Best Two Supplements for Increasing Lean Muscle Mass Backed by Science

by: Robbie Durand

There are lots of supplements advocating increases in size and strength, but when you look at the science supporting the validity of these supplements that increase muscle mass there are not many. Two supplements have consistently been shown to favor increases in lean muscle mass: Creatine and Whey Protein. We are going to get into some hardcore science on the two supplements that have more research than any other product.

Whey Protein Packs on the Muscle

Several studies have found that whey protein supplements are associated with an increase in muscle mass size and strength. Whey is known as the “fast-acting” protein, it’s absorbed very quickly, as opposed to slow acting proteins such as casein. Supplementation with whey protein results in a high blood amino acid peak and stimulation of protein synthesis similar to a dose of essential amino acids. Whey protein containing meals provide a higher leucine content compared with casein protein makes it more advantageous for muscle mass. Whey has been advocated both pre and post workout for increases in muscle mass. Whey consists of a high branched chain essential amino acids, especially leucine, in particular. Whey protein enriched with Leucine has been extensively studied due to its roles in stimulating muscle protein metabolism, glucose homeostasis, insulin action, and recovery from exercise. A previous study reported that two whey protein shakes a day stimulate increases in lean muscle mass.

Whey Protein’s Powerful Muscle Building Effects

One of the best examples of whey proteins powerful muscle building effects was demonstrated when subjects added two whey protein shakes a day to their resistance training routine. The subjects were randomly assigned to either a whey protein group, placebo group or a control group. During the 21-week-resistance training period, total-body heavy resistance exercise workouts were carried out twice a week. During the 21-week-resistance training period, total-body heavy resistance exercise workouts were performed twice a week. Either 15 grams of whey protein dissolved in water or an equivalent amount of non-energetic placebo was ingested immediately before and after each bout of resistance exercise in the gym. The researchers examined muscle growth, and muscle anabolic signaling genes, and also the muscle catabolism gene myostatin. The major findings of the present study investigating both acute and long-term effects in previously untrained young men were as follows:

Both groups increased lean muscle mass, but they whey protein group improved more. At the end of the 21 weeks, the placebo group had gained 2.57 kg lean body mass. The whey protein group had gained 3.1 kg lean body mass. Timed intake of 15 g of whey protein both immediately before and after each exercise session further increased resistance training-induced vastus lateralis (i.e. quadriceps) muscle hypertrophy. Anabolic gene responses were further enhanced with whey protein compared to the control group.

In conclusion, high-quality whey protein intake before and after resistance exercise appears to augment further resistance training-induced muscle hypertrophy in subjects. Whey protein intake close to resistance exercise workouts may alter mRNA expression in a manner advantageous for muscle hypertrophy.

Whey protein is probably one of the most important supplements you can add to your supplement arsenal not only for increasing lean muscle mass but also its potent health benefits. Acute studies have reported that whey protein isolate (60 grams per day) evaluated over six months resulted in lower cortisol levels (lean muscle preservation). Whey is nutrient dense but relatively low in energy (~4 kcal/g), supplementation is an efficient method to promote skeletal muscle anabolism while promoting catabolism in fat cells and therefore is hypothesized to improve both muscle growth and fat loss. In addition to resistance training, whey protein ingestion may play a significant role as a regulator of muscle mass and recovery from exercise. Whey is high-quality protein source containing large amounts of essential amino acids, important in the protein synthesis. It is thus possible that addition of whey, when used chronically in conjunction with resistance exercise may be more anabolic for skeletal muscle than ingesting only typical mixed meals such as chicken breasts and tuna fish throughout the day.

