How a Molecular “Switch” Inside Your Muscles Motivates You To Exercise More
This Week’s Research Highlight
Background
According to recent data from the CDC, only about 1 in 4 adults in the United States meet the current physical activity guidelines.
The reasons for this, of course, are complicated. Modern work and leisure activities are often sedentary. Infrastructure is optimized for automobiles, rather than biking or walking. Indeed, our own minds often work against us, favoring rest over movement at every opportunity.
But the good news is that if you manage to stick with an exercise routine for long enough, it usually gets a bit easier and more positively reinforcing over time.
Reminds me of this scene from Bojack Horseman
We see this in rodent models, wherein rats that are exposed to running wheels for six weeks become more intrinsically motivated to run, compared to those who only spend two weeks in proximity to such wheels.
But why?
Perhaps we should look to muscle itself, for the answer.
One thing we have come to realize in recent years is that skeletal muscle is actually an endocrine organ. When muscle contracts, like during physical activity, hundreds of tiny proteins known as myokines are secreted from muscle cells into the bloodstream, where they can circulate throughout the body. Remarkably, there are myokine receptors distributed in our liver, pancreas, bone, heart, and so forth, enabling muscle to effectively interact with other organ systems — including the brain.
From Severinsen & Pedersen, 2020
Notably, the cognitive benefits associated with physical activity are thought to be mediated, at least in part, by these factors.
So could myokines influence motivation to exercise through the central nervous system?
Sounds far-fetched, but there might be something to it.
Study
When we exercise, the p38 signaling pathway is activated.
Now, p38 is what you might call a Janus-faced enzyme. On the one hand, p38 activation has been shown to boost sugar uptake by muscle during exercise, thus lowering blood glucose and enhancing insulin sensitivity. But at the same time, this pathway has also been linked to insulin resistance and glucose intolerance.
The reason for this apparently contradictory behavior is p38 is actually composed of multiple kinases that have opposing functions. Specifically, p38γ seems to promote greater glucose uptake and insulin sensitivity, while p38α has the opposite effect.
To gain more insight into this puzzling pathway, a team of Spanish researchers conducted a series of rodent experiments.
First, in order to disentangle the impact of the different members of the p38 family, the scientists genetically engineered mice to lack p38α inside their muscles, while leaving p38γ intact. This, as one might expect, elicited an array of metabolic benefits: the p38α knockout mice were leaner, had lower blood sugar, better glucose tolerance, and were resistant to obesity and type 2 diabetes, even while being fed a high-fat diet.
When the researchers dug a little deeper, they determined that the absence of p38α in muscle was leading to hyperactivation of p38γ, and this appeared to be driving the extraordinary health of these critters. Sure enough, when the researchers deleted p38α and p38γ, the metabolic benefits were abolished — indicating that p38γ was indeed responsible.
But the researchers noticed something else about p38γ activation — it seemed to cause the rodents to run around more. To examine this, they deliberately overexpressed active p38γ in muscle. Subsequently, the mice engaged in more wheel running of their own volition. A lot more.
Not only did they choose to run more, they also got faster. When subjected to a treadmill exhaustion test, mice with overexpressed p38γ ran longer and at a greater max velocity.
So p38γ activation not only seemed to drive greater activity, but also triggered performance enhancement.
In order to understand why, we need to look a little further downstream of the p38γ signaling pathway.
Role of interleukin-15
Activation of p38γ triggers secretion of interleukin-15 (IL-15). IL-15 is a myokine that is thought to play a role in muscle remodeling in response to exercise.
When the researchers analyzed the muscles of p38α knockout mice, they found increased expression of IL-15, and overexpression of p38γ led to a boost in IL-15 levels in both the muscle and blood.
Finally, administering IL-15 intravenously led to greater running and energy expenditure — basically confirming that this was the mechanism through which p38γ leads to increased voluntary exercise.
But how exactly does IL-15 do this?
That’s not totally clear, but we do know that IL-15, like other myokines, interacts with the brain, and specifically that it regulates movement through signaling in the motor cortex.
To test whether IL-15 might be affecting spontaneous exercise via the central nervous system, the team selectively suppressed IL-15 signaling in the primary motor cortex of the p38α knockout mice. Sure enough, the beneficial metabolic effects of p38α knockout status were reversed, and the rodents became less active.
