Muscle Research Update: Maximize Protein Synthesis and Maximize Muscle Mass!

by Paul Cribb, B.H.Sci HMS
AST Director of Research

In recent years, the science of how to build muscle hasn’t made big advances, its made friggin’ quantum leaps!

If you’re into building muscle then listen up, I’m going to share with a number of critical breakthroughs in how to do it. This information will save you years of wasted effort. Armed with this knowledge virtually anyone should be able to make tremendous gains and add pounds of drug free muscle to their physique.

Great strides in the application of stable isotope tracer technology, immunohistochemical muscle fiber typing, more accurate body composition assessments and powerful microarray methods (that can measure genetic responses to training and diet) are all contributing enormously to a better understanding of the factors that ultimately control the size of human muscle mass.

Okay, all that may sound a little geeky, but hey I’m a scientist……It’s the geeky stuff that gets me going! Especially if it’s got anything to do with muscle.

The best part about my job is that I can pass on this information to others so that more people understand exactly what is required to build muscle, shed body fat and achieve the physique they’ve always wanted.

It is now clear (about as clear as it gets in research) that stimulating muscle protein synthesis is THE facilitating process that underlines changes in the size of muscle mass [1,2]. In essence, a high stimulation of muscle protein synthesis (let’s just shorten that to MPS) is absolutely essential to gaining muscle. Now to some of you, this may not sound like an incredible, scientific revelation. However, rest assured this info’ is an incredibly important piece in the overall picture of how to improve your physique with diet and exercise, and I’ll explain why.

Without a doubt, the mechanisms that regulate the size of human muscle mass are complex. I sure as hell don’t profess to know all the answers about how to build muscle, but I’m getting there! Seriously, there are many, many factors that influence the muscle growth process including, but not limited to, physical activity, hormones, disease, age, genetic factors as well as the quality and quantity of nutrition.

In reality, scientists have only just begun to scratch the surface on how these aspects influence our ability to build muscle. However, don’t despair. Armed with our new, exciting information, I’m going to show you how to utilize it to your advantage. Best of all, it’s going to save you months or even years of wasted time, particularly if you’re one of those guys or gals that has to work their butt off just to add a molecule of muscle to their frame.

Building Muscle Mass 101

If building muscle was a subject at University or college then there would be three fundamentally important rules you would need to learn in order to pass. We’ll get to these in a moment. First we’ve got to cover some basic ground work. If we get right down to the scientific nuts and bolts of it, an ultra-high stimulation of MPS, 24:7 really is the name of the game if you want to build muscle and transform your physique. Stimulating MPS simply means that muscle proteins are being synthesized. As Paul Delia has told you many times, muscle is protein and protein is muscle. It’s true. However, there are other factors that work against your ability to build muscle.

The quality and quantity of protein within your muscles is essentially maintained through a continuous remodeling process that involves constant synthesis and breakdown [3]. It is a process that never stops. Even without the influence of exercise, muscle proteins are constantly being broken down and regenerated. Even when you’re doing nothing physical except tapping on a key board or just kickin’ back watching the tube, muscle protein synthesis and breakdown is always occurring. Scientists call this process protein turnover.

As I said, this process never stops but it can speed up or slow down in response to various circumstances. For example, dieting (calorie restriction) slows down this process. Ageing also slows down protein turnover, or the rate at which new muscle proteins are regenerated. Alternatively, after you’ve hit the gym for your Max-OT workout, protein turnover is accelerated, enormously.

Because muscle tissue is the body’s largest reservoir of bound and unbound proteins (amino acids) (it constitutes 50-75% of all proteins in the human body), this means that muscle protein turnover is synonymous with whole body protein turnover.[3] What’s happening within your muscles has an enormous impact on the entire body. In fact, muscle’s huge impact on whole body protein turnover is a clear reflection of the key role this tissue plays in the regulation of protein metabolism. In other words, muscle is drawn upon constantly to supply the amino acids that are required for a vast array of physiological demands, every single day.

For example, muscle mass is the main reservoir of fuel that powers immune function and the development of every new cell [4]. Cells are important; they make up all tissues and organs within the body (we go through several thousand gut cells every day alone!) Just like your bank account, muscle tissue is constantly being tapped by these regular withdrawals. If you don’t make some rather substantial deposits, the balance just keeps diminishing. A clear example of this is the muscle loss that is common in ageing. Conversely, if you haven’t been gaining muscle the way you’d like to, are you starting to understand at least one reason why?

As I mentioned earlier, it is quite clear that any change in muscles mass such as growth (or hypertrophy is the technical term), is a result of an increase in protein turnover. Particularly, the stimulation of MPS. Hypertrophy can only occur by increasing the synthesis rate of muscle proteins faster than they are broken down [2]. Therefore, if the stimulation of MPS is the critical regulatory event that leads to muscle growth, let’s look specifically at how to stimulate an increase in this vital process.