The Perfect Diet Fuel: More Muscle, Less Fat

A previous study reported whey protein supplementation resulted in more weight loss than a control group receiving maltodextrin while in conjunction with a calorie-restricted diet. After 12 weeks, weight loss was consistently higher in the whey protein subjects, primarily the result of losing body fat (subjects taking whey protein lost 6.1 percent of their body fat mass). The whey protein group subjects also lost significantly less lean muscle mass compared to control subjects. During the 21-week-resistance training period, total-body heavy resistance exercise workouts were carried out twice a week. Either 15 grams of whey isolate protein dissolved in water or an equivalent amount of non-energetic placebo was ingested immediately before and after each bout of resistance exercise in the gym. The researchers examined muscle growth, and muscle anabolic signaling genes. Some of the key findings of the study were:

• Both groups increased lean muscle mass, but they whey protein group improved more. At the end of the 21 weeks, the placebo group had gained 2.57 kg lean body mass. The whey protein isolate group had gained 3.1 kg lean body mass. Timed intake of 15 g of whey protein isolate both immediately before and after each exercise session further increased resistance training-induced vastus lateralis (i.e. quadriceps) muscle hypertrophy.

• Anabolic gene responses were further enhanced with whey protein isolate compared to the control group.

Long Term Whey Protein Use Ups Muscle Mass

One of the problematic issues with research studies is that many last a few weeks, as in the above study that lasted only twelve weeks. What about the lifter that trains every day and uses whey protein? Researchers took 61 healthy subjects, and randomly allocated into either whey protein, soy protein, or carbohydrate groups and followed a resistance exercise program for nine months. All subjects performed a periodized resistance training, training three times per week in 3 mesocycles of 3 months each. The program comprised multiple (3 – 5) sets of a range of exercises. All groups consumed their supplement every day with breakfast or after exercise.

-The whey protein group consumed 21.6g of whey protein concentrate plus 22.5g of maltodextrin,

-the soy protein group consumed 20.0g of soy isolate plus 24.5 g of maltodextrin and,

-the carbohydrate group ate 45.2g of maltodextrin.

The researchers found that body mass increased significantly across the three groups, and the whey protein group was resulted in significantly greater muscle mass than both the soy and carbohydrate groups. The researchers concluded that a 9-month resistance training program increased body weight, lean body mass, and resting metabolic rate (by around 5%) and while the addition of whey protein supplementation produced superior increases in lean body mass.

How to Make your Whey Protein More Anabolic

Leucine is a key amino acid involved in the regulation of skeletal muscle protein synthesis. Leucine triggers the anabolic mTOR pathway, which is essential for muscle growth; additionally, leucine has proven to build muscle, maintain lean mass when in a caloric deficit, improve endurance, and boost recovery. Researchers wanted to examine how adding leucine to a protein drink would affect muscle protein synthesis. Researchers assessed the effect on muscle protein synthesis at rest and after resistance exercise. The men completed unilateral knee extensor resistance exercise before the ingestion of various intakes of whey protein, BCAAs, and leucine:

The subjects received either:

-25 g whey protein (W25) (3.0 g leucine)

-6.25 g whey protein (W6) (0.75g leucine)

-6.25 g whey protein supplemented with leucine to 3.0 g total leucine

-6.25 g whey protein supplemented with leucine to 5.0 g total leucine

-6.25 g whey protein supplemented with leucine, isoleucine, and valine to 5.0 g total leucine.

The researchers found that muscle protein synthesis remained above baseline after all treatments but was greatest after 25 grams of whey and 6.25 grams whey protein supplemented with leucine to five grams total leucine (low-protein/high leucine group). The really interesting finding was the low protein (6.25 grams) mixed beverage was as effective as a high-protein whey (25 grams) shake at stimulating increased muscle protein synthesis rates when supplemented with a high amount of leucine (five grams). These results, indicating that high leucine can have enhanced muscle anabolism effects, are important for athletes who are on a strict diet and cutting back on total calories.

Creatine Increases Lean Muscle Mass

Creatine is a compound naturally produced in the body from reactions involving the amino acids arginine, glycine, and methionine. Creatine has previously found to result in significant increases in muscle mass and strength. Emerging evidence now suggests that creatine supplementation, close to resistance training, is an important strategy for creating an anabolic environment for muscle growth.

