In this second interview, Professor Dr Martin Flück reveals how his research aims to shed light on the mechanisms that govern skeletal muscle function in health and disease, with the goal of translating the findings into more effective clinical applications
To kick things off, Professor Dr Martin Flück explains how the research at the Laboratory for Muscle Plasticity at Balgrist University Hospital aims to shed light on the mechanisms that govern skeletal muscle function in health and disease, with the goal of translating the findings into more effective clinical applications. Martin notes that the approach of a head of a department is to make a patient-directed question that you must elucidate in a laboratory setting and he adds that the mechanisms in this respect need to be described in a coherent manner. This is because the words used to describe active processes when it comes to the muscle can be wrongly used and do not match what we would use to describe the biology of the patient. Martin then continues these themes in his own words, including the importance of accelerating translation for the benefit of the patient.
“We have been investing much in rediscovering older ideas – ones that surgeons originally rejected – based upon an incomplete description of the time course of muscle degeneration following a musculoskeletal injury. Previously, they looked at what happened in rotator cuff disease quite late in the degenerative process, which is quite common when a tendon ruptures, but much of the negative remodelling has already occurred at this point. As such, things have to be checked early on which brings us back to a previous hypothesis that was rejected, Martin tells us. He goes on to expand this point in his own words.
“Basically, our approach is to translate the clinical problem in an experimental scenario that allows to test therapies for emerging bottlenecks in the recovery of musculoskeletal function of the patient. In this respect, we now revisit early ideas for solutions of the negative remodeling of the injured muscle-tendon tissue composite which were set out 15 years ago, but rejected based on preliminary studies with a negative outcome. We do this because we identify that the first window of opportunity for treatment after injury and reconstructive surgery, is short and not addressed experimentally, and consequently a number of active mechanisms were overlooked.
This can be explained for example by the destruction of the cellular powerhouse, mitochondria, with immobilization that was not considered important; but we now know now that this exerts a dominant negative influence on the maintenance of muscle mass and fatigue resistance. Based on these findings one can reasonably argue that the treatment of disuse-related aspects of musculoskeletal disease, such as after tendon rupture, should start early before the deterioration of clinical endpoints such as a loss in strength and fatigue resistance of muscle can be diagnosed and established as a chronic disability.
We also have a window of opportunity here to translate what we see in other muscle affections, such as during recovery from anterior cruciate ligament injury and repair and cardiovascular disease (CVD) that also involves the deconditioning of peripheral skeletal muscle (Flück et al, 2018). The critical factor here is how long the muscle is in a semi-stable state after an injury before it enters into a devastating spiral of muscle wasting. So, we aim to provide evidence in a coherent manner for how many days and weeks you can keep using the muscle before surgery needs to takes place. We now know, for instance, when muscle loss occurs and when it transfers into fat.”
The power of medication and the importance of timing
While it is not one of his main priorities, Martin then shares his thoughts on educating the patients in this respect, as a dentist would when advising that teeth should be brushed three times daily but if one does not follow such advice then things will go bad. When it comes to translation for the benefit of the patient, Martin believes that while very simple forms of medication are available, such as steroids, there are new drugs on the market that have passed governmental tests, and as such, their use is safe for humans to ingest.
Martin’s opinion is that the power of existing medication can be improved by timing when it is taken so that muscle deterioration can be delayed. For example, if medication is administered under neuromuscular electric stimulation during the first two weeks after injury when surgery typically does not take place because the patient is in a lot of pain and experiencing tissue swelling. This approach is the way forward, according to Martin, who adds that he works hard with the surgeons because they are not used to working in such a manner, so a rethinking of priorities is, therefore, essential when you have the first meeting with a patient.
The benefits of excellent research facilities
The conversation then turns to explore Martin’s thoughts on the superb new research facilities at the Balgrist Campus, and the benefit they have had on the valuable work and research at the campus. We find out how different parts of the Balgrist Campus are grouped together to enable easier access to research facilities and the pipelines are, therefore, tighter. In addition, there are other routines which allow for the acceleration of research because new investments have been made for the functional exploitation of muscle structure during movement.
