We Are the Champions – How music helps us exercise.

In March this year, I participated in the most-excellent Science Media Space. One of the activities was to write a blog post about an interesting science topic. Yes, it has taken a while, but here's my take on the use of music in sport.

Couldn’t have made it through Run Geelong
 without my favourite playlist!

My birthday has passed for another year, signalling not only that I’ve made it through another year in the lab, but also the shift to cooler weather. Yes, summer is over (BOO!), and I actually wore my scarf for the first time this morning. But with autumn comes my return to a regime that 30C days sees fall by the wayside…

Roller Derby Fitness!

Yes, back to suicide runs, ridiculous looking squats, and the universally hated Spiderman Climbs. As a ref, we skate the full hour game, having to keep up with the fastest jammer, break hard with every tumble, and dodge each other nigh constantly. Sadly, our 2x3hr training sessions a week just don’t cut the mustard for that level of endurance. But before your quadriceps begin aching in sympathy, this increase in physical activity has one serious upside…

New Workout Playlist!

I’ve currently got a few new playlists that I’m trialling, spending a few minutes after each session pruning the slow tracks (The Vines “Ms Jackson” sadly cut), and finding the exact spot to place that motivating power song (Hello, Flogging Molly’s “Seven Deadly Sins”!). But questionable musical taste aside, I was excited to learn there’s an increasing body of science studying how music can affect our exercise performance.

Lets Get Physical

There are plenty of different factors that may influence the effect that music has on us during exercise. These can be loosely divided into the internal (rhythm response, and your own innate ‘musicality’), and the external (Cultural influences, and associations to particular music).  We’re going to focus more on the former here today, but as you can see in Figure 1, there is a complex interplay between all these factors that impact on how we react to music during physical exertion.

Music can affect us in many different ways, with many potential benefits (RPE= Rating of Perceived Exertion; Karageorghis & Priest 2011 Creative Commons)

Little is actually known about the mechanisms of how this occurs, because the equipment you would normally use to measure neurophysiological responses is notoriously immobile. Imagine trying to MRI someone in the middle of a footy field! That said, scientists are developing a good picture of the end result of listening to music while you work out.

Music exerts what is known as an ergogenic effect on our bodies, that is it improves physical exercise performance by delaying the onset of fatigue or increasing our capacity for work, which manifest as “higher-than-expected levels of endurance, power, productivity or strength”. It also has a psychological effect, influencing mood, emotion, thought processes and behaviour, and psychophysiological effects, such as the perception of effort and fatigue.

Big Distraction

The nervous system is complex, but sensory stimuli, like music, can actually block the feedback signals created in response to exercise. Literally a sensory overload, you’re distracting the body from responding to fatigue. This varies at different exercise levels, i.e. the harder your body is working, the stronger the physical feedback signals, so the inhibiting effect of music gets drowned out. Even so, your choice of music may actually make you feel better about being fatigued, so don’t write it off if you’re pushing your boundaries!

Totally Addicted to Bass

We all do it. You’re favourite song comes on, and you start using your fingers, feet, and the nearest surface to start tapping out the percussion. Humans are hard-wired to synchronise our movements to music. Its been suggested that we have a pattern generator, much like a pacemaker in our brain, that coordinates afferent (incoming/sensory) & efferent (outgoing/motor) nerve signals, resulting in the syncing we see when our stride starts matching the beat.

The part of our brain that processes pre-movement signals shows increased activity with a ‘preferred’ tempo, making it easier to key-in to a beat that appeals to us. Our body relaxes more into exercise when it can follow a repetitive rhythm, like that throbbing baseline, increasing efficiency by taking away the need for minute kinetic adjustment, letting you maintain that steady state longer than in the absence of music.

It’s not just that bass drum either: When scientists just played the extracted drumbeat to participants, while still better than no music, endurance decreased. This pushes the case that it is a collective impact, the beat, lyrics and harmonies, that make the difference.

Pump Up the Jam

Changing the tempo of your music can lead to a change in your work rate. There have been a couple of studies that have shown that when we switch to a higher tempo, the faster pace seems more stimulating, and we up our output. Its great for when your enthusiasm starts to plateau, especially when you’re hitting the later stages of your workout. Long live the power song!

Faster music is generally preferred at higher exercise intensities, i.e. when your heart is really pumping. However, this relationship is not linear, and actually tapers off at higher levels of exertion. So while that 180 bpm espoused as the golden rule by running music webpages everywhere may be perfect for elite athletes, your mileage may vary depending on your fitness level, how hard you’re pushing, and what your goals are.

Louder fast paced music can also be beneficial, leading to high output, though changing volumes at slow tempos does little. Just keep in mind that loud music can damage your ears, or drown out things like traffic. Your danger response reflex will be dampened, so you may not notice a hazard until its too late.