Creatine not only increases workout performance but also has recently been shown to increase muscle hypertrophy through activation of anabolic genes post-exercise. Another added benefit of creatine is that it may also reduce post-exercise inflammation and muscle damage. Creatine may have antioxidant properties which can have protective effects on muscle damage. Creatine also increases lean muscle mass by boosting intracellular water content, but other studies have shown that creatine increases the activity of satellite cells, which increases the potential for growth of muscle fibers and also aids in muscle recuperation.

Creatine is a naturally generated endogenous guanidine compound synthesized in the kidneys, pancreas, and liver from methionine, glycine, and arginine and released into the blood. Most creatine is localized in skeletal muscle and stored as creatine phosphate (PCr). CK and PCr play a pivotal role in short-term (only a few seconds) exercise.

Creatine has become the most widely researched ergogenic aid to date, and the research is overwhelmingly clear that creatine not only increases muscle strength but now creatine does what no other supplement can do…creatine lowers myostatin. Myostatin in this nasty hormone that suppresses muscle growth. Many muscle wasting diseases such as AIDS and cancer result in increased levels of myostatin that may be the reason for the muscle wasting. On the other hand, suppression of myostatin results in increased muscle growth.

1.) Creatine Lowers Myostatin

In a study in the Journal of Molecular and Cellular Endocrinology, researchers examined how creatine impacted myostatin levels in resistance-trained men. In a double-blind design, 27 healthy male subjects were assigned to resistance training and creatine supplementation groups. Amazingly, the study found that creatine supplementation added to a resistance-training program amplifies the training-induced decrease in serum levels of myostatin, increasing the effects of exercise on muscle strength and mass. Other studies have reported that ingestion of creatine enhances muscle IGF-1 responses as well in conjunction with increasing satellite cell activation. Just when you think creatine can’t get any better, it does.

2.) Creatine Increases Resting Testosterone and Reduces Cortisol

Another study reported than creatine may also enhance testosterone levels in lifters. Twenty active males were randomly assigned to either a creatine group or placebo group. During each resistance training session, subjects performed three sets × 10-repetitions of 9 exercises that included: Bench press, shoulder press, lat pull down, arm curl, squats, leg press, leg extension, leg curl, and abdominal crunches. The intensity of program was determined at 75 or 85% of one repetition maximum. A minute break between sets of the exercise was allowed for rest. At the end of the study, subjects of the Cr group showed significant increases in testosterone concentrations and decreases in cortisol levels, in comparison with placebo and baseline, after five and seven days of creatine loading. Results of the study suggest that more than five days of creatine supplementation, associated with resistance exercises is sufficient for increasing testosterone concentrations and decrement in cortisol levels. If your not taking creatine, this is the perfect study to get you motivated to take creatine monohydrate.

3.) Creatine Reduces Muscle Damage and Soreness

In the most recent article published in the Journal of Exercise Rehabilitation titled, “Role of creatine supplementation in exercise-induced muscle damage: A mini review” researchers discuss the many benefits of creatine for increasing muscle recuperation. The ergogenic effect of creatine is well-known to improve exercise performance such as explosive muscle power and increased lean body mass after resistance exercise. Several studies have reported that creatine attenuates exercise-induced muscle damage showed that healthy males ingesting creatine beginning five days before exercise until 14 days after exercise improved maximal isometric strength and decreased markers of muscle damage (i.e., creatine kinase) compared with those who consumed a carbohydrate placebo only. Creatine may be a useful dietary supplement for preventing muscle damage and facilitating recovery from high-intensity exercise, which applies to the sports rehabilitation field.

Some potential mechanisms explain the effect of creatine on exercise-induced muscle damage, including the inflammatory response, oxidative stress, calcium homeostasis, and satellite cells activities in damaged muscle.

Creatine Monohydrate Results in Similar Increases in Strength as Creatine HCl

Creatine monohydrate has become the most widely researched ergogenic aid to date, and the research is overwhelmingly clear that creatine not only increases muscle strength but now creatine does what no other supplement can do…creatine monohydrate lowers myostatin. In a study in the Journal of Molecular and Cellular Endocrinology, researchers examined how creatine impacted myostatin levels in resistance-trained men. In a double-blind design, 27 healthy male subjects were assigned to resistance training and creatine supplementation groups. Amazingly, the study found that creatine supplementation added to a resistance-training program amplifies the training-induced decrease in serum levels of myostatin, increasing the effects of exercise on muscle strength and mass. Other studies have reported that ingestion of creatine monohydrate enhances muscle IGF-1 responses as well in conjunction with increasing satellite cell activation.