Martin says that while his research output has not yet concretely benefited from the new facilities, interactions with other scientists who carry out anatomical measurements of the muscle has been a plus for him. “It is much easier for the students or researchers to train using these methods to measure muscle volume, get a 3D image and analyse the muscle. The facilities are good because they are open during weekdays and the weekend so people can come in and get things turned around.”
State-of-the-art methods and technologies
This compelling interview continues, with Martin keen to detail the very important role that state-of-the-art methods and technologies play in the field of muscle research when it comes to the work taking place at the Balgrist Campus and in their fruitful cooperation with the Functional Genomics Center of the University of Zurich/ETH. Knowledge gathering can be accelerated, Martin reveals, in terms of exploiting paradigms in more breadth and in a higher resolution. State-of-the-art methods and technologies enable the measurement of multiple species and the use of powerful tools that enable researchers to work at a very fast pace. Still, much work needs to be done in the field, Martin underlines.
“We still need good knowledge on the cell, biological, chemical and anatomical aspects of disease because it can be misleading to rely solely on results from one novel method. An image tool can always be used to draw conclusions about the raw numbers but nevertheless, combining that in a very elegant approach that relates to a systems biology that people advocate was raised at a conference around 11 years ago (Flück et al. 2008). “Now, we get biomarkers that allow us to screen patients out of the acceleration of numbers that we can relate to the relevant sizes of muscle, and we can more easily determine something in blocks, for example, or by a simple genetic test.”
Personalised sports medicine and exercise rehabilitation
When it comes to disruptive ideas for personalised sports medicine and exercise rehabilitation, Martin says that one of his thoughts around this is the problem of getting economically viable pipelines established for medics. If it be for reasons of wisdom, or economic causes, the medical profession has typically been shy when it was to implement paradigm shifting approaches this demanded the reconsideration of established clinical routines. Now, it is about how a patient is aware of a problem and goes to a doctor to seek a solution. Sometimes, a doctor has a fair and good knowledge, but a researcher can be very well-informed about an aspect of health that perhaps a doctor doesn’t know about. It might be that a doctor needs to do a literature search but although ultimately powerful and justified, this slows down decision taking. The latter in fact is a very active area of Research and Development in the Polytechnical School of Zurich (ETH) to identify faster and more comprehensive ways to approach a disease, Martin notes.
“Here, progressive methods could be used for other treatments even if it is not generally accepted nowadays. For example, if you had a bone fracture as I did, would you only do the training they tell you to do or would you do more, especially if you are experienced in physical training and know the limits of (your) human performance and capacity for the improvement through the stimulation of musculoskeletal plasticity? Would you train hard to ensure a better recovery? Or do you want to get access to treatment that some people are using, such as biohacking that concerns legally allowed biological principles? For example, there are ways in which people can enrich their stem cells and reinject into them during training.
“Gene therapy won’t solve everything and when looking at this field of atrophy, it needs to be administered in doses because that is how we grow. We renew or grow, our active muscles one by one, 1% every day. Using this method repeatedly is way too much for the health system, indeed, we don’t visit a doctor daily for two years, so we may anticipate to inject the agent in small doses. People who do biohacking reinject their stem cells when training daily for one month and then either stop or continue. This is not good for control and it is questionable if you carry this out in large numbers. But this is how these processes work. Improvements in strength and endurance rely on adaptations in muscle and tendons to (daily) repeated stimuli that if reach a specific threshold of mechanical or metabolic overload. The potency of it is enhanced by a high load of medication but the problem is that it uses far too many resources from the perspective of the health practitioner. Certainly, it is getting too expensive, so how do we deal with that? There will be big solutions to translate and in some cases, to abandon stem cell gene therapy for patients with many risks; but if it works, it will be quite disruptive. Martin then details his thoughts on rehabilitation after muscle injury occurs.
“Another more practical consideration is the contribution of the chiropractor or physiotherapist in rehabilitation. In the U.S., as the American Academy of Orthopaedic Surgeons sees it, the post-operative rehabilitation is conditioned by new ideas on the load, the intensity and volume of training. Physiotherapy often takes over that part but may overrule the researcher and possibly the orthopaedic surgeons because they have greater experience, and the pharmacist has even more experience of the drug.
