To truly be able to understand topics, we need to be able to see the forest through the trees, but we also have to stare at some bark. The big picture in regards to muscle growth says that we have to stress the body with mechanical loading, create some heat, and feel an acid load during training, and then we have to recover effectively in the aftermath. The small details of muscle hypertrophy can be quite confusing, and modern researchers are far from understanding all of the intricacies of the pathways associated with growth and breakdown of skeletal muscle tissue. Despite the long road ahead for anabolism based researchers in elucidating all of the pathways associated with what it takes to pack on muscle tissue, there are some things that we can point to with some certainty as being extremely important factors involved with the cellular and molecular regulation of muscle mass.
The Rate Limiting Factor
Discovering the rate limiting factor of complex inter and intracellular physiological pathways is a critical component that researchers are always interested in discovering. The rate limiting factor is the thing that typically determines whether progress continues or halts in any endeavor. Suppose I own a shoe factory, and I have a few employees who have assigned roles. Tom puts the lace holes into the leather of the shoes, Mary puts the laces in the shoes, and Jimmy puts the rubber soles on the bottom. My team simply is not making as many shoes per hour as I would like. Is it the team, or is there a rate limiting factor. I put up cameras in the factory to see what’s going on. When I analyze the film from the assembly line, I see that Mary is not cutting it. Tom is pumping out shoes with lace holes, but Mary seems more interested in checking her cell phone than diligently lacing up the shoes. The shoes are piling up into Tom’s work station. Tom simply stops doing his thing, because the log jam is happening one step ahead of him. There’s no need for Tom to keep doing his job. I have a talk with Mary, and she agrees to not use her phone at work. Suddenly the production of shoes leaving the factory increases markedly. I figured out what the rate limiting factor was and I used an intervention strategy that mitigated that component from decreasing productivity.
When discussing muscle growth, we see that it is governed by the interaction between protein synthesis and protein degradation. If synthesis exceeds the rate of degradation, then we have a net increase in protein fibers that accumulate in muscle tissue, aka, we gain muscle mass. When discussing responses to resistance training, we see that it’s a process based more on increasing protein synthesis rather than greatly diminishing degradation; whereas, responses to endurance training are more based on limiting degradation. Therefore, when examining what people who lift weights are interested in, we have to discuss the factors associated with protein synthesis.
Protein synthesis is the manufacturing of new proteins inside of a muscle cell. The two phases of protein synthesis are transcription and translation. Transcription is the act of copying the instructions from the DNA on how to build a new protein in the form of messenger RNA (mRNA). Translation is the process by which the ribosome assembles a protein based on the instructions coming from the mRNA that travels from the nucleus to the cytosolic region where the ribosome resides. The question of greatest import is, which of the two components of protein synthesis is the rate limiting factor? The answer is that translation seems to be the lynch pin in the operation.
Diving deeper into the translational process, can we identify what is the rate limiting factor within this puzzle? The answer is that the scientific community is not there yet, and it seems as though there are many possible pathways that can be utilized in this process, but one that seems to be of critical interest is that which is called, the mTOR dependent pathway. The other critical factor is how much ribosomal biogenesis is taking place. Essentially protein synthesis is dependent upon ribosomal efficiency, which is driven to a large part by the ability to activate mTOR, and ribosomal capacity, which is related to the overall content of the number of ribosome complexes present inside a muscle cell. If we can maximize ribosomal efficiency and content, we should have the best case scenario for building muscle mass.
Readers of this article are encouraged to explore this topic within the peer reviewed articles associated with this topic. This article certainly will not present to you the full scope of what is happening in this convoluted and extremely involved logistical beehive of translational steps. Instead, the author would like to present to you key concepts that are associated with the major theoretical phenomenon involved in what governs the translational machinery’s activities.
Transcription is a nuclear based phenomenon. The instructions for assembling all of the proteins that the body is made of are coded for in the DNA. We need to copy the code before we can begin the building process. The copy of the code is mRNA, and the process of transcription is the act of creating the mRNA strand. The first thing that we need to do is to unwind the DNA double helix to get the necessary structures into the proper place to copy the appropriate code. A signal to activate transcription (STAT) is sent to the nucleus to begin the process. Transcription can be increased by influences from steroid hormones or peptide hormones. Steroid hormones such as, testosterone move directly through the sarcolemma and bind to the androgen receptor which is located on or near the nuclear envelope. Once the steroid hormone binds to the androgen receptor, the hormone/receptor complex then migrates into the DNA and starts the transcription process.
