeletal muscle, with a dose-response, meaning the more Testosterone the more lean mass gains. 

These were well-performed studies in which they:
- Suppressed endogenous Testosterone to isolate the effects;
- Measured total body lean mass by DEXA;
- Measured and observed an increase in Quadriceps and vastus lateralis muscle volumes and cross-sectional areas of type I and type II muscle fibers (7,8);
- Measured and observed an increase in myonuclear number and satellite cells (7);
- And even controlled for total body water increase (lean mass) vs. water retention to determine whether the apparent changes in fat free mass by DEXA scan and underwater weighing represented water retention. The increase did not represent water retention in excess of that associated with protein accretion (6).

These studies rustle some jimmies and induce discomfort and extreme dissonance in some people who won’t or can’t admit the effects attributed to Testosterone alone (even with exercise) and keep arguing it is all about their special training and diets, especially the ones who want to promote their services, but that’s for another article.

As noted before, one study combined 600mg of testosterone with training (5). The training consisted of a cycle of weight lifting at heavy intensity (90%RM), light intensity (70%RM), and medium intensity (80%RM) on three nonconsecutive days each week. The training was held constant at four sets with six repetitions per set for bench-press and squatting exercises. 

Subjects had experience with weight lifting.

After 10 week there was an increase in lean body mass of 6kg in 10 weeks (12). The percentage of body fat did not change significantly in any group.

Of note testosterone only produced 3kg of LBM gain and coupled with exercise the results were doubled, suggesting that exercise plays a major role in augmenting the results of testosterone, up to a certain point!

For perspective here is a graph comparing gains from these 4 studies (5,2,3,4):

Credit to Joseph Agu

If we scale the Bhasin et al. study to 12 weeks, assuming a linear response over time and a 600g LMB gain per week, the LBM gains would be 7.2kg vs. 4kg vs. 7 kg vs. 8.5kg. 


In other articles you can read more about The Greatest Gains Ever Recorded, Genetics and Hyper-responders, and not to make this TL;DR:

In short, it is clear that some exercise methods can produce great results, and that some are hyper-responders for hypertrophy, experiencing big increases in muscle size:

- 6 % increase in muscle size in 5 weeks; 21.4 - 39.4 % increased in muscle size in 24 weeks; 9-15 % LBM increase in 5 weeks;

This is without supplements and with a basic exercise program. These results are usually seen in untrained subjects. 

Training programs between these studies were greatly different, with the programs for the untrained being “basic” training 2 or 3 muscles only (as most studies), with the exception of the Kraemer et al. study with a full body training program with daily undulating periodization (with supplementation).

To produce such results in trained population is another game and more difficult. The Wilson et al. studies were all done with trained subjects, had a full body training program even more advanced and hard than Kraemer et al., and also supplementation. These studies also resulted in decreased body fat (not seen in the other studies).

If we scale the Bhasin et al. study (5) to 12 weeks with the assumption I followed above, gains would be equal for the HMB-FA study (3), and only become “better than steroids” for the latest study with HMB-FA and ATP supplementation (4).

Such results in trained populations are to be looked at with great skepticism. If subjects were carefully chosen/cherrypicked as hyper-responders (as argued by the authors), and had an advanced program and supplementation, the results are more plausible. 

We also have to take into account all of Wilson et al. studies were diet controlled (rare in such studies), with 23-25% protein.

For a group mean of 83kg, 179cm and 21 years as in the HMB-FA study (3) and calculating the energy requirements for maintenance (Harris-Benedict) with an moderate activity factor we are dealing with 3450 estimated kcal for maintenance, 25% of which from protein leaving us with 215g of protein or 2.6g/kg per day. 

Now let’s take a lot at one study by Jose Antonio et al. (9) in trained subjects with one group consuming a normal protein diet of 2.3g/kg/day with a full body training split throughout the week. Body composition was assessed by whole body densitometry using air displacement via the Bod Pod. 

For the normal protein group (2.3g/kg) and also the higher protein group we can see a mean change in FFM of +1.5kg in 8 weeks, but thankfully we have individual data which is more telling of what can happen:

See those 4 subjects in the NP group above +2kg, and those 2 up there above +4 kg? What about in the HP group those 3 up there around +6kg LBM in 8 weeks? Same with the body fat individual data.

At the high end, there were subjects in the normal and high protein group that gained up to 7 kg of FFM and lost up to 4 kg of fat mass. Conversely, there were subjects who lost FFM or gained fat mass” (9). 

While the Bhasin et al. had trained subjects and a basic exercise program, the other studies had trained subjects (and possibly all hyper-responders) and full body daily undulating periodization program.

Even if we compare the placebo groups from the studies:
- In the ATP study the placebo group had already gained 2.7kg LBM after 8 weeks, but then dropped 0.7kg to 2kg LBM after the overreaching cycle at 12 weeks (2);
- In the HMB-FA study the HMB-FA placebo gained 2.9kg LBM after 8 weeks, and then dropped 0.8 to 2.1kg LBM after the overreaching cycle (3);
- In the HMB-FA+ATP study the placebo group gained about 2.8kg LBM after 8 weeks, and then dropped 0.7kg to 2.1kg after 12 weeks (4);
- In the testosterone study the placebo group gained 2kg LBM after 10 weeks (5).

This means all the placebo groups from Wilson et al. made more gains (2.7-2.9kg LBM) than the testosterone placebo group (2.1kg LBM) and in less time (8 weeks vs 10 weeks). After 8 weeks however they all dropped to 2-2.1 kg due to the overreaching cycle.