Push It Real Good

Self-paced exercise, like what we do when we go for a run, ride or skate, is where the effect of music really shines. It has been demonstrated that motivational music (generally 140+ bpm) can enhance exertion without increasing perceived exertion. This means that they are increasing their speed, power, distance, what-have-you, without actually realising they are working harder!

So how do we put this all together? Get an idea of where you are now, and where you want to be. Then, put together a play list of tracks that you love, aiming for a BPM range that matches your style, varying the tempo for your chosen workout, For example, my intervals playlist starts with a 140 warm-up, a 130 stretch song, then jumps around between 140-170, with a 180 ‘sprint’ song thrown in every now and then to pump up the motivation. Last season, I had a great ‘pyramid’ list, which started at 130, and got incrementally faster with each song, peaking with 3 minutes of 180 bpm before incrementally decreasing again. Then, like every good scientist, test, refine, repeat!

So load up your mp3 player, lace-up your boots, and get that heart rate pumping. Step aside dodgy AFL ‘peptides’: Music is the drug, a 100% legal performance-enhancing drug.

SeeMyScience: Cancer Cachexia Cell Lines - The Why and The How

In order to study cancer cachexia, we need to use a type of cancer that will cause cachexia in a controlled way. We need to know exactly how long it will take, how the cancer will act, and be confident that it will always produce the same result. There are different lines of cells that will cause cachexia, each with its own benefits and drawbacks. Our lab uses the well-characterised Murine Adenocarcinoma 16 (MAC16) model of cachexia.

They may not look much, but these are lean,
mean, cachexia-causing machines

What do the MAC cells do?

The MAC16 cell line produces a round, isolated tumour at the site of injection. The rate of growth varies a small amount from animal to animal, but it will usually appear as a small bump, like a grain of sand under the skin, at 3-7 days. The MAC16 model is not invasive, in that it does not migrate or infiltrate other organs and cavities, but remains wrapped in its own thin-membraned compartment.

Weight-loss begins around the same time as the tumour appears, gradually at first. Weight-loss is usually significant from around the 12 day mark, and may reach up to 15% of initial body-weight by the end of the study. The weight-loss is caused by a number of different factors, including a number of particular chemicals, or “tumour factors”, secreted by the cancer.

Unlike many other cancer types used in the lab, this cell line does not, in our experienced, decrease appetite. This is very important, because it allows us to make sure that the weight loss is being caused by the cachexia, rather than starvation.

How does your cell-line grow?

Cells can be very temperamental when they are growing outside of an organism. We grow them in plastic flasks, in a liquid nutrient mixture, containing proteins and sugars to nourish them, buffers to keep them at the right pH level, and antibiotics to fight off bacteria. The cells take up the nutrients in this “growth media”, and excrete their waste into it. This means it needs to be changed every 48 hours, so that they aren’t poisoned by their own waste.
The cells are kept at a constant 37C, with 5% Carbon Dioxide, which is roughly the same conditions as they would experience if they were living in a mammal. It takes anywhere between 3 days and 2 weeks for the cells to reach “80% confluence”, which means they have multiplied to the point that cells are taking up 80% of the media volume.


Once they reach 80%, we can do one of three things: split them into new flasks, so they keep growing without smothering themselves, freeze them down to place them in storage, or study what they do in an animal model, which is what we will talk about next.

Neysa

“See My Science” aims to explain the science done by our group in a manner accessible to the public. The current series focuses on the following publication: Vaughan VC et al (2012) Eicosapentaenoic Acid and Oxypurinol in the Treatment of Muscle Wasting in a Mouse Model of Cancer Cachexia. PLoS ONE 7(9): e45900. doi:10.1371/journal.pone.0045900

SeeMyScience: Fighting Back – EPA & Oxypurinol to treat Cachexia

As a condition that affects so many people, and so negatively impacts on treatment success and quality of life, the effective treatment of cachexia is increasingly acknowledged as imperative for improving patient care.

Unfortunately, there is no ‘Silver Bullet’ where cachexia is concerned. As a complex condition, involving many convoluted pathways, many potential treatments only treat one section of the syndrome, only work on a certain part of the cachectic population, or are simply ineffective. It’s like a game of Whack-A-Mole: you hit one thing on the head, and another pops up somewhere else.

For this reason, we need to look at what is called “multi-target therapy”, a treatment that hits the cachexia pathways in lots of places, rather than just one.

EPA

Salmon & other oily fish are rich sources of EPA

You know all those adverts on TV talking about fish oil, or krill oil, and how excellent for your health it is? There are two main reasons for that: EPA and DHA.