Peptide hormones bind to the sarcolemma and activate a secondary messenger cascade driven by janus kinase (JAK) enzymes. JAK phosphorylation activity causes the release of STAT, which migrates to the DNA. STAT signals for DNA helicase to begin unwinding the double helix. DNA helicase travels along the length of the helix, unwinding it as it goes. Riding on the tail of DNA helicase is RNA polymerase, which is copying the code from the DNA inscribed instructional palate. mRNA begins forming from the back end of RNA polymerase. Once RNA polymerase has copied all of the necessary components of the DNA to construct the appropriate mRNA segment, mRNA breaks away from RNA polymerase and migrates through the nuclear pores into the cytosol. mRNA then travels to a ribosome where it is situated between the two segments of a ribosome (almost like mRNA is the meat that goes in between the two buns of a burger).
Now that mRNA has reached the ribosome, we can see the translational process in action. Translation is based on the ribosome instructing transfer RNA (tRNA) to collect appropriate amino acids from the cytosol to bring back to the ribosome for construction of the appropriate protein. tRNA brings amino acids back to the ribosome, which are assembled in the proper triplicate orders to create the desired protein product. The act of getting translation to start seems to be the critical matter in this entire process, and there are multiple options that the body can utilize to try to pull off this building procedure. The most discussed method of initiating translation is the mTOR dependent pathway. There are two separate mTOR complexes, mTORC1 and mTORC2. mTORC1 is regarded as the critical component, and seems to be a potentially powerful rate limiting factor in protein synthesis. When mTORC1 is activated, it seems as though translation takes place and muscles continue to grow, so being familiar with factors which can activate mTORC1 is of critical importance.
There are many steps that take place at the ribosome involving various proteins and enzymes that must be initiated to begin the actual process of translation. The enzymes involved in this process are kinase enzymes. Kinase enzymes participate in phosphorylation based actions. Phosphorylation essentially refers to any time that a phosphate is passed from one enzyme to another…much the same way that a bucket brigade works to put out a fire. If a phosphate continues to be passed in an appropriate manner from one enzymatic reaction to another, the resulting reaction will take place. mTORC1 seems to be a big player in whether the phosphorylation cascade will continue on the route towards achieving the translation phenomenon at the ribosome. The kinase enzyme, p70s6k must be activated to begin translation. If we can get p70s6k to go through a phosphorylation reaction, then translation will take place. p70s6k is an mTOR dependent step though. So what we see is that mTOR is the show. How then do we ensure that mTOR participates in this process?
mTor activation appears to be dependent on a few cellular mechanisms. Leucine availability in the ribosomal region of the cytosol appears to be a powerful player, as does the state of protein kinase B (Akt). Akt is an enzymatic step that takes place prior to reaching mTOR in the pre-translational cascade system. Excessive oxidative stress appears to be a factor that will inhibit Akt and prevent mTOR from being activated, thus shutting the process down. The actions of anabolic peptide hormones, such as IGF and GH appear to be players in opening intercellular portals that admit leucine into the ribosomal region of the cytosol. Therefore, it seems that if we can create an internal environment where we have chronic states of low oxidative stress and high levels of circulating anabolic peptide hormones, we provide the appropriate setting for mTOR to be activated and muscle growth from a ribosomal efficiency standpoint to be maximized.
Achieving optimal states of circulating anabolic hormones is associated with good, hard training sessions that are not excessive in duration (not much longer than 1 hour maximally). Having low oxidative stress seems to be associated with not having prolonged glucocorticoid responses during resting states of the body. The presence of appropriate content of circulating amino acids, namely leucine is also of critical importance. This is where the merger of proper training and sound nutrition coalesces.
When discussing ribosomal content, it seems as though beta-catenin levels are critically important for driving an increase in ribosomal biogenesis. Beta-catenin/c-Myc signaling is independent of the mTOR pathway. This is still as yet an area in the literature that is not strongly understood, but identifying factors associated with this type of activity seems to be crucial.
The empirical process is reductionist in nature. We continue to break things down into smaller and smaller constituent parts as we attempt to deduce what the rate limiting factor of an operational procedure is. When it comes to hypertrophy, it seems as though there are multiple options. When faced with consistently applied mechanical stress, the body will find a way to make a compensatory change. The compensation is hypertrophy. The robustness of an organism on this planet is driven by the plasticity of that lifeform. Lifeforms need options and contingency plans to be able to survive in face of threatening situations. Hypertrophy is the response to mechanical threat. While variability is a critical component, it does seem that the mTOR dependent pathway towards ribosomal efficiency and the beta-catenin pathway for ribosomal biogenesis are the primary drivers of the two ways in which we maximize translational activity, which is the rate limiting factor of protein synthesis.