Science has confirmed that weight lifting exercise is a most potent stimulus for increasing MPS. A single bout of weight lifting exercise stimulates an increase in MPS by 100% for at least 24 hours and maybe up to 48 hours [1]. In people that don’t train with weights, any old protocol should create this effect. Obviously, if a person has never lifted a weight before, no matter what exercise, sets and reps they perform is going to be a “stimulus” their muscles have never experienced before. However, if there is one thing we do know about human physiology is that it adapts to stimuli very quickly.

For example, as a result of regular weight training, less muscle mass is recruited to lift a given load, [5] and the stimuli to increase MPS for a given load is diminished [6]. Therefore, if lifting weights has the potential to cause a tremendous increase in MPS but regular training diminishes this response, then the most important question is, what type of weight training program is most effective at providing a high stimulation of MPS?

Let’s take a look at what the science tells us.

Recent work in molecular physiology has provided some very important clues as to how we should train to build muscle. Recent research has confirmed earlier work (and that’s a good thing in science) that gains in muscle mass observed in response to loading, correlate with the magnitude of stimulation of MPS.

For you muscle research buffs, seminal work completed by Baar & Esser [7] confirmed that the degree of overload placed on muscle correlates with the magnitude of stimulation of MPS and the subsequent increase in muscle mass. In other words, muscle mass gains are directly proportional to the stimulation of MPS which, in turn is proportional to the amount of overload placed on muscle.

The greater the overload (amount of weight used), the higher the stimulation of MPS, this sets the stage for gains in muscle mass!


If you want to build muscle, there are two rules that you must understand. The first is, the stimulation of MPS is the critical regulatory event that leads to muscle growth.

The second is that the degree of overload placed on muscle determines the magnitude of stimulation of MPS.

Kind of straight forward isn’t it? However, think about this for one second; how many weight training programs and techniques deviate from this fundamental rule?

High overload = high stimulation of MPS = more muscle.

Next, we'll take a look at the specifics of program design that maximize MPS and muscle mass gains, In the previous article I reported that exercise science research has now confirmed some important breakthroughs in obtaining the most from all of those jaw-clenched, teeth-grinding hours spent in the gym.

That is, the stimulation of muscle protein synthesis (MPS) is the critical regulatory event that leads to muscle growth [1,2,]. Without a high stimulation of MPS, muscle gains just won’t happen. It is also clear that the degree of overload (amount of weight used) determines the magnitude of stimulation of MPS and subsequent gains in muscle mass [7]. In this article we'll deal specifically with the research that leads us to the most effective weight lifting program that stimulates MPS and accelerates muscle mass gains.

If we look to the classical prescription for gaining muscle mass, that is, muscle size is directly proportional to the magnitude of functional overload [8,9]. This fundamental prinicple has been around for over 20 years but its been buried in the hype and bullshit that is the bodybuilding magazine industry. I mean, imagine trying to sell 12 magazines every year with just that piece of information? It's not the most stylish, sexy scoop is it? But if you're really serious about quality gains from every workout then you'd be getting excited by now. This information leads us to rule number three in our Building Muscle Mass 101 course.

It's a question of strength

If research has confirmed that the stimulation of MPS comes down to the amount of overload placed on muscle, then obviously, strength will determine the amount of overload used. A person’s strength becomes the limiting factor in their potential to build muscle. More particularly, improvements in strength will enable greater overload to be placed on muscle. In turn, this provides a consistently greater stimulus for MPS and muscle growth.

Previously, you may have thought you understood the importance of building strength for gaining muscle, but now you know the science-based reason why!

The relationship between muscle size and strength is clear. Exercise scientists have known for a long time that maximum voluntary strength is closely associated with muscle size [10]. Texts books on resistance training tell us that muscle fibers in general, show a linear relationship between their cross-sectional area (size) and the amount of force they can generate. It is true that a number of factors may influence the expression of strength. However, I previously explained two universal rules that do not change. The first was that stimulating a high rate of MPS is the only way to stimulate muscle gains. The second was that load determines the degree of stimulation of MPS [6].


Rule number three; improvements in strength enable greater overload. Greater overload means a higher stimulation of MPS and more muscle mass. A clear focus on building strength ensures that mass will follow.

In terms of exercise prescription for gaining muscle mass, all the science-based information on this topic basically suggests that if a weight lifting program focuses on increasing strength, it will ultimately result in hypertrophy to some degree. New improvements in strength enable greater overload to be placed on the muscle(s) and therefore, provide further potential for hypertrophy. It’s a pretty straight forward concept that a lot more gym buffs would do well to take on board. I mean in all my years visiting gyms, I’ve never seen a skinny guy bench press 400 pounds!