Creatine Hydrocloride (CrHCl) is a new form of creatine that is supposed to be 41 times more soluble in water than creatine monohydrate. The authors then propose that greater solubility and permeability could decrease the amount of creatine needed to fill the muscle. That would mean more absorption, less creatine excretion, and less gastrointestinal discomfort. Many companies claim that creatine HCL results in greater increases in muscle strength than creatine monohydrate. A new study published in the Journal of Food and Nutrition Sciences reports that creatine HCL results in the same increases in muscle strength as creatine monohydrate.

Researchers from Brazil compared the effects of two different doses of creatine HCl (1.5 g and 5 grams of Creatine HCl) with creatine monohydrate (5 grams) on the strength and body composition of recreational weightlifters. All groups performed 4 weeks of strength training and they were asked to maintain 4 weeks without participating in any regular physical exercise before the start of the training program. The program was composed of four exercises of chest and back muscles, three to shoulder muscles, four to legs muscles, three to biceps and triceps, and two abdominal exercises. Subjects performed four sets of 10 to 12 reps (80% to 90% of 1 MR) of each exercise and the sets were executed until momentary exhaustion.

At the end of the study, there was no difference in strength between the creatine monohydrate group and the creatine HCL group, but the creatine HCL group did have greater improvements in body composition (% bodyfat decreased and increases in lean muscle mass). Before you run to the nearest store to buy creatine HCL expecting bigger arms, lets look at the study closely. On average, however, both groups gained almost the same amount of muscle and lost almost the same amount of fat, but the creatine HCL 1.5 grams and 5 grams lost 8% bodyfat whereas the monohydrate group lost 5%. Another big problem with the study is that they used skin folds for bodyfat testing which is notoriously off compared to DEXA testing which is the gold standard for measuring body composition. Skinfolds can be way off when it comes to determining body fat percentage in individuals. When it comes to tracking change over time in groups, then skinfolds do pretty well. However, errors for tracking change in individuals over time can be up to 3-5%. Based on this one study, it seems that creatine HCL can be used at lower doses than creatine monohydrate but the results are just the same. So you can pick the right creatine for you but there is no superiority of creatine HCL over monohydrate. Creatine monohydrate has had over 1500 peer reviewed studies but its too early to establish the validity of creatine HCL until more long term studies are conducted.

Big on a Budget Stack: Creatine and Whey Protein Research

Creatine Monohydrate combined with whey protein also has been shown to augment muscle strength and lean body mass when compared with carbohydrate or whey protein supplementation The Infinite Labs Big on a Budget Stack comes from a couple of great studies. In a 10-week, single-blind, randomized study, 17 resistance trained males were matched for strength and placed in one of two groups:

– A group that consumed a supplement containing protein, creatine, and glucose immediately before and after a workout or

-A group that drank the same supplement in the morning before breakfast and late evening each training day.

At the end of the 10 weeks of training, supplementation whey protein and creatine before and after each workout resulted in significantly greater improvements in strength and lean body mass with a decrease in body fat percentage compared with those who took a supplement in the morning and late evening. The authors concluded a whey protein/ creatine/carbohydrate supplement may enhance the desired changes from strength training when taken immediately before and after a workout session.

In another meta-analysis of studies examining the validity of whey protein and creatine. Researchers examined whether whey protein-containing supplements, administered alone or as a part of a multi-ingredient (i.e. creatine containing) could improve the effects of resistance training on fat-free mass or lean body mass, and strength in resistance-trained individuals when compared with other iso-energetic supplements containing carbohydrates or other sources of proteins.

