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Myokines: The Magical Molecules of Muscle

Exercise is good for you. That much is beyond dispute – good for your metabolism, your blood vessels, your bones, your brain, your immune system (unless you overdo it), and on and on.

But how does it work its magic? Trying to answer that question has become a kind of holy grail for exercise physiologists and molecular biologists. The latest and most ambitious effort is a projected 6-year-long NIH-funded (to the tune of 170 million dollars) study called MoTrPAC, to identify and measure the thousands of molecular changes that occur during exercise, the first results released in Nature on May 1.


But MoTrPAC is just the latest iteration of a story that begins with something called “myokines.” A little background.. Back in the ‘70s, cytokines were identified – tiny peptides (in between amino acids and proteins in size and complexity) which travel the bloodstream and have hormone-like effects. They help drive inflammation, a good thing when the body is responding to injury or infection, a bad thing when it becomes chronic. In 2000, a pioneering Danish researcher Bente Klarlund Pedersen discovered that interleukin 6, a well-studied cytokine, was synthesized and secreted in contracting muscles. But in this context, IL-6 served as a signaling molecule to activate other cytokines in the interleukin family which cumulatively had an anti-inflammatory effect when the muscles were firing.


This was the starting gun to identify other such peptides– she dubbed them myokines, as in, from muscles. Today, over 650 myokines have been identified. While Pedersen estimates we only have a basic understanding of what 5% of them actually do, it’s a fair assumption that, in sum, they help explain, at a mechanistic level, many of the good things that exercise does for us. 


Beyond the details, most of which remain to be filled in, a new conception of muscle has taken root. Not only is muscle the largest organ in the body (about 40% of our total mass), it is the largest endocrine organ, that is, connected with the other major systems in the body. (Technically, myokine effects may be autocrine, affecting only the muscle cells that actually produce the peptides; or paracrine, affecting neighboring cells; or endocrine, the result of myokines circulating throughout the body like hormones.) Muscle is now seen as essential to the “cross-talk” that allows different body systems -- metabolism, immune system, brain, bones, etc. – to interact with each other. The right hand knows what the left hand is doing, the result being an efficient integration of different parts that redounds to the health of the entire organism. That is, you.


The current myokine research magnet is irisin, discovered in 2012. With the significant caveat that most of the work has been done in rodents, the evidence suggests that this protein can help turn normal fat cells, adipocytes, into “thermogenic” brown fat. This brown fat increases the number of calories the body burns at rest, improving one’s overall metabolic profile and pushing back against the deposition of fat tissue. At least as intriguing, irisin looks to be able to cross the blood-brain barrier and stimulate the activity of BDNF, a growth factor that promotes neuron growth in the brain’s hippocampus. This may provide at least a partial explanation for studies that have consistently found exercise to be associated with improved cognitive health and memory in seniors.  One academic paper published this past April investigates irisin as a potential therapeutic for Alzheimer’s disease.  


What’s the practical take-away of all this myokine research? Not much. Not yet. A recent meta-analysis of some 62 studies concluded that we can’t yet make any definitive recommendations about which forms of exercise stimulate which myokines and what optimal dose. While there is some evidence that aerobic exercise may have an edge over resistance exercise when it comes to myokine production in general, the data really is all over the place. When we do start to fill in those gaps, clinicians should be able to prescribe exercise in a more targeted way to combat specific medical conditions.  Certainly, Big Pharma is waiting for basic science to give them the ammunition they need to begin developing plausible “exercise mimetics” – exercise in a pill. How close that will ever come to the real thing remains to be seen.


In the meantime, lace up your sneakers. You’ll be the beneficiary of “exercise as medicine,” even if I can’t yet tell you exactly what’s going on.



Muscle-Organ Crosstalk: The Emerging Roles of Myokines 


Exercise training mode effects on myokine expression

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