Training to become physically stronger enhances your potential for hypertrophy. Conversely, its extremely difficult to pack on muscle mass without significant gains in strength.

Without focusing on building strength, you're making a tough job (bodybuilding) imposible!

However, many bodybuilders are confused about this basic relationship. Its no wonder when you take a look at the recommendations made by many of the organizations that we look to for resistance training accreditation and resource information.

A mass of confusion about building muscle mass!

Organizations such as the American College of Sports Medicine (ACSM) and the National Strength & Conditioning Association (NSCA) have attempted to distinguish differences between weight lifting for strength as opposed to building muscle (hypertrophy-specific training). Yet as I have shown you, a science-based distinction between the two is very difficult. The principles of one are intertwined within the other. As a consequence, in an effort to provide clear distinctions in their exercise recommendations for strength training as opposed to hypertrophy-specific training, these organizations have drawn on some rather flimsy evidence to justify their recommendations.

For example, the guidelines for strength and hypertrophy development recommended by ACSM are very similar in most respects such as exercise selection and training frequency [12]. However, things get a little confusing when it comes to the recommendations for loading (RMs) and training volume. For strength development, the ACSM recommends the use of maximum loads (1-6RM), a lower number of total work sets and long rest intervals (3 to 5 minutes) between working sets. However, when it comes to “hypertrophy-specific” training they recommend the incorporation of lighter loads (8-12RM), more volume and shorter rest intervals. In light of the fundamental principles I’ve presented to you thus far, I fail to see how this recommendation could be more effective for building muscle than the recommendations made for building strength.

The justification the ACSM provides for these hypertrophy-specific training recommendations is that a higher increase of some anabolic hormone concentrations (in the blood) have been observed by this type of training [12]. This isn’t totally correct. Other studies [11] have shown a higher increase in circulating anabolic hormone concentrations with a low volume, high overload, traditional strength training approach. Above all, at the time these recommendations were published (three years ago), the authors knew that the significance of any minor differences in acute hormone responses was a moot point. No physiological consequences (such as improvements strength or muscle mass) had been documented.

The recommendations for bodybuilding training made by the NSCA are even worse. In their accreditation text, the NSCA recommend the use of up to 20 working sets per muscle group! The use of moderate loads (as opposed to heavy loads) and one minute rest intervals between sets [13]. That’s not bodybuilding training, that’s circuit training!

No longitudinal studies are provided that may substantiate these rather definitive recommendations. However, things get really confusing when in a different chapter of the very same text, the author states It would appear from recent studies that heavy loads, in the 3-5RM range, are most effective in stimulating growth of all muscle fibers because all types are recruited.[14] Confused? Me too!

The aspect of rest intervals between sets is a particularly contentious issue with me. Any aspect of training that limits the amount of overload you place on muscle is going to short-circuit the potential for muscle growth. If we look to the research on the topic of rest intervals, it is crystal clear that short rest intervals (one minute or less) between sets reduce workout performance and reduce the ability to overload the muscle.

Weight lifting workout performance is defined as the total number of repetitions completed in a predetermined amount of sets with a designated load. Workout performance is shown to be compromised with short rest periods (30-60 seconds) and improved by longer rest intervals (such as two three minutes), particularly when complex exercises are involved; squats, bench presses, deadlifts, rows etc [15,16]. In fact, some longitudinal resistance training studies have shown greater strength gains with longer versus shorter rest intervals between sets (two-three minutes vs. 30-40 seconds) [17, 18].

The results of a recent study smash these hypertrophy-specific training recommendations completely.

A recent 6 month long training study has confirmed that the use of lighter weight, more reps and shorter rest intervals was no more effective than a traditional strength training program for building muscle [19]. In this cross-over study, no differences were observed in terms of anabolic hormone responses, neurologic adaptations, strength or muscle mass gains between a hypertrophy-specific program and a traditional strength-building program [19]. In fact, when the bodybuilders followed the high overload approach that utilized longer rest intervals (up to 5 minutes between heavy sets), they experienced better strength gains. (Remember, greater strength means greater potential for hypertrophy in the longer term.) The traditional strength training program stimulated just as much muscle growth as the hypertrophy-specific program.

I’ve worked in the fitness industry for a long time, and my concern has always been the lack of credibility that inaccurate/unfounded training recommendations create within the industry. For example, where do these “hypetrophy specific” recommendations leave the average gym instructor or personal trainer who needs to know the best way to train their clients? Where does this leave the average Joe who listens to these professionals to gain the best advice for building muscle? Do you think both groups would be confused or frustrated? You bet.

