By Professor Mike Ferenczi
Have you ever wondered how you can land a jump without tearing your muscles apart, breaking the bones in your leg or damaging your ankles, hips and knees?
The answer to this question lies in the elasticity of your muscles. The tendons attaching leg muscles to the bones behave as elastic bands, instantaneously absorbing elastic energy. However, this energy is quickly used to stretch leg muscles, and this is where the story becomes interesting, because the muscles are not only responsible for jumping and running, but also function as effective brakes to absorb energy.
The role of muscles as brakes is usually overlooked, and yet this is an essential and complex function which requires specialised processes by the muscle proteins. We are now able to understand some of the key molecular details which turn muscles from jumping machines into efficient brakes within a fraction of a second. This new understanding of the way skeletal muscles work is now being applied to a study about the way heart chambers respond to being stretched when they are filled up with blood prior to every contraction.
So where is the brake?
The muscle engine is made up of two sets of protein filaments - actin and myosin. Myosin filaments (sometimes called myosin heads) have protrusions on their surface which are the molecular motors and move along the actin filaments during contraction. The movement of thousands of molecular motors along actin filaments results in the two types of filaments sliding past each other. This causes the shortening of muscle and the development of muscle force.
Movement by the myosin heads, which leads to a series of changes in the tightness of binding to actin filaments and also changes the shape of the myosin head, is powered by the burning of molecular motor fuel called ATP. The fuel molecules bind to the myosin heads for conversion into other molecules called ADP and inorganic phosphate. This chemical reaction results in an energy change which drives the molecular motors, much like how petrol works in our car engines. ATP is quickly replenished by the cells using the energy-rich molecules that circulate in the blood, such as sugars, fats and proteins.
Our recent work has shown that these very same myosin heads that move along actin can act as brakes. Under certain conditions, the myosin heads will bind to actin and become inseparable, thus making muscles far less extensible and able to absorb the kinetic energy of the jump.
Using a fluorescent molecule which becomes brighter when it binds inorganic phosphate, the molecule acts as a marker for the appearance of the ATP breakdown products, with the fluorescence signal indicating the rate of energy utilisation. Measuring the rate of energy utilisation when muscle cells are working, such as shortening against a load, we found that a muscle is most efficient when operating at a defined velocity - one third of the maximum velocity to be exact.
What was most intriguing, however, was the observation that when muscle cells are stretched - the laboratory equivalent of landing a jump - energy utilisation stopped immediately and completely. The protein filaments in the muscle cell sensed the stretch, shut down ATP breakdown and made sure all myosin heads remained attached to actin so that the cell was taut enough to prevent elongation and damage. In short, a brake was applied!
A segment of cardiac tissue, taken by Dr Valentina Caorsi at Imperial College London. Actin filaments are labelled in green. Regions where collagen is deposited show up in purple.
What lies ahead
Using X-ray diffraction of muscle cells, we showed that recruitment of myosin heads to bind actin filaments increases dramatically at the beginning of a stretch, and that the structure of the heads attached to actin filaments is such that ATP breakdown cannot proceed, thus saving on energy.
Applying similar techniques to cardiac muscle preparations yielded similar results: ATP breakdown by cardiac muscle cells is arrested by stretch. Furthermore, we found that stretch causes the myosin heads to accumulate in a favourable state for the subsequent synchronised movement of the myosin heads, to enhance the power of the next cardiac contraction.
In the heart, stretch is key to maximising subsequent contraction. Such a mechanism bears similarities to what is known as the Frank-Starling law of the heart, by which the force of cardiac contraction increases as a function of the volume of blood that fills the heart, namely the stretch of the heart.
The mechanism we have uncovered is potentially a new contributory explanation for the Frank-Starling law of the heart and may lead to new ways to deal with heart deficiencies. In our Cardiac and Muscle Biophysics Laboratory at Research Techno Plaza at NTU, we intend to further explore the effect of stretch in cardiac tissue as this may lead to new ways of alleviating the symptoms of a defective or damaged heart.
Key to our research is the observation that cardiac performance is affected by phosphorylation of regulatory proteins. We have shown that phosphorylation of the regulatory light chain of myosin affects the contractile properties of the heart and plan to determine how phosphorylation affects the response to stretch. This is in order to understand the interactions between the various mechanical and biochemical factors that control the way the heart works, when in a healthy state or otherwise.
The LKCMedicine team working with me on this include Dr Yu Haiyang, Dr Song Weihua, Dr Samya Chakravorty and Darren Lim. We are also grateful for the continued support of the laboratory of Martin Webb at the UK's MRC National Institute for Medical Research and the National Heart and Lung Institute, Imperial College London.