Exercise in a pill: A distant dream or the near future?

Story By; Yildiz Kelahmetoglu & Ben Libberton

Exercised muscle will help eliminate substances that can accumulate in the brain under stress or pathological conditions and can be toxic to your brain

– Associate Professor Jorge Ruas

It’s the future and it’s time to work out. You’re not going to a gym of course. Such barbaric practices have been banned for decades. You go to your medicine cabinet, pop a small pill out of a blister pack and put it into your mouth. Gulp. Gulp. You just ran a marathon. A medal icon appears in your wearable intelligent device. All of the perks of a good workout come along: better sleep, higher metabolism, low blood pressure, and this is just scratching the surface. All but the niggling injuries and wasted time. Can you imagine the impact this would have on our everyday life?

Over time, our lifestyle has gradually become more sedentary. We want everything to be fast and perfect. Now. Not later. And we want it to be effortless. Combined with our delicious but dangerous high-calorie diet, it is a recipe for disaster and the bill comes enwrapped in several folds: poor mental health, low productivity, elevated stress levels, health problems.

To unwrap them, let’s think about how our bodies function. Just as machines, our bodies also maintain a working order: our metabolism. The secret to keep an optimal metabolism lies in the delicate balance between calorie intake and energy expenditure. A shift to neither side is favorable. Not getting enough input would break the machine. Overloading the machine makes it dysfunctional.

In Sweden, 18% of population were obese in 2014. Projected to rise to 24% by 2030

And we’re overloading it more than ever. According to the WHO, obesity has reached unprecedented levels, bringing along a long list of metabolic, mental, and other health problems. Over one third of the adult population was overweight and 1 in 10 individuals were obese in 2014. In Sweden the incidence of obesity is set at 18% and projected to rise to 24% by 2030.

One way – arguably the best way – to fix and tip the balance to equilibrium is physical exercise. But what if you can’t exercise? Many people who suffer from debilitating diseases would benefit a lot from regular physical exercise and yet they are unable to do it. Science may just come to the rescue again. Surely, for those that have been known to skip the odd gym session an exercise pill cannot come quickly enough. But this wouldn’t just be great for the couch potatoes. The potential impact on global health is far greater. In recent years, the idea of an exercise pill has been gaining more traction to help people whose disabilities prevent them from being physically active. A magic pill could change their lives.

The question is, will this ever be possible?

What happens when you exercise?

In a world where the fittest survive, the physiology of exercise has been subject of research for a long time. The biological effects of regular physical exercise at the whole-body level are shown to be quite diverse: you become more confident, energetic, happier, leaner, healthier, and fit. Not to mention that you reduce the odds of nasty diseases, such as diabetes, stroke and the like, and increase your cognitive power close to IBM’s Watson computer channeling the spirit of Albert Einstein.

All of the biology that we know can be defined on a molecular level and exercise physiology is no different. Scientists have been trying to understand which molecular pathways are activated during exercise and which molecules are the keys to unlock these pathways.

The most common approach to decipher the molecular code of exercise physiology is by dissecting the components of the exercise effect into smaller bits. “We generate mouse models to study one part at a time to see if we can isolate the individual components” says Associate Professor Jorge Ruas, group leader at Department of Physiology and Pharmacology at the Karolinska Institutet. His journey in exercise physiology started as a post-doctoral researcher in Professor Bruce Spiegelman’s lab at the Dana-Farber Cancer Institute and Harvard Medical School. His work in Boston showed that it is possible to activate a lot of what exercise does to the muscle, without the muscle performing actual exercise, through a molecule called PGC-1. PGC-1 is a transcriptional co-activator and has been shown to be an important regulator of metabolism. It is activated in muscle by endurance exercise, such as running. In the report that Dr. Ruas and his colleagues published in Cell, they showed that the alpha4 isoform (PGC1-a4) played an important role in muscle growth following resistance training. As a principal investigator at Karolinska Institutet, he is further exploring how muscles can crosstalk with other organs in exercise versus sedentary conditions, and how this is affected in diseases including but not limited to diabetes, obesity and mood disorders.

Not everyone achieve such a’high’: 

‘It all depends on how you psychologically perceive the exercise and whether you push yourself just at the right level’

Fitter, happier?

Besides the physical effects, there are other benefits of physical exercise that should not be overlooked as Dr. Ruas underlined, “When you start exercising, it induces a lot of changes in your life. People that regularly train also take good care of what and how much they eat, their sleep pattern, daily organization etc. There’s also a social component. If you are part of a group of people that are all into exercise, you are more likely to start exercising as well. You reduce stress levels, [your] mood is improved as exercise reduces overall levels of systemic inflammation, which is tightly related with mental health”.

By now, there is a consensus that regular physical exercise improves mental health. But “How?” remains as the main question in the field. The paths that lead to that effect seem quite tangled. To start with, there are direct effects on the brain, an immediate result of physical exercise. Our home-brewed morphines called endorphins are the most famous of those fast messengers and they are often credited for the feel-good effect after aerobic exercise. In 2008, German researchers reported the origin of this endorphin effect by using brain scans of runners in Cerebral Cortex. During two-hour-long runs, the brain regions that light up in response to emotions like love (pre-frontal and limbic regions) released endorphins. The more endorphins these brain areas secreted, the more euphoric the runners felt. But not everyone achieves such a “high”: “It depends on how you psychologically perceive the exercise and whether you push yourself just at the right level”, says Dr. Ruas. Not too much. Not too little. Lagom.

It seems like teaming up with others can also help. An Oxford University study in Biology Letters reported that rowers who exercised together had significantly higher endorphin release compared to solo rowers. Although the endorphin high is not long lasting, the social benefits of the exercise are. The supportive circle and team spirit amplify the reward and keep us committed to the activity.