Not all omega-3s are created equal. While you can find some omega-3s in plant products, such as flax, soy and canola, our bodies have a hard time converting these to long-chain omega-3s, like EPA and DHA. EPA (Eicosapentaenoc acid) and DHA (docosahexanoic acid) are long-chain omega-3 fatty acids, oily substances found in fish, which are essential for the growth and health of our bodies. I am particularly interested in EPA, and how it may help us stop muscle loss in cachexia.

In my last post, I mentioned how oxidative stress, the imbalance of antioxidants and free radicals, is a key player in cachexia. There has been research suggesting that EPA added to your diet can encourage certain antioxidants to be more active, increasing the body’s capacity to deal with excess free radicals. We’re giving the body a few extra security guards to throw the rowdy footy-trippers back onto the bus.

Interestingly, when eaten in high levels, EPA also replaces Arachidonic Acid (AA). AA is an omega-6 fatty acid, which, for the purposes of this discussion, you could think of as an opposite of EPA. While EPA can be used by the body as an anti-inflammatory, mopping up after sometimes harmful chemicals released in response to the tumour, AA is used to create inflammation, which can lead to the release of factors that cause muscle wasting.

There have already been lots of trials looking at EPA in cachexia, with mixed results. Normally, it appears to work really well in animal models, slowing down muscle loss, and even slowing tumour growth. Unfortunately, when you give it to humans, it’s not terribly effective on its own. The most recent studies suggest that you need to combine EPA with exercise, good nutrition support, and some form of pharmaceutical agent. This is where oxypurinol comes in.

 

Oxypurinol

Oxypurinol is a strong inhibitor of the enzyme xanthine oxidase (XO), which produces free radicals as part of its normal processes. It blocks the ability for XO to convert hypoxanthine to xanthine to uric acid.

It might look cool, but Xanthine Oxidase could be
causing major problems for cachectic patients

Blocking this process could have several benefits in cachexia:

1.   Uric acid encourages the release of AA from cell membranes. AA is thought to be a key point in the pathway that leads to muscle wasting in cachexia. By making less of it available, we might slow down the muscle wasting
2. Blocking XO will mean less free radicals being produced, meaning less oxidative stress, and the damage it causes.

Oxypurinol hasn't been studied as a treatment for muscle wasting in cachexia previously,  but has been used to successfully treat gout, another XO linked disorder, and its pre-cursor, allopurinol, has been used in the treatment of muscle injury for many years.

Putting it all together

So, we have our two treatment strategies – a pharmaceutical (Oxypurinol), and a nutritional supplement (EPA). How do they work together to target cachexia?

Figure 2. How EPA and Oxypurinol may act to interfere in the muscle wasting pathways of cancer cachexia. Adapted from Vaughan et al 2012, J Cachexia Sarcopenia Muscle

As you can see in the diagram, EPA is stopping the release of tumour factors, and increasing antioxidant activity, while also replacing AA. Meanwhile, oxypurinol is blocking the production of free radicals by XO, and stopping the formation of uric acid, which stops the release of AA.

With this hypothesis in hand, we began the process of testing our treatments. In the next "See My Science" post, I’ll begin looking at the methods we use to study cancer cachexia in the lab, and how we can tell if the treatments are working. 

Neysa

“See My Science” aims to explain the science done by our group in a manner accessible to the public. The current series focuses on the following publication: Vaughan VC et al (2012) Eicosapentaenoic Acid and Oxypurinol in the Treatment of Muscle Wasting in a Mouse Model of Cancer Cachexia. PLoS ONE 7(9): e45900. doi:10.1371/journal.pone.0045900

SeeMyScience: Why is the Muscle Gone? Altered pathways in Cancer Cachexia.

Cachexia is a complex condition of muscle wasting affecting about half of all cancer patients. In the last installment of “See My Science”, we discussed what cachexia is, and how it affects patients. In this post, I’ll expand on some of the key pathway changes we focus on, and how they lead to muscle loss.

 

Antioxidants are the enzymes keeping destructive
Free Radicals under control. Source: Doctor Fun

Stressed Out

The body is fighting a constant battle to maintain the status-quo, a fine balancing act where the smallest change in one area could have huge effects down the track. One of these on-going fights is between free radicals and antioxidants. Free radicals are a normal product of bodily function, and are used in the day-to-day functioning of cell systems. However, if overproduced, and not kept in check, these highly reactive species can become seriously destructive, causing damage to DNA, proteins, and other parts of the cell, a state known as “Oxidative Stress”.

Of all the free radical producing enzymes, I’m most interested in one called Xanthine Oxidase (XO). XO is responsible for the conversion of purines, and makes the free radical superoxide (O₂-) as a byproduct. Both superoxide and the end-products of purine conversion help drive the cells in the direction of protein breakdown.