A structured literature search was conducted on all the available research from PubMed, Science Direct, Web of Science, Cochrane Libraries, US National Institutes of Health clinicaltrials.gov, SPORTDiscus, and Google Scholar databases. Main inclusion criteria comprised randomized controlled trial study design, adults (aged 18 years and over), resistance-trained individuals, interventions (a resistance training program for a period of 6 weeks or longer, combined with whey protein supplementation administered alone or as a part of a multi-ingredient), and a calorie equivalent contrast supplement from carbohydrates or other non-whey protein sources. Continuous data on fat-free mass and lean body mass, and maximal strength were pooled using a random-effects model.

Data from nine randomized controlled trials were included, involving 11 treatments and 192 participants. Overall, with respect to the ingestion of contrast supplements, whey protein supplementation, administered alone or as part of a multi-ingredient, in combination with resistance training, was associated with small extra gains in fat-free mass or lean body mass. Whey protein alone or as a part of a multi-ingredient (i.e. creatine) appeared to maximize lean body mass or fat-free mass gain, as well as upper and lower body strength improvement with respect to the ingestion of an iso-energetic equivalent carbohydrate or non-whey protein supplement in resistance-training individuals. This enhancement effect seems to be more evident when whey proteins are consumed within a multi-ingredient containing creatine.

Dunford, M, and Doyle, JA. Nutrition for sport and exercise. Belmont: Thomson Wadsworth, 2008.

Beasley JM, Shikany JM, Thomson CA. The role of dietary protein intake in the prevention of sarcopenia of aging. Nutr Clin Pract. 2013 Dec;28(6):684-90.

Naclerio F, Larumbe-Zabala E. Effects of Whey Protein Alone or as Part of a Multi-ingredient Formulation on Strength, Fat-Free Mass, or Lean Body Mass in Resistance-Trained Individuals: A Meta-analysis. Sports Med. 2015 Sep 24.

Kerksick, C, Harvey, T, Stout, J, Campbell, B, Wilborn, C, Kreider, R, Kalman, D, Ziegenfuss, T, Lopez, H, Landis, J, Ivy, JL, and Antonio, J. International Society of Sports Nutrition Position Stand: Nutrient Timing. Journal of the International Society of Sports Nutrition 5(17): 2008.

Burke, DG, Candow, DG, Chilibeck, PD, MacNeil, LG, Roy, BD, Tarnopolsky, MA, and Ziegenfuss, T. Effect of creatine supplementation and resistance-exercise training on muscle insulin-like growth factor in young adults. Int J Sport Nutr Exerc Metab 18: 389-398, 2008.

Burke, DG, Chilibeck, PD, Davison, KS, Candow, DG, Farthing, J, and Palmer TS. The effect of whey protein supplementation with and without creatine monohydrate combined with resistance training on lean tissue and muscle strength. Int J Sport Nutr Exerc Metab 11: 349-356, 2001.

Casey, A, Constantin-Teodosiu, D, Howell, S, Hultman, E, and Greenhaff, PL. Creatine ingestion favorably affects performance and muscle metabolism during maximal exercise in humans. Am J Physiol 271: E31-E37, 1996.

MacKenzie-Shalders, Kristen, et al. “The effect of a whey protein supplement dose on satiety and food intake in resistance training athletes.” Appetite (2015).

Effect of resistance training on resting metabolic rate and its estimation by a dual-energy x-ray absorptiometry metabolic map, by Aristizabal, Freidenreich, Volk, Kupchak, Saenz, Maresh & Volek, in European Journal of Clinical Nutrition (2014)

Hulmi JJ, Kovanen V, Selänne H, Kraemer WJ, Häkkinen K, Mero AA. Acute and long-term effects of resistance exercise with or without protein ingestion on muscle hypertrophy and gene expression. Amino Acids. 2009 Jul;37(2):297-308.

de França, Elias, et al. “Creatine HCl and Creatine Monohydrate Improve Strength but Only Creatine HCl Induced Changes on Body Composition in Recreational Weightlifters.” Food and Nutrition Sciences 6.17 (2015): 1624.