Could we reasonably assume that they would keep making progress if they didn’t intentionally overreach and perhaps going from 2.9kg to 4kg in the last 4 weeks? Possibly. I think it is reasonable to assume the training protocol did had an effect in the exceptional results reported by Wilson et al. studies.

Certainly HMB-FA or HMB-FA+ATP is not better than 600mg of testosterone, but perhaps if you combine a full body daily undulating periodization for 12 weeks (vs. 10 weeks) and use (trained) hyper-responders results might come close to 600mg of T and a basic exercise program for bench-press and squat only (70-80-90%RM), perhaps.

Having looked at the testosterone raw data (unpublished), the mean was about 627-653, with some having 800-930 and even one subject above 1000 (values fluctuated a bit over the 12 weeks). Subjects had a mean of 21.6 years. Perhaps these individuals among the already “carefully selected” responders were even more exceptional or outliers and pulled the group mean up? Look at those 2 guys here at the top from another study:

Other “tricks” that can be used is detraining and then retraining subjects for the experiments, and even carb-depletion pre-study and carb-loading post study for the DEXA measurements, which would make them “gain”  an additional 2kg of LBM (as water).

Recently several researchers wrote a letter to the editor (10) about the HMB-FA+ATP study questioning the results and asking for clarification on several points. 

As a final note, I am not arguing for or defending the Wilson et al. studies, just presenting some evidence of some of the biggest gains ever reported in other studies, and offering some context and perspective of what can be possible if the right conditions (training methods, programs and supplements) and populations are met

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2. Jacob M Wilson1, Jordan M Joy, Ryan P Lowery, Michael D Roberts, Christopher M Lockwood, Anssi H Manninen, John C Fuller Jr., Eduardo O De Souza, Shawn M Baier, Stephanie MC Wilson and John A Rathmacher. Effects of oral adenosine-5-triphosphate supplementation on athletic performance, skeletal muscle hypertrophy and recovery in resistance-trained men. Nutr Metab (Lond). 2013 Sep 22;10(1):5 Eur J Appl Physiol.
3. Jacob M. Wilson, Ryan P. Lowery, Jordan M. Joy, J. C. Andersen, Stephanie M. C. Wilson, Jeffrey R. Stout, Nevine Duncan, John C. Fuller, Shawn M. Baier, Marshall A. Naimo, John Rathmacher. The effects of 12 weeks of beta-hydroxy-beta-methylbutyrate free acid supplementation on muscle mass, strength, and power in resistance-trained individuals: a randomized, double-blind, placebo-controlled study. Eur J Appl Physiol. 2014 Jun;114(6):1217-27
4. Lowery, RP, Joy, JM, Rathmacher, JA, Baier, SM, Fuller, JC Jr, Shelley, MC II, Ja ger, R, Purpura, M, Wilson, SMC, and Wilson, JM. Interaction of beta-hydroxy-beta-methylbutyrate free acid and adenosine triphosphate on muscle mass, strength, and power in resistance trained individuals. J Strength Cond Res 30(7): 1843–1854, 2016
5. Shalender Bhasin, M.D., Thomas W. Storer, Ph.D., Nancy Berman, Ph.D., Carlos Callegari, M.D., Brenda Clevenger, B.A., Jeffrey Phillips, M.D., Thomas J. Bunnell, B.A., Ray Tricker, Ph.D., Aida Shirazi, R.Ph., and Richard Casaburi, Ph.D., M.D. The Effects of Supraphysiologic Doses of Testosterone on Muscle Size and Strength in Normal Men. N Engl J Med 1996; 335:1-7July 4
6. Shalender Bhasin, Linda Woodhouse, Richard Casaburi, Atam B. Singh, Dimple Bhasin, Nancy Berman, Xianghong Chen, Kevin E. Yarasheski, Lynne Magliano, Connie Dzekov, Jeanne Dzekov, Rachelle Bross, Jeffrey Phillips, Indrani Sinha-Hikim, Ruoquing Shen, Thomas W. Storer. Testosterone dose-response relationships in healthy young men. Am J Physiol Endocrinol Metab 281: E1172–E1181, 2001
7. Indrani Sinha-Hikim, Jorge Artaza, Linda Woodhouse, Nestor Gonzalez-Cadavid, Atam B. Singh, Martin I. Lee, Thomas W. Storer, Richard Casaburi, Ruoquing Shen, Shalender Bhasin. Testosterone induced increase in muscle size in healthy young men is associated with muscle fiber hypertrophy. Am J Physiol Endocrinol Metab 283: E154–E164, 2002.
8. Linda J. Woodhouse, Suzanne Reisz-Porszasz, Marjan Javanbakht, Thomas W. Storer, Martin Lee, Hrant Zerounian, and Shalender Bhasin. Development of models to predict anabolic response to testosterone administration in healthy young men.
Am J Physiol Endocrinol Metab 284: E1009–E1017, 2003.
9. Jose Antonio*, Anya Ellerbroek, Tobin Silver, Steve Orris, Max Scheiner, Adriana Gonzalez and Corey A Peacock. A high protein diet (3.4 g/kg/d) combined with a heavy resistance training program improves body composition in healthy trained men and women – a follow-up investigation. Journal of the International Society of Sports Nutrition (2015) 12:39
10. Phillips SM, Aragon AA, Arciero PJ, Arent SM, Close GL, Hamilton DL, Helms ER, Henselmans M, Loenneke JP, Norton LE, Ormsbee MJ, Sale C, Schoenfeld BJ, SmithRyan AE, Tipton KD, Vukovich MD, Wilborn C, Willoughby DS. Changes in body composition and performance with supplemental HMB-FA+ATP. J Strength Cond Res. 2017 Mar 13.