Physiology Friday #216: The "Molecular Map" of Why Exercise is Good for Us
Going for a run sounds simple, but a complex cellular symphony underlies the benefits we receive from every workout.
Greetings!
Welcome to the Physiology Friday newsletter.
ICYMI
On Wednesday, I published a post discussing the different metabolic effects of the ketogenic diet and exogenous ketones during exercise.
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There’s not a single organ in our body that doesn’t benefit from exercise. Accordingly, participating in regular aerobic and resistance exercise is the best way to reduce your risk of dying or developing a number of preventable diseases. We’re well-informed about how exercise is good for us.
But understanding why exercise is good for us has been an ongoing and complicated effort. That’s because there is no one “exercise gene” or “exercise protein” through which all of the benefits of activity are mediated.
Rather, exercise results in an incredibly complex and coordinated molecular response throughout every tissue in the body. This response is mediated by so-called exerkines — signaling molecules released in response to exercise.
Exerkines allow for inter-organ crosstalk: skeletal muscles can communicate with our brain, our heart, and other organs to provide information about the exercise stimulus we’ve received and how our body should respond.
Understand the molecular response to exercise is a new area of research that is being spearheaded by the Molecular Transducers of Physical Activity Consortium (MoTrPAC), which has the goal of “developing the compendium of molecular transducers (the “molecular map”) that respond to acute and chronic exercise.”
MoTrPAC hopes to identify the specific pathways by which exercise improves health and prevents disease using a multi-omics approach (‘omics’ refers to the study of biomolecules and molecular processes that contribute to the structure and function of cells and tissues) involving proteomics, metabolomics, epigenomics, and transcriptomics, among others.
Recently, one of the first studies identifying the “molecular map” of exercise was published, and it reveals some incredible insights about the time course of events that occur during endurance exercise training.1
For the study, male and female rats underwent endurance exercise training for 1, 2, 4, or 8 weeks and had over 18 different tissues harvested 48 hours after their last exercise bout (this was done to prevent the acute influence of exercise on study outcomes). The exercise training intervention was progressive, meaning that the intensity and duration of the exercise was increased each week.
Briefly, the entire analysis involved over 200,000 and almost 3 million non-epigenetic and epigenetic measurements, respectively.
Some typical exercise-associated improvements were observed after 8 weeks of training: an increase in VO2 max of 16–18% and a reduction in body fat percentage by 5% (male rats only).
A total of 6 primary tissues were used to analyze the molecular response to exercise: white adipose tissue, lung, kidney, the gastrocnemius (calf muscle), heart, and liver.
A number of tissue-specific adaptations were observed in response to training, including responses related to the recruitment of immune cells and tissue remodeling in the lungs, cholesterol synthesis in the liver, ion flux in the heart, and metabolism and muscle contraction in the gastrocnemius.
Across all of the 6 tissues analyzed, heat shock response pathways stood out as being particularly responsive to exercise. Heat shock proteins (HSPs) are stress-response proteins that are highly conserved across species — they increase in response to stress and lead to beneficial adaptations that make cells stronger and protect against stress. All of the major HSPs were upregulated after exercise.
Enzymes known as kininogenases 1 and 2 (KNG1 and KNG2) also increased after exercise. KNG1 and 2 are speculated to play a role in exercise’s effect on improving blood pressure and insulin sensitivity.
Several transcription factors in the blood responsible for hematopoiesis and a transcription factor known as MEF2C were enriched after exercise: these are known to be involved in red blood cell production, blood vessel development, and neuron differentiation, among other effects.
In the liver, increases in signals of liver regeneration were observed, including epidermal growth factor 1, insulin like growth factor, and hepatocyte growth factor.
The researchers also sought to identify the molecular “hubs” of exercise adaptation, which revealed the following:
In the liver, substantial increases in chromatin accessibility (the physical access to DNA) were observed as compared to other tissues.
In the gastrocnemius muscle, several pathways related to lipid storage, lipid synthesis, and lipid metabolism were enriched.
In the blood, pathways related to red blood cell mobilization were enriched.
In the gastrocnemius muscle, heart muscle, and vastus lateralis muscle, a consistent increase in the enrichment of pathways involved in mitochondrial metabolism and biogenesis and heat stress responses was observed.
Of course, while understanding these molecular patterns is novel and insightful, what most of us really want to know about is how these response translate into improving our health or reducing our disease risk.
Using an approach in which they compared the findings from this multi-omics analysis with findings from other long-term exercise training studies in rats and humans, the researchers found significant overlaps between many of the molecular responses to their exercise regimen with human diseases including type 2 diabetes, cardiovascular disease, obesity, and kidney disease.
It’s been well-established that males and females respond differently to exercise. This was also observed in the current analysis — in which 58% of the training-induced responses were different between the sexes.
Of note, a strong enrichment of immune-related pathways was observed in the adipose tissue in males only. In females, a more robust immune response in the small intestine was observed, with a down-regulation of several immune cell types that, mechanistically, may confer a lower risk for inflammatory bowel disease and better gut barrier integrity.
Lastly, there were some interesting findings related to metabolism, including:
An increase in 1-methylhistidine, a marker of muscle protein turnover, in the kidney
An increase in cortisol in the kidney
An increase in glycolytic/gluconeogenic enzymes (enzymes responsible for carbohydrate breakdown and glucose production) and oxidative phosphorylation in the heart
Increased mitochondrial biogenesis in skeletal muscle, the heart, and the liver
In the liver, there was an increase in the abundance of proteins in pathways related to mitochondrial metabolism, amino acid metabolism, and lipid metabolism. The authors speculate that these liver-specific changes to lipid metabolism may explain much of the protection that exercise affords against the accumulation of liver fat in diseases like nonalcoholic fatty liver disease (NAFLD).
This ‘omics’ business is complex stuff, and unless you’re an expert in this area (which I admittedly am not), all of this jargon about proteins and pathways and enrichment may not make much sense.
That’s not really the reason why I chose to write about this study.
Rather, I think that it is incredibly fascinating to understand — even at a surface level — the complex molecular symphony that is happening every single time we exercise. It’s easy to grasp that when we workout, our heart gets stronger and our muscles grow bigger. Knowing that tens of thousands of cellular signaling events occur to help your heart or your bicep grow leads to a greater appreciation of the benefits of exercise, in my opinion.
As our understanding of the “molecular map” of exercise grows, I have no doubt that this will lead to incredible applications like therapeutics to treat diseases and even, dare I say it, an “exercise pill.”
None of this information should change how you approach exercise though: it’s beneficial whether you’re aware of the underlying adaptive mechanisms or not.
But the next time you’re out for a long run or pumping some iron in the gym, take a second to think about the organized chaos that’s happening in your body to make it stronger and healthier. It might make you appreciate every second you spend exercising a bit more.
Thanks for reading. I’ll see you next Friday.
~Brady~
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