Ostojic, S.M. and Ahmetovic, Z. (2008) Gastrointestinal Distress after Creatine Supplementation in Athletes: Are Side Effects Dose Dependent? Research in Sports Medicine, 16, 15-22.

Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol, 2009 Dec 22.

Deldicque L, Louis M, Theisen D, Nielens H, Dehoux M, Thissen JP, Rennie MJ, Francaux M. Increased IGF mRNA in human skeletal muscle after creatine supplementation. Med Sci Sports Exerc, 2005 May;37(5):731.

Dash, A.K., Miller, D.W., Huai-Yan, H., Carnazzo, J. and Stout, J.R. (2001) Evaluation of Creatine Transport Using Caco-2 Monolayers as an in Vitro Model for Intestinal Absorption. Journal of Pharmaceutical Sciences, 90, 1593-1598.

Gufford, B.T., Sriraghavan, K., Miller, N.J., Miller, D.W., Gu, X., Vennerstrom, J.L. and Robinson, D. (2010) Physi- cochemical Characterization of Creatine N-Methylguanidinium Salts. Journal of Dietary Supplements, 7, 240-252.

Gufford, B.T., Ezell, E.L., Robinson, D.H., Miller, D.W., Miller, N.J., Gu, X. and Vennerstrom, J.L. (2013) Dependent Stability of Creatine Ethyl Ester: Relevance to Oral Absorption. Journal of Dietary Supplements, 10, 241-251.

Bird SP. Creatine supplementation and exercise performance: a brief review. J Sports Sci Med 2003;2:123-132.

Claudino JG, Mezêncio B, Amaral S, Zanetti V, Benatti F, Roschel H, Gualano B, Amadio AC, Serrão JC. Creatine monohydrate supplementation on lower-limb muscle power in Brazilian elite soccer players. J Int Soc Sports Nutr 2014;11:32

Zuniga JM, Housh TJ, Camic CL, Hendrix CR, Mielke M, Johnson GO, Housh DJ, Schmidt RJ. The effects of creatine monohydrate loading on anaerobic performance and one-repetition maximum strength. J Strength Cond Res 2012;26:1651-1656

Rosene J, Matthews T, Ryan C, Belmore K, Bergsten A, Blaisdell J, Gaylord J, Love R, Marrone M, Ward K, Wilson E. Short and longer-term effects of creatine supplementation on exercise induced muscle damage. J Sports Sci Med 2009;8:89-96.

Veggi K FT, Machado M, Koch AJ, Santana SC, Oliveira SS, Stec MJ. Oral creatine supplementation augments the repeated bout effect. Int J Sport Nutr Exerc Metab 2013;23:378-387.

Saremi A, Gharakhanloo R, Sharghi S, Gharaati MR, Larijani B, Omidfar K. Effects of oral creatine and resistance training on serum myostatin and GASP-1. Mol Cell Endocrinol, 2009 Dec 22.

Deldicque L, Louis M, Theisen D, Nielens H, Dehoux M, Thissen JP, Rennie MJ, Francaux M. Increased IGF mRNA in human skeletal muscle after creatine supplementation. Med Sci Sports Exerc, 2005 May;37(5):731.

Brilla LR, Haley TF. Effect of magnesium supplementation on strength training in humans. J Am Coll Nutr. 1992 Jun;11(3):326-9.

Candow DG, Chilibeck PD, Burke DG, Mueller KD, Lewis JD. Effect of different frequencies of creatine supplementation on muscle size and strength in young adults. J Strength Cond Res. 2011 Jul;25(7):1831-8.

Cinar, V., Polat, Y., Balaci, A., Mogulkoc, R. Effects of Magnesium Supplementation on Testosterone Levels of Athletes and Sedentary Subjects at Rest and after Exhaustion. Biological Trace Element Research. 2011. 140, 18-23.

Arazi, F. Rahmaninia, K. Hosseini, A. Asadi Effects of short term creatine supplementation and resistance exercises on resting hormonal and cardiovascular responsesScience & Sports, , Available online 4 February 2015,