In the first in a new series of ‘In Brief’ articles, Andrew Gladman provides a helpful insight into the science behind fairly common topics and explores how they relate to ME/CFS. This time he looks at the muscles, exploring how our reported symptoms might be associated with our condition and considers why such problems could occur…
When ME/CFS is discussed, conversation quickly passes into the realm of infectious agents, immune system defects and, often, the autonomic nervous system.
Little heed is generally paid to one of the most obvious systems affected by the condition – the muscles. The network of tissue throughout the human body, and to which the more traditional name for our disease is directly related: myalgic encephalomyelitis.
A patients, what we experience as muscle-related symptoms are actually not all that unique to our condition. For the vast majority of chronic conditions, muscle fatigue, muscle aches and feelings of, or even actual, muscle weakness etc., are frequently reported associations.
It is perhaps because of this that the importance of muscle function, or dysfunction, in ME/CFS has been overlooked.
But let’s begin with an exploration of the fundamentals and consider how our muscles work, and then return our thoughts to asking why such symptoms are seemingly so common in ME/CFS and what they could be telling us about our disease.
What are Muscles?
Muscles are an integral fibrous and elastic tissue in the human body, comprised of highly specialised myocytes (muscle cells). The primary function of muscles is maintaining posture, locomotion (movement) and further movement of the internal organs.
It is estimated that upwards of 50% of the total body mass in humans is comprised of muscles — a sobering thought as to how important muscles truly are.
Muscles are often divided into three categories depending upon their unique structure and function:
- Skeletal Muscle:
This muscle type is often better known as ‘voluntary muscle’. These muscles are anchored to bone via strong (non-flexible) tendons, and often work in pairs around a single joint – when one contracts the other relaxes allowing movement.
An example of this would be the bicep and tricep in the arm. When the bicep contracts the tricep relaxes, because of the shortening of the bicep the arm bends. Similarly, when straightening the arm, the tricep contracts and the bicep relaxes.
Skeletal muscle is striated (appears striped across the length when observed under a microscope, with light and dark bands). The importance of this is discussed later in the article. Such muscle tires rapidly, only being made up of 1-2% of mitochondria.
- Smooth Muscle:
This muscle type is better known as ‘involuntary muscle’. Smooth muscle is tasked with non-conscious muscle movement such as peristalsis of the esophagus, stomach and intestines, vasoconstriction/vasodilation of blood vessels and also the muscles of the eyes – controlling pupil dilation and contraction.
These muscle are controlled primarily through the action of the autonomic nervous system. Smooth muscle is not striated and it tires very slowly.
- Cardiac Muscle:
This muscle is also involuntary, however its structure is much closer to that of skeletal muscle, showing similar striation under a microscope. Cardiac muscle, unlike both skeletal and smooth muscle, does not tire due, for the most part, to the myocytes comprising 30-35% mitochondria.
How are muscles composed?
While muscles are incredibly important throughout the body their method of action is quite remarkable in evolutionary terms.
The task of converting the stored chemical energy within the body into mechanical movement is no easy feat on the large scale at which muscles operate.
Before understanding the mechanism, it is quite important to have a basic grounding in the structure of a muscle down to the near-molecular level.
For ease of explanation this article will focus upon skeletal muscles, however much of the fundamental information on the process is directly transferable to cardiac and smooth muscle, except for some notable differences.
The diagram to the left helps to explain the fundamental parts of a muscle. This explanation moves from the large scale of a muscle down to the basic units that comprise muscle tissue. As discussed previously, a skeletal muscle is generally attached to a tendon which is in turn attached to a bone.
The muscle itself is made up of numerous bundles of individual muscle fibres along with blood vessels that help innervate the muscle (or supply it with nerves), and are sometimes referred to as muscle fascicles. The muscle fibres are in themselves individual, highly specialised cells – myocytes as referenced previously.
The myocyte is very elongated and is quite unlike any standard cell. They are multinucleate (have numerous nuclei along their length), contain quite high concentrations of mitochondria (to provide the required volumes of ATP, that being the energy currency of the body), and they have specialised organelles in the place of standard cellular ones.
Instead of a a cell membrane, a myocyte has a sarcolemma (a specialised cell membrane) which has infoldings of the membrane into the sarcoplasm. Similarly, instead of the smooth endoplasmic reticulum which most standard cells contain, they have a sarcoplasmic reticulum which stores and releases large concentrations of calcium which is vital for the functioning of a muscle.
Likely the standout feature of a myocyte, however, is the myofibril, shown closest to the front in the above diagram. There exist hundreds of myofibrils within each separate myocyte.
The myofibril is a long chain of proteins, namely actin and myosin. It is in the myofibril that the action of a muscle is generated.