What keeps free radicals in check? Antioxidants. You may know of antioxidants as something you get from heavily hyped “super foods”, but our body actually already has antioxidants in place, their sole purpose in life being to take highly reactive free radicals, break them down (or rather, build them up by donating elections) into less destructive molecules. For example, superoxide can be broken down into hydrogen peroxide and oxygen by SOD, and the hydrogen peroxide can be further broken down into oxygen and water by Catalase and GPx.

My boss explains it in a great way: think of free radicals like a rowdy football team on their end of season trip. They’ve had a few drinks, things have gotten out of hand, and they’re starting to get a bit rowdy. The second they are off the bus, things get a bit rough, and maybe they start breaking a few things, getting into fights. Antioxidants are the bus and the security guards: they keep them contained, and limit the amount they can damage.

When there aren’t enough antioxidants, or they’re not working efficiently enough to mop up the excess free radicals, we start to see the accumulation of damage we associate with oxidative stress. Oxidative stress is known to be a key player in many conditions, including cachexia.

Figure 1. An example of muscle wasting pathways in cachexia. A complex cascade of reactions is triggered by molecules released by the tumour. Source: Vaughan et al 2012, J Cachexia Sarcopenia Muscle.

 

How is Oxidative Stress involved in Cancer Cachexia?

Levels of free radicals and the damage they cause have previously been shown to increase in patients with cancer and cachexia. Several studies have also shown that antioxidants are present in lower levels, or are not working as efficiently in cachexia as they would in a weight-stable or healthy person. This means that they are not able to compensate for the increased activity of free radical-producing pathways, resulting in oxidative stress.

In addition to the damage they cause, free radicals play an important role in cell signaling, where they are involved in the pathways that drive muscle break-down. An example of this is the key muscle-degrading pathway we are interested in, the Ubiquitin Proteolytic Pathway (UPP; See Figure 1).

The Ubiquitin Proteolytic Pathway

The UPP is basically a system that uses ubiquitin molecules to tag proteins that are to be broken down. Ubiquitin is activated by an E1 enzyme, moves to a carrier protein (E2), which then recognizes E3 protein ligases. Two E3s in particular, known as MuRF1 (Muscle RING-finger protein-1) and Atrogin1/MAFbx (Muscle Atrophy F-box), have been suggested as key to the loss of muscle in wasting. Together, the E2 and E3 enzymes attach a chain of ubiquitin enzymes to the target protein (in our case a muscle protein), which can then be unfolded and broken down by a unit called a ‘proteasome’. The proteasome breaks the protein into its smaller building blocks, peptides, which then get broken up into even smaller bits, amino acids. This sudden surge of amino acids can be used to make proteins that further drive the UPP, creating a vicious cycle of muscle destruction, as shown in the bottom section of Figure 1.

Certain components of the UPP are increased in experimental models & patients with cachexia, which means increased potential for them to be tagging our muscle proteins. Increased levels of free radicals can help drive the reactions that lead to the activation of the UPP, by signaling for the control of rate at which the various components are produced.

How are we looking at these pathways?

In order to determine whether there is an increase in potential free radical production in cachectic muscle, and an increase in damage caused by them, we look at the expression levels of genes for our two free radical-producing enzymes of interest,XO and NOX. We also look at the activity of XO, as an increase will indicate that more free radicals are being produced as a by-product. To identify damage caused by free radicals, we look at a marker referred to as 8-OH-dG, which is produced when free radicals damage DNA. We also check what the levels of gene expression are like for certain components of the UPP, as increased expression gives an indication that there is greater potential for the breakdown of proteins by that method.

To figure out what’s going on with antioxidants, we do similar work. I look at the gene expression levels of the different SODs, GPx, and Catalase, and their activity levels in muscle samples. If there is no change in their levels or activity, but there is an increase in free radical production, it means the body is not compensating for the increased potential for damage.  If they have decreased compared to healthy or weight-stable tissue, it means that the there is a decreased ability for the cell to clean up the excess free radicals. Either way, oxidative stress is on the cards.

For this particular study, we were more interested in whether these pathways can be returned to normal (or at very least cleaned up after!) by our two treatments, fish oil and oxypurinol. In my next post, I’ll explain why I think these treatments will be beneficial to cancer patients, and how they fit into the above systems.

Neysa

“See My Science” aims to explain the science done by our group in a manner accessible to the public. The current series focuses on the following publication: Vaughan VC et al (2012) Eicosapentaenoic Acid and Oxypurinol in the Treatment of Muscle Wasting in a Mouse Model of Cancer Cachexia. PLoS ONE 7(9): e45900. doi:10.1371/journal.pone.0045900