Now, for the record, I am a proud member of both the NSCA and the ACSM. The points I’ve made are not derogatory toward these excellent organizations. In many ways they have bought the science of weight lifting out of the dark ages and into a highly professional realm. My point is that building muscle has become an important issue. Sarcopenia (muscle loss in aging) costs the United States health care system $18 billion dollars a year. We need clear, uniform guidelines based on the latest research available to combat a problem that is going to reach epidemic proportions in an ageing population. The hypertrophy-specific training recommendations made by the NSCA, ACSM and other organizations must be up dated to comply with the research that is most relevant to this topic. It’s as simple as that.

The research-based exercise prescription for gaining muscle mass.

If we can step back into the real world for a moment, back to what science can really tells us about an effective way to train to build muscle. It all comes down to overload and the stimulation of MPS; the critical regulatory event that leads to muscle growth. However, it may interest you to know that less than a handful of weight training studies have actually assessed the effects of different training protocols on muscle hypertrophy. Of these, not one has shown that the use of “moderate” loads is more effective than the use of heavy loads to build muscle. Not one has shown that shorter rest intervals build more muscle than taking longer rest intervals. In term of training volume and frequency, there is no data on hypertrophy responses other than the old “3 working sets are better than one” finding. While it is clear that performing more than one working set on a muscle group is required, no studies have determine how many sets, per workout maybe optimal for muscle growth.

The amount of research that can give us a dose-response relationship between training frequency, volume and muscle hypertrophy, is pitiful. This is about as clear Charlie Sheen’s ability to remain monogamous. (Yeah, it’s that bad). This is why I just can't understand how such specific guidelines can be handed down from the ivory towers of academia.

The only research-based, quantifiable prescription for training frequency and volume can be found in recent meta-analyses on strength development [20,21]. Meta-analyses research can be very useful as it groups all the results from relevant studies on a particular topic and statistically, provides the conclusions of all this research. The reports on a dose-response relationship between training frequency,volume and optimum strength development provide some interesting results.

These studies report that trained or advanced individuals (as opposed to novices) obtain the best strength gains by using a high overload approach; 80 to 85% of the one-rep max (which would equate approximately to working with a maximal rep range of around 3-8 RM). Each muscle group should be trained twice a week with a total of only 4 to 8 working (non-warm up) sets per muscle group each workout [20,21]. Remember, optimum strength development is important; strength improvements clearly increase the potential for muscle mass gains.

Many bodybuilders and strength athletes fail to understand that it’s impossible to isolate muscles during training. Anyone that performs a training day that involves the chest muscles and another day devoted to the arm and/or shoulder muscles automatically ensures that these muscle groups receive two workouts a week. If you’re a bodybuilder that typically performs a “chest day”, a “back day” and an “arm day” each week then your shoulder muscles, (traps and delts) are worked at least three times a week no matter what exercises you perform. Same can be said for legs and back muscles. That is, the deadlifts you perform on “back day” will always involve the hip and leg muscles. The variety of squats you perform on “leg day” also recruit the back muscles heavily. Therefore, with regard to the current research-based prescription for optimum strength development, hopefully you can see how easy it is for bodybuilders to overtrain.

To summarize what research can tell us about an optimum training prescription for muscle growth; overload appears to be the fundamental aspect. In particular, the amount of overload placed on muscle determines the magnitude of stimulation of MPS and any subsequent gain in muscle mass.

Therefore, weight training programs designed to maximize muscle growth must use protocols that ensure maximum overload and focus on strength development. That means selecting only those exercises, repetition ranges and rest intervals that enable maximum overload. In terms of volume and frequency, the research on optimizing strength development reveals that less is more beneficial than many “experts” will have you believe. For best strength gains, it appears that muscle groups should be worked no more than twice a week; and if you train each muscle group directly once a week you will automatically work most muscles within your body at least twice a week! In terms of volume, a total of only 4 to 8 working sets each workout appears to be optimal. Obviously, the lower end of this range is for the smaller groups such as arms, and the higher end is for the large muscle groups such as legs and back. Not the other way around!

The funny thing is, AST has been prescribing this approach to training for many years in the, Max-OT program. Now it appears that the research is finally catching up. Best of all, rather than spend hundreds of hours wading through the research on resistance training to construct a science-based program, the hard work has been done for you. Max-OT is an easy to follow, step-by-step, science-based program that will help most people build more muscle in the shortest possible amount of time. Max-OT is a free-access, science-based approach to resistance training that has proven incredibly effective to many that desire the best results in the shortest possible amount of time. Isn’t that what training is all about?