The myofibril however is further divided up into small segments known as sarcomeres which are frequently described as the basic unit of muscle contraction.
An over-simplification would be that, upon stimulation by a motor neurone the individual sarcomeres, making up the myofibrils, shorten.
This means that the myocyte shortens, therefore the bundle of muscle fibres shortens, and as a result the entire muscle shortens, or contracts. This contraction then pulls on the ligament and as a result, the bone moves around the joint.
How do muscles contract?
It is clear that muscle contraction is a fairly complex process, but I will attempt to break it down into a step-by-step process and use a final analogy to hopefully make things even simpler.
There is also a video attached to the adjacent image which goes into even greater detail if you’re interested in the process.
As discussed previously, the sarcomere within the myofibrils is where the action of muscle contraction is generated. I’ve also referenced two key proteins — actin and myosin. The adjacent diagram is a very useful tool in understanding this process.
Within the diagram the blue ‘thin filaments’ are representative of actin while the red ‘thick filament’ are representative of myosin. Take note that along the red myosin there are numerous protrusions or heads. These heads have two conformations which are switched between by the release of energy from the breakdown of ATP. (The myosin head has a binding site for ATP).
Under normal circumstances, the myosin heads are at a near-right angle to actin filament, however when the myosin head is activated, the myosin head stretches outwards. This process is known as the cross-cycle bridge.
The process that takes place is the binding of the the aforementioned myosin heads to specific binding sites on the actin filaments. The head is then unbound from the actin binding site and binds to the next binding site. With numerous myosin heads doing this simultaneously, the result is that the myosin in fact drags the actin filaments on the left and right closer together, resulting in the contracted sarcomere as portrayed in the diagram above.
To ensure this only occurs when required, there is a protein coiled around the actin known as troponin. This protein covers the binding sites on the actin, preventing the myosin heads from binding.
This troponin, however, changes shape when calcium (stored in the sarcoplasmic reticulum) is bound to it, hence uncovering the binding sites of the actin and therefore allowing the myosin heads to bind. It is for this reason that calcium is integral to muscular contraction.
Step-by-step process of muscle contraction:
A nerve impulse travels down a motor neurone and eventually causes the release of a neurotransmitter (acetylcholine) at a neuromuscular junction – a specialised synapse between a neurone and a myocyte.
The neurotransmitter binds to receptors on the surface of the sarcolemma, causing the impulse to spread across the surface of the sarcolemma.
The nerve impulse enters the infoldings of the sarcolemma (T-tubules) and sarcoplasmic reticulum, stimulating the release of calcium ions that are stored within the sarcolemma.
Calcium ions (charged calcium molecules) bind to troponin, changing the shape of troponin and exposing the myosin binding sites on the actin filament.
ATP breaks down to ADP + P (phosphate). The released energy activates the myosin cross-bridges and results in a change of the myosin head shape which drags the actin filaments closer together.
The sliding of the myofilaments draws the left and right actin filaments closer together, the sarcomere shortens, the muscle fibers contract and therefore the muscle contracts.
The neurotransmitter is eventually inactivated by an enzyme in the cleft, or the space between, the neuromuscular junction, inhibiting the nerve impulse conduction across the sarcolemma.
Nerve impulse is inhibited. As a result the calcium ions are actively transported back into the sarcoplasmic reticulum using the energy from the earlier ATP breakdown.
The low calcium concentration causes the myosin cross-bridges to separate from the thin actin filaments and the myosin filaments return to their relaxed position.
The filaments of the sarcomere return to their resting position. Hence the sarcomere returns to its resting length, the muscle fibers relax, and the muscle as a whole relaxes.
Analogy of a muscle contraction:
The following is an analogy of the process of muscle contraction in terms of the sarcomere:
Imagine the myosin as a climber with sheets of Velcro upon each of his hands and feet. He is climbing a wall interspersed with patches of Velcro and has nothing to help him climb other than the Velcro.
He initially starts by attaching one arm to a patch of Velcro. He has had to change the conformation of his hand to do this. This required the input of energy much the same as the changing of the position of the myosin head requires the release of energy from an ATP molecule, on the wall and places the next above it — again requiring an energy requiring conformation change.
Then he pulls the first arm from the Velcro wall and places it above his other arm. He uses his feet in the same type of motion and slowly but surely can climb the wall.
In principal this analogy is the same process as the sarcomere undertakes. The climber’s Velcro-covered hands and feet are the myosin heads, his body is the myosin and the Velcro sections of wall are the binding sites on the actin.