The balance of p38α and p38γ
What we are seeing here is that these two kinases of p38 play opposing roles in regulating physical activity.
p38γ enhances production of IL-15, which in turn promotes physical activity. Meanwhile, p38α inhibits the action of p38γ, acting as a molecular brake.
The researchers suggest that this regulatory function may have developed to avoid overexertion or injury through excessive activity. And if we try to look at it from an evolutionary perspective, it’s easy to see why controlling energy expenditure would be critical in a natural environment where access to food is not guaranteed. This may also explain why p38α increases blood sugar and lowers insulin sensitivity — in certain contexts, insulin resistance is actually adaptive for survival.
But the good news here is that regular exercise, over time, seems to tilt the balance in favor of p38γ.
Long term impact
Finally, the researchers wanted to see how exercise training, over time, affected the relative activity of the two kinases. To that end, they compared p38α and p38γ levels in mice that engaged in regular aerobic exercise to sedentary counterparts.
After five weeks, they observed increased activation of p38γ in exercising mice, while p38α activation was attenuated.
As the researchers state,
“This suggests a shift in the balance between these regulators during training, where increased p38γ activation may contribute to enhanced exercise tolerance.”
Does this apply to humans? Perhaps.
In humans, levels of IL-15 increase acutely after aerobic exercise by more than 5-fold. Interestingly, athletes have been shown to experience a significantly greater and more prolonged increase in circulating IL-15, compared to sedentary individuals and even trained participants. This is thought to reflect an adaptation to training, wherein chronic exercise leads to greater intramuscular supply of IL-15, ultimately leading to boosted secretion in response to exercise.
Levels of IL-15 after exercise are much higher in masters athletes than in young and middle-aged controls
From Minuzzi et al, 2019
So, to sum up:
- Physical activity leads to greater secretion of IL-15 during exercise via the p38γ pathway
- After the exercise bout, IL-15 travels through the blood to the brain, where it interacts with the cerebral motor cortex
- Chronic exercise leads to boosted p38γ activation and enrichment of IL-15 in skeletal muscle
- This produces a virtuous cycle, wherein higher IL-15 expression in muscle and higher IL-15 levels in the blood post-workout signal to the motor cortex to engage in even more physical activity
Random Trivia & Weird News
Peter the Great imposed a tax on men who grew beards.
Peter the Great is so known because of his role in modernizing Russia. In the early eighteenth century, Peter traveled incognito through Western Europe, and was blown away by the cultural and technological advancements that he observed there. He came to see Russia, in contrast, as hopelessly backward, and felt that the empire needed to be pushed forward at all costs.
One dimension of his vision of modernity was aesthetic. Russian men commonly grew long beards at the time, but the style had fallen out of fashion in the rest of the continent, and clean-shaven was the norm throughout Western Europe. To spur progress, Peter promoted a “beard tax.” Any man who wanted to keep his beard had to pay this tax, and carry a token on his person to prove that he had paid. Those who failed to comply would have their beards sliced off by the Tsar’s inspectors.
The ban on beards sounds frivolous at best (and tyrannical at worst), but it was emblematic of Peter’s larger reform agenda, which aimed to break away from old traditions and align Russia with Western customs, and hopefully making the nation competitive on an international stage.
Image credit: Getty
Podcasts We Loved This Week
- Kevin Tracey: Neuro-immunology and the treatment of inflammatory disease. Via STEM-Talk.
- Michael Varnum: Could “season creep” affect human behavior? Via Science Friday.
Products We Like
Fitbites Boba Protein Powder
This is a fun way to get some more protein in your diet if you’re a fan of boba tea. They have eight different flavors (I would recommend ordering the sample box from the website), which mirror common styles of boba tea. I’m a fan of the taro — it blends relatively well in milk, and is very satisfying with some tapioca pearls.
humanOS Catalog Feature of the Week
How Much Physical Activity Do We Need?
In this course, we:
- Examine how physical activity is defined and measured
- Explore the physical activity of our ancient ancestors and modern day hunter-gatherers, to get a sense for “natural” patterns of physical activity for which we evolved
- Look at how physical activity and fitness affect health and lifespan
- Review the key components of a smart activity program, so you can get the right dose of physical activity for you!
Wishing you the best,