If I am thinking in a personal and reflective manner on the ways in which I would attempt to maximize the mTOR dependent pathway of translation, I would go with the following approaches based on my understanding of the science and my, “in the trenches” experience as a strength athlete.
- 1. I need to have a decent amount of oxidative fitness. If I’m going to maintain chronically low oxidative stress, it really helps if I have a fairly high number of mitochondria. Oxidative stress in local muscle tissue is often times the product of being unable to inhibit tissue neurologically, and having that tissue exist in non-oxidative conditions for excessive periods of time. Increasing the mitochondrial content of a muscle improves the ability of that muscle to go into an inhibitory state. Also, having a better aerobic system will allow me to exist under more of a parasympathetic condition as my resting heart rate will be lower.
- 2. I would not perform excessive amounts of high intensity cardiorespiratory exercise that is of long duration. Plasma leucine levels seem to be highly linked to whether or not sufficient leucine can be transmitted into the ribosomal region of the cytosol. Aerobic exercise that is of high intensity and long duration is associated with decreasing plasma leucine levels to the point where it is below a threshold point that allows mTOR to be inhibited by an insufficient intr-ribosomal leucine content. I would perform aerobic exercise that is of moderate intensity for moderate amounts of time. 140-160 HR for 30 minutes to an hour maximally 2 to 3 times per week maximally.
- 3. I would manage my insulin levels well. Chronically high insulin levels are associated with existing in an inflamed state. This inflammatory state, which comes from downstream effects of insulin (such as increased interleukin-6 and reactive protein C) cause oxidative stress, which would reduce the activity of protein kinase B. This reduction in the activity of protein kinase B would be problematic for the m-TORC1 pathway.
- 4. I would try to get plenty of sleep. Growth hormone is critically important for the translational machinery. The actions of GH at the plasma membrane when it binds to its receptor involve a secondary messenger cascade that ultimately activates the JAK/STAT pathway for transcription related matters, but also opens a portal that admits leucine into the ribosomal region of the cytosol (facilitating the activity of mTOR)
- 5. I would train hard. Most importantly, I need to have significant amounts of mechanical loading, which seem to be the primary signaling method for activating the transcription and translational machinery through what appears to be some kind of structural protein, piezoelectric flow communication phenomenon that transmits messages from extra-cellular, sarcolemmal, and intercellular strain related forces to the nucleus and the ribosomal regions.
- 6. I would try to eat quality carbohydrates and proteins and perhaps supplement with amino acids in the peri-workout time period. IGF-1 is a potent driver of facilitating the mTOR dependent pathway. IGF-1 also creates myogenic activity in the basement membrane of muscle cells, which causes proliferation and differentiation of satellite cells. These satellite cells will ultimately turn into new nuclei inside that cell, which will become new sites for transcription. IGF-1 levels in the circulation are intimately connected with the state of the amino-acid pool. Low levels of amino-acids in the circulation and within cells will reduce the IGF-1 responses that an individual can have.
- 7. I would find relaxation methods that work for me so that I can calm down and recuperate between training sessions. The energetics of protein synthesis and the recovery process in general is an autonomics driven phenomenon. If I can’t relax and have fun, then I can’t enter quality parasympathetic states. Parasympathetic activity is associated with anabolism. Staying sympathetic, constantly on, and being under stress too often will kill gains. Relax with friends and have fun.
Good training combined with appropriate nutrition and allowing for recovery are the hallmarks of successful mass building programs over the years. The science is beginning to explain why these approaches worked. Maybe by understanding what’s going on a little bit more clearly you will be more highly motivated to hit all the details in the mass building process required to maximize gains. If you are interested in following a good program to maximize muscle growth, I recommend picking up a copy of the e-book, MASS. That book is my best attempt to organize a plan that jives with my understanding of the science that I laid out for you in this article. Good luck to you in your pursuit of gains, my friend. As you were.
Be sure to pick up a copy of Pat's newly released ebook MASS today. It's only available for one week, and who knows when it'll be available again.
about the author
-Director of Training Methodology and Continuing Education at Peak Performance, NYC.
-Assistant Professor at Brooklyn College, 2009-2011
-Assistant Professor, Springfield College 2011-2014
-Head Coach Springfield College Team Ironsports 2011-2013
-175 pound Strongman competitor. Two time qualifier for world championships at Arnold Classic
-Renaissance Meat Head