Switchbacks on the Molecular Pathway to Muscular Development

There may be a “molecular switch” which controls how we build muscle.

Specific adaptations to imposed demands (the SAID principle), the idea that the body adapts specifically to the demands that you place upon it, is one of exercise physiology’s most accepted concepts. Those who have trained for athletic performance or body composition at a high-level recognize that your training must go through cycles, because as astonishingly plastic as the human body is, like the mind, it is not an effective multi-tasker. Attempting to concurrently increase muscle size and strength while improving aerobic performance is generally a zero-sum game; unless you are significantly deconditioned or a genetic freak, you’ll more than likely inhibit progression towards either goal. Although the foundation of this principle is strengthened by centuries of bro-science anecdotes, modern science has yet to fully explain the mechanisms behind this unfortunate physiological phenomenon since Berkeley exercise physiologist Franklin M. Henry first proposed it in 1958. In their quest to develop more effective exercise protocols to treat metabolically-related diseases, Harvard metabolic disease researchers may have just discovered the why.

The c-Jun N-terminal kinase (JNK) pathway is one of the major signaling cassettes of the mitogen-activated protein kinase (MAPK) signaling pathway. In other words, it is one of a chain of cellular proteins which communicates signals from a receptor on the surface of the cell to the DNA in the nucleus of the cell. This has vast implications in a number of cellular processes: embryonic development, cellular death (apoptosis), and (as recently discovered) inflammatory and metabolically-related disease conditions. This is specifically what the researchers from Harvard’s Joslin Diabetes Center were examining when they identified this previously unstudied exercise-activated biological pathway. There may actually be a muscular “switch” that regulates the benefits of exercise.

As published in a recent edition of Nature Communications, scientists discovered that JNK helps to drive response to exercise by using genetic models to identify low and high adaptive response to varying exercise modalities. In follow-up to previous research in which the same team collected data to suggest that hyper-activation of JNK was associated with the failure of a particular muscle to undergo endurance remodeling with exercise, they decided to test their hypothesis that JNK was one of the primary mediators of muscle remodeling. The researchers randomly allocated 16 men, average age of 29 and in “normal” health, to either endurance or resistance training testing. The subjects completed the initial round of testing, which measured either maximal endurance or strength capabilities. They then were asked to abstain from any exerting physical activity for 48 hours after which they returned to the laboratory, following an overnight fast, for further testing. Those participants in the endurance group underwent a standardized 60 minute bout of exercise (cycling), with intensity based upon the results of the initial testing. Those in the resistance training group underwent a similar training session where they were asked to perform 8 sets of 5 repetitions of leg extensions with 3 minutes of rest between sets, with the load determined by their performance in the baseline testing. Muscular biopsies were taken before starting the exercise bout, immediately post exercise, and at 15, 30, and 60 minutes post exercise to determine activation of JNK signaling. Analysis of the biopsied muscle fibers confirmed that JNK effectively acts as a molecular switch that, when activated, stimulates muscular hypertrophy (fiber growth). As expected, when JNK was inhibited there was an increase in endurance adaptations, enhanced aerobic capacity, and limited increases in muscle fiber growth. It is believed that these effects are due to JNK’s ability to influence phosphorylation (a process important in the production of muscular energy) and regulation of the myostatin/TGFβ pathway (a growth factor that acts to suppress muscular growth).

While not shocking in its results – is it a surprise that strength training promotes muscular fiber growth and endurance activity promotes aerobic capacity? – these findings are groundbreaking in our understanding of the mechanisms responsible for muscle remodeling and adaptation. They may also have future implications in athletic conditioning and developing therapeutic approaches to the prevention of various cardiovascular, metabolic, and muscle-wasting conditions. The immediate health implications are obvious. Understanding how muscle decides whether it will grow or adapt for endurance may have direct significance in the prevention of various lifestyle-related diseases, such as metabolic syndrome and cardiovascular disease, and possibly even muscle-wasting diseases, including Amyotrophy and Cachexia. However, the exercise physiologist and athlete in me is looking at this through an entirely different lens. The most interesting discovery was the significant individual variances in the degree of JNK signaling which appeared to be associated with muscle fiber size and performance in maximal aerobic and anaerobic performance, and also exercise history. In other words, individuals are genetically inclined to be better at either the development of muscular strength or endurance, but our muscular strength and endurance potential can be altered with specific training. This fact provides more evidence for my growing theory that exercise is the least complex of sciences. This means:

  1. Specificity matters. A lot. We all have inherent genetic capabilities and we may now know precisely why. There are those who can look at a pair of dumbbells and magically sprout bulging biceps. Or we all have that friend who gets off their couch a few minutes a week to leisurely stroll to the refrigerator, yet agrees to do a local 5k with you…and wins. Then there are those athletic anomalies (I’m looking at you CrossFit competitors, combat athletes, and ninja warriors) who can defy all laws of exercise physiology and cross-train their way to elite levels of both strength and muscular endurance; however, outliers don’t invalidate how the human body works. Whether you are a high or low-responder, the optimal way to increase muscular size and strength is to lift increasingly heavy implements and rest; any muscular endurance-related activities will inhibit one’s progress towards that specific goal, and vice versa. There are different conditioning requirements for every athletic endeavor, but there is no way around the physiological fact that peak muscular strength and endurance are most effectively developed when trained separately and in isolation. So, define specific goals and develop your training around them; even if that goal is simply to be well-rounded and healthy. Progression in any endeavor begins with a plan.
  2. Your physical fate is not set. In their previous animal model studies, these same researchers were able to breed Haile Gebrselassie mice by altering JNK pathway response. Over a few generations, this led to a progressive increase in blood vessels and more slow-twitch muscle fibers, by slowly increasing the time each individual mouse spent running on a wheel. Yes, genetics play a significant role in how one responds to exercise, and you should all know where along this muscular strength/endurance spectrum you reside, but it isn’t finite; you can improve your endurance capabilities no matter how genetically inclined you may be towards building muscular size and strength. You do so with every training session. Every time you hit the road for a grueling running session you are increasing your ceiling for aerobic performance, and through the scientific magic of epigenetics, doing it for your future offspring as well.

So, while genetics may preclude one from ever being a world-class powerlifter or winning the Boston Marathon, the more you train and the more directed that exercise is, the greater your potential to reach your individual goals becomes. Whether you want to increase your muscular size and strength, improve your long-distance cycling performance, or decrease your risk for metabolically-related chronic conditions, don’t let anything (especially JNK signaling) stop you.

Dr. Damian Rodriguez is the health and exercise scientist for doTERRA International, LLC. He holds a doctorate in health science, a master’s degree in exercise physiology, and countless professional certifications. He has spent most of his life researching nutrition, exercise, and the lifestyle behaviors associated with optimal health. Along with his passion for health, as someone who lives with Asperger’s Syndrome, he is also involved in bringing awareness to autism spectrum disorders.