The key point of this analogy is that alone, the myosin heads do not produce the movement. Only when numerous myosin heads work in conjunction can the process procede. There always needs to be at least one myosin head bound to ensure the actin does not move back to its starting position, just as the climber would need one hand or foot bound to ensure he doesn’t fall.
There are shortcomings in this analogy as there are in any analogy, for example, in the sarcomere, the actin moves, not the myosin. However, I hope, this has helped to simplify the concept.
Why are muscles important in ME research?
As discussed previously, while muscular weakness, muscle pain, and muscle fatigue are common and traditional symptoms of ME/CFS, research looking into the reason such symptoms exist has been limited.
There are, however, some researchers who have noted the frequency with which this symptom is seen, and have undertaken studies trying to understand the reasons.
One researcher looking closely at muscle function is of course Professor Julia Newton from the University of Newcastle in the UK. Prof. Newton and her team carried out a study in 2012 where they collected muscle samples from 10 diagnosed ME/CFS patients and 10 healthy controls for in-depth analysis of the muscle tissue, examining its affinity for respiration.
The findings of this study were quite surprising. It appeared that patients with ME produced upwards of 20 time more lactic acid upon ‘exercise’ stimulation than healthy controls.
This pilot study suggests a potential pathological problem during the process of muscle contraction, namely a problem during the process of aerobic respiration causing anaerobic respiration to take place at much higher incidence than healthy individuals.
Prof. Newton explores where the skeletal muscle respiratory abnormality may originate, in the video opposite: click the image for access.
Everybody has experienced the build-up of lactate in the muscles following intense periods of exercise. This research however indicates the possibility that ME patients experience this at much lower levels of exercise intensity.
The question then becomes, why might his happening?. But there are, unfortunately, many possible reasons that need exploring before such a question can be answered.
The first line of thought could be a fundamental and primary respiratory problem originating either from the enzymes within cellular cytoplasm that control the process or a mitochondrial abnormality. Through either, the result is a limited affinity for exercise due to a build-up of waste products such as lactic acid.
One such enzyme Prof. Newton appears to be focusing upon through this research is AMP kinase, a cytoplasmic enzyme which acts as something of a metabollic master-switch within the cell. It controls whether anabolic (the building of larger molecules from smaller ones) or catabolic (the breakdown of larger molecules into smaller ones) processes dominate.
Because of this research Prof. Newton has tentatively stated that two independent phenotypes within the ME/CFS group appear to be emerging, split by whether or not phosphocreatine is depleted during exercise. Phosphocreatine functions as a short term (5-10 seconds) energy supply upon high levels of exertion.
A second possibility may be a nervous system problem, with over-stimulation of a muscle when such stimulation is not required. As a result the cellular concentrations of ADP may be overly depleted, or perhaps even AMP is being produced, causing a longer duration required for recovery. Perhaps this could even allude to a reasoning behind post-exertional malaise.
Numerous other possibilities likely exist to explain this phenomenon. It certainly poses an interesting question which deserves further exploration going forward, with links to many areas such as cardiovascular function and mitochondrial abnormalities.
The big question that this research does raise is whether this now observed muscle abnormality is causative of ME/CFS or, and unfortunately more likely, a downstream result of a another problem.
Another piece of interesting research data regarding ME/CFS and muscles comes from Fulle et al (2007). As the paper states,
“Oxidative stress is an emerging focus of research, in view of recent ﬁndings that it contributes to the pathology and clinical symptoms of CFS.”
As has been well-established, oxidative stress for a short duration can provide potential health benefits. However, when unregulated, such stress causes distinct pathological damage. The paper goes further in this discussion and also reveals that oxidative damage may be a major contributing factor for the muscular symptoms seen in ME/CFS.
“Recently, Kennedy et al. (2005) published results obtained from a large number of CFS patients divided into two groups those previously identiﬁed with cardiovascular risk factors and those that were not.
Both groups displayed signiﬁcantly increased levels of isoprostanes and oxidized low-density lipoproteins, indicative of lipid peroxidation induced by ROS accumulation.
Moreover, CFS symptoms correlated with isoprostane levels in patients with low cardiovascular risk. This is the ﬁrst report on elevated levels of the gold-standard measure of in vivo oxidative stress and its association with CFS symptoms.”
Given the research discussed in this article, and quite a lot of research besides, it seems that the symptoms of muscular weakness and pain seen in ME do have the potential to indicate lines of thought for further research.
While other areas may appear, at the outset, more exciting and immediate, research into the mechanisms behind the symptomatic presentation of diseases is incredibly important for the development of treatments going forward.
We are unfortunately not yet in the situation where the pathophysiology of ME is understood. Only through exploring different avenues of research will the answers be found, but it is clear that there is a profound skeletal muscle abnormality to be observed in those suffering with ME/CFS.
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