The previous post in this series can be found here.
In my last post I talked about how we are all powered by tiny spinning motors that work tirelessly to convert the chemical energy of our food into electrical potential energy, and then back into chemical energy in the form of the cellular energy currency, ATP . This week, I thought it would be interesting to look at how that ATP gets used up in a process that will be very familiar to you but that you probably know little about: muscle contraction.
As I mentioned last time, ATP is used by just about every active process that takes place in your cells. Most of these processes siphon only tiny amounts of ATP from the ever-replenished pool that is available in your cells – as far as they’re concerned there is an infinite amount of ATP available because they could never use is all up on their own. For this reason, a lot of our cellular machinery is, frankly, wasteful. The mechanisms that regulate DNA repair, movement of organelles within cells, and many other processes consume ATP with gay abandon because their impact is so miniscule on the total energy consumed by your body as a whole. There has been no need to evolve more cost-efficient mechanisms, such as those employed by our single-celled relatives for whom every ATP counts!
For some components of the human machine, however, their impact on total ATP consumption is far from insignificant. One often overlooked example is neural transmission, which is why the brain consumes around 20% of your total calories on an average day, and why you may find yourself famished after a tough exam even though you’ve just been sat down for three hours! Nonetheless, the clear winner in the ATP-expenditure competition is muscle contraction. Your muscles are responsible for using nearly 60% of your total calories on an average day – potentially far more if you’re very active (or very muscular!). Motile animals have to consume far more energy to survive than non-motile animals or plants, and this is primarily down to their muscles. Fortunately, this is very much worth it because being able to move gives you far broader options in terms of finding food in the first place. Moreover, because of its huge significance in terms of total energy consumption, the molecular basis of muscle contraction has evolved to be a highly efficient affair. In fact, in terms of work achieved per ATP used, muscle contraction is one of the most efficient processes in your body – it’s simply the fact that it’s used on a huge scale that makes it such an ATP-hungry mechanism.
The fine detail of mechanical beauty
Your musculature system is built on a very simple idea: individual muscles pull parts of the body in one direction, others in the opposite direction. Muscles never push, indeed they can’t push – they can only pull. The reason for this is found in the fine structure of the muscle tissue. All of your muscles are made up of a dense collection of individual muscle fibres that pack together to form the entire muscle. These fibres are made from special cells known as myocytes that fuse together within the fibre to form one huge structure that acts, in effect, as one massive cell. Each fibre is capable of independent contraction, in which it actively shortens and thickens its whole structure. When every fibre in your muscle contracts at once, the overall difference in length becomes enormous (on a cellular level anyway) and so the familiar effect of muscle contraction is achieved. Every movement you've ever made has been possible because of the simultaneous cooperation of innumerable fibres working in unison. But how does each fibre actually contract? Each one is further subdivided into cylindrical structures known as myofibrils. These are the unit of contraction in which the action happens. The rest of the fibre contains plenty of mitochondria to constantly pump out ATP for use in contraction, and a specialised bag-like structure known as the sarcoplasmic reticulum that contains heaps of calcium ions, the significance of which will be discussed later.
|Your muscles are not as simple as they look!|
As we move down to smaller and smaller scales, we learn that each myofibril also has an internal structure. It is at this scale that we finally meet the mechanical components responsible for contraction. Within each myofibril are a number of tiny fibres made up of repeating units of two proteins: actin and myosin. These proteins are organised into discrete units known as sarcomeres, in which actin (also known as the ‘thin’ fibre) is attached to the two ends of the sarcomere and extends into the centre, whilst myosin (the ‘thick’ fibre) is primarily attached to the centre and extends towards the ends. This generates a structure in which the two halves of the sarcomere are capable of moving relative to one another. When the fibre contracts, the two halves are pulled closer to one another, thereby shortening the whole sarcomere: hence the whole myofibril; the whole muscle fibre; and the whole muscle shortens. Pulling the two halves of the sarcomere together is the process that uses up so much of your ATP, and has evolved to be a highly efficient process.
The process by which the sarcomere is shortened is a stroke of evolutionary genius that works with all of the elegance of any manmade machine. It all centres around what’s known as the ‘power stroke’ between actin and myosin. Actin itself doesn’t actually do any of the work, it simply provides a scaffold for myosin the latch onto in order to pull the two ends of the sarcomere together; myosin is the real workhorse. The structure of myosin contains a distinct head-like structure that protrudes out from the main myosin fibre and is capable of grabbing and moving actin. When you decide to contract a muscle, signals are sent from your brain to the nerves connecting to the muscle in question. These final nerves form a contact known as theneuromuscular junction, and when activated they release a neurotransmitter called acetylcholine onto the surface of the muscle fibres and the chain of events is now irreversibly set in motion that will cause contraction. Acetylcholine binding to receptors at the surface of the muscle fibres causes a cascade of signalling that sweeps through the whole fibre. The primary outcome of this is that the sarcoplasmic reticulum, which I mentioned earlier, disgorges all of its stored calcium into the surrounding myofibrils. Calcium plays a vital role in the regulation of muscle contraction because it binds to a protein called tropomyosin that winds its way around the actin fibre. In a resting muscle, tropomyosin sits in the clefts within the actin fibre that the myosin head is capable of binding to, and so actin and myosin are unable to interact. Calcium binds to tropomyosin and acts as a charge bridge (since calcium ions are positively charged) between two distinct parts of the protein. Pulling together these two sections of tropomyosin causes the whole shape of the protein to alter – the tropomyosin rotates relative to the actin filament and so exposes the myosin-binding site. This all happens without the need for ATP, although ATP is required to pump all of the calcium back into the sarcoplasmic reticulum at the end of contraction.