“The well-trained physiotherapist is knowledgeable about rehabilitative interventions the patient should do post-operatively during musculoskeletal rehabilitation to achieve maximal benefit. The physiotherapist will do what is allowed in the window of intervention for the patient but maybe it could be done more aggressively and earlier? We have seen how in some hospitals in Germany, that certain post-operative interventions are starting much earlier to allow lymphatic drainage and reperfusion, for instance, after anterior cruciate ligament surgery. We know that this is very beneficial for healing from the experience of other surgeries as it is applied worldwide. So – this is something that we should actively pursue – that the physiotherapist or the people with knowledge of that aspect have more to say. This is the current practice of the American Academy of Orthopaedic Surgeons and hasn’t yet been fully carried over to larger parts of Switzerland.
“What is also a problem is that because there is an economic pipeline, defining within which duration post-operative interventions can be performed in a hospital setting. New knowledge on therapeutic interventions which would extend beyond this window, or which are complicated to carry out in ambulant sessions of rehabilitation, may fall out of consideration for an implementation. This is particular concern for the reconditioning of an atrophied muscle, which must be tackled as early as possible by enhancing (or mimicking) the mechanical and metabolic load of an active muscle. There is a classic study from a famous English researcher which clearly shows that immediately after bone fracture, the contractile activity of concerned muscle groups must be increased for instance with sessions of neuromuscular electric stimulation (NMES) to maintain its protein balance.”
Martin adds that studies have been done around these aforementioned areas but they had not been carried out for a long enough duration to really gain benefit from. NMES may be used for some very high profile sports individuals, such as the number one acrobatic skier who has treatment at the Balgrist University Hospital and uses EMS for an hour or two daily which works. While there are not enough resources to understand how it works, the patient needs to be willing to do NMES for many months or years as shown successfully in rare cases of tetraplegic patients, Martin stresses, which is disruptive.
“I know of athletes using EMS at night and I know it works but there is a big disconnect between the basic knowledge and how you apply it. Only committed people use EMS, often externally through Balgrist University Hospital. The patient will stay in the hospital for a month and this approach works but this method it is only disruptive if it is translated to all patients and the benefit for society would be great.”
The priorities for musculoskeletal disorders
Martin then sheds light on the priorities ahead for the diagnostics, treatment and rehabilitation of all musculoskeletal disorders. He says that his priorities for the future are very practical ones, in terms of the areas identified in this interview which need to be pursued. A willingness to change the system is needed, Martin notes and adds that if a treatment is available, it is important to ask at the Balgrist University Hospital with whom one can collaborate to apply such a genetic test. This involves much rethinking of the legal procedures when it comes to data protection and risk around genetic tests, Martin tells us.
In closing, Martin underlines that there is an issue today around health insurance because you cannot fully evaluate people in terms of numbers. Martin asks us to imagine that if we own a car and there is a problem with it then we go to the garage to get it repaired so that it works properly. This helps us to understand Martin’s areas of research, and that Balgrist University Hospital sends out people who can walk again even though they may have a functional deficit following treatment but thresholds are not set to provide the patient with a map of the individual aspects of its musculoskeleton which require further improvement through therapy and training to empower a full regain of functional work capacity. Martin develops this point and adds his concluding remarks to this in-depth interview.
“Translating effective measures for the patient is a priority, so that they recover and that the form of treatment given is acceptable, such as gene therapy. Of course, gene therapy is far too expensive but the question is how can you do that? Do you have a risk priority in some areas? Or do you have the basic genetic tests that predict that such an approach will not help some patients, the health system or even the hospital?
“The priority must be to substitute for a subtle, often unnoticed, genetic deficit with an effective treatment which is what we do in the cardiovascular field, where with a non-responder to rehabilitation we try to have another treatment that the patient can respond to.
“Finally, I want to add that I am not connected with my European colleagues who have two approaches. One is a centralised setting tied to the way the state is organised, such as in the UK, the Netherlands and Scandinavian countries that rely on an institutional monarchy who have specifically robust, but sometimes rigid, ways of tackling some diseases. But interestingly, there is a disconnect in terms of what we aim to do in Switzerland where we have a federal system to gather information and administer a solution in a totally different way.
“In the UK, for example, there are the state organs to indicate how to