Exploring the indirect biological effect of exercise on mental health is still navigating in largely uncharted waters. One theory is that the imbalance in neurodegenerative and neuroprotective metabolites in the brain plays a role in pathological conditions and exercise could have an effect on this aspect. The idea that muscles are blunt instruments with the sole purpose of exerting a force is ancient. Dr. Ruas explained how this works, “Exercised muscle will help eliminate substances that can accumulate in the brain under stress or pathological conditions and can be toxic to your brain. It acquires something that I call ‘detoxification capacity’. It almost resembles your liver. Your liver helps you to deal with nutrients and toxins that come in, trained muscle does kind of the same.” His team investigated this further by breaking it down to a specific pathway and a particular type of molecule called kynurenine. The kynurenine pathway is a metabolic pathway that produces the coenzyme NAD+ from the essential amino acid tryptophan. Kynurenine accumulates in the blood  under stress conditions. It can cross the blood-brain barrier via blood circulation and has been shown to have neurotoxic effects. There is growing evidence from both animal and human studies showing that the kynurenine pathway is disrupted in major depressive disorder.

To keep our muscles toned, our routine should include resistance training exercises that build up muscle mass

Dr. Ruas and his team published their findings about the molecular mechanism behind the exercise-induced detoxification of the kynurenine molecule in the journal Cell, “It also works through PGC-1 in the muscle. Once you exercise, PGC-1 is  activated. In turn, it activates the enzymes that detoxify kynurenine in the muscle”.

This finding can have immediate implications in the clinic. People suffering from depression are often told to keep a level of physical activity by their physicians. However, when you are fighting with depression, even getting out of bed might feel like a huge task as the patient has a very low energy and motivation. How to convince patients to do regular physical exercise that takes their breath away? There was no detailed explanation the doctors could provide, other than ´it is good for you´. Until recently, “I have given talks about this paper several times and I have clinicians coming up to me and saying ‘This is very interesting, now we can tell the patient we are telling you to exercise, because it’s going to take away molecules from your body that are toxic.’ Regarding physical exercise, patient compliance is a huge problem for depression disease and the explanation helps to improve that.”

To improve our mood, how do we activate our PGC-1 in the right way? Turns out PGC-1 comes in different flavors and the PGC-1a isoform that brings about the clean-up crew (PGC-1a1) is activated most by endurance training. “The most convincing line of evidence is that endurance exercise has a direct and the best effect on mental health compared to resistance training,” said Ruas. In other words, by doing cardio, you are clearing your system of toxic metabolites that are linked to depression. Unfortunately, the metabolic costs of having PGCs activated all the time are too high and your muscles shut it down after a while. The trick is to stick to it and do it regularly.

We are trying to see if we can find the chemical that activates this [PGC-1] pathway and could have a beneficial effect on our health. And I think we might get there

Enhanced exercise

The other end of the spectrum is about people who mostly do resistance training either to “perfect” their body and get that six-pack or to buff themselves up for strength. Does this produce the same detoxification? “We haven’t finished that part of the  study yet, but preliminarily, it seems that it doesn’t,” explained Dr. Ruas.

It is common among resistance trainers to use protein and amino acid supplements to stimulate and maintain muscle growth and strength, enhance energy utilization and increase protein synthesis (necessary to increase muscle mass). Or so the supplement providers claim. The problem is modern fitness supplements are not well defined at all, in fact they are not even that tightly regulated, “Do we actually need this kind of supplements, and is there a price to pay in the long run? ” says Ruas. This raises questions about how we combine fitness supplements and exercise.

Having too many amino acids around in the muscle environment can contribute to inflammation, which has been shown to have many negative effects on health.

Ongoing research in the Ruas lab is trying to address what happens when people perform endurance versus resistance training and take amino acid supplements. However, resistance trainers tend to do only resistance, have you seen a muscle-tough running on treadmill?  If we take fitness supplements and only do resistance training, we could risk a build-up of toxins. The best would be to combine resistance with endurance training.

Regarding physical exercise, patient compliance is a huge problem for depression disease and the explanation helps to improve that

There appears to be no evidence showing that any particular protein supplement has a positive effect on performance. Yet the absence of evidence cannot be considered as proof that there is no supplement that might be useful. Hence the supermarket shelves full of whey proteins, amino acid mixes, protein shakes.

Are we there yet?

If we can map the important molecular pathways involved in exercise, then would it be possible to mimic them just by taking a pill? Dr. Ruas is skeptical due to the incredible complexity of the exercise effect, “When you run there are direct effects on your brain, liver,cardiovascular system, etc. And there is also an indirect effect that comes associated with it. It’s not just about skeletal muscle. To achieve mimicry, we would need to find the right mixture of compounds that hit the right biochemical pathways in the right way in all of these organs. I am not a believer of that happening in the near future.”

But he is still optimistic about activating individual components of the network to achieve some of the perks of exercise. “We’re not trying to mimic all the beneficial effects of exercise. Since we know that PGC-1a is a master regulator of the detoxification, we are trying to see if we can find the chemical that activates this pathway and could have a beneficial effect on our health. And I think we might get there.”

While the idea of a pill that completely replaces exercise seems a long way off, the ability to mimic certain beneficial aspects of exercise is becoming a reality. Bioenergetic aspects of exercise are most achievable while the integrative effects seem to be least likely. Even without a detox pill on the horizon, research from Ruas lab shows how to protect our mental health by the good old fashioned way, doing a bit of cardio.[divider]

This text was previously published in Medicor 2017 #2
Proofread by: Joanne Bakker

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