Now that myosin is free to bind actin, the power stroke can begin in earnest. To start with, the myosin head is bound to the two components that are used to make up ATP: ADP and Pi. In this state, its head is in an extended conformation and points away from the rest of the myosin fibre, and it is like this that it binds to actin. Once it is tightly latched on to the actin filament, the myosin head lets go of its ADP and Pi. This has a profound impact on myosin structure as the ADP and Pi are required to keep the head pointing away from the rest of myosin, without them the head swings backwards by 40˚, equating to a movement of around 6nm. Since it’s attached to actin, the actin also has to move that far to stay bound, and so the sarcomere is partially shortened. However, 6nm is not very much so the process must be repeated over and over again, gradually ratcheting the sarcomere shorter and shorter. In order for the cycle to restart we need our old friend ATP, which binds to the myosin head and stabilises a form in which it is able to release the actin. Nonetheless, the myosin head is still in its ‘contracted’ state and so must return to its original, extended conformation before the process can begin again. This is achieved by breaking down the newly-bound ATP into ADP and Pi, thus returning the system to its starting state. So, the energy that you use in muscle contraction is not actually directly used to make your muscle contract, but instead to allow the cycle to be reset. This is why a cramp in your leg is characterised by painful over-contraction of the muscle: you’ve over exerted yourself and so can’t produce enough ATP to allow efficient detachment of myosin from actin and thus can’t stop contracting. The same is true in the case of rigor mortis, as your muscles use up what little ATP is left in their cells and stiffen up never to be relaxed.
The overall effect of your muscles contracting is achieved by billions of tiny power strokes taking place at unimaginable speed over and over again until full contraction is reached. This is in turn powered by countless ATP synthase motors spinning furiously to prevent a shortfall in ATP, as mentioned in my previous post. We are, in a very real sense, highly-tuned machines that have individual moving components working in unison to accomplish set goals. Often when I’m running or cycling I will think about the unimaginably enormous number of individual processes that have to constantly rage in my muscles to allow me to keep going; but the same is true for any movement at all – you evoke the same response just by moving your eyes along this line of text.
What's left to learn?
The details that I have related to you above have been slowly pieced together over the last hundred years or so in ever increasing depth and understanding. We are now at a point where we understand the process of muscle contraction and its regulation very well. However, many of the ways in which the structures that I have described above (sarcomeres, myofibrils, etc.) develop are still a mystery. Much headway has been made in recent years in our understanding of how the developmental processes behind these structures are regulated. This is often due to the investigation of a number or developmental disorders that highlight the role of specific gene and allow researchers to use that as a starting point. For example, our understanding of the role that the DMPK gene plays in muscle development has come primarily out of work looking into the genetic disorder myotonic dystrophy. Such investigations often have unexpected relevance to other fields since all biology is connected and we are unbelievably complex organisms. An example of this is the study of Emery-Dreifuss muscular dystrophy, a genetic disorder characterised by muscle wasting and cardiac problems. It was discovered that this is sometimes caused by mutations in genes encoding the lamin proteins. Lamins are responsible for the correct organisation of the nucleus within each cell, but this discovery revealed that correct muscle development is also highly dependent on them. Many of the proteins that are required for muscle development and contraction also have other roles (actin, in particular, acts as the internal skeleton for all cells), and much of the work that is currently ongoing is looking at how these different roles are reconciled with one another and how they are pushed into one job or the other.
All of this brings us closer to fully understanding our own complex construction, but also offers more immediate potential for the treatment of various disorders. For example, our understanding of what causes Duchenne muscular dystrophy has allowed the development of targeted gene therapies that may offer hope to sufferers by partially restoring normal function of their defective dystrophin genes. Similar trials are ongoing in several areas of neuromuscular developmental disorders, but none of it would be possible without a detailed biochemical understanding of how muscles work in the first place.
If you're at all interested, a highly interesting account of the evolution of muscle is given in Nick Lane's 'Life Ascending: The Ten Great Inventions of Evolution' along with, surprise, surprise, nine other cornerstones of life. It is definitely well worth a read!
The next post in this series can be found here.
The next post in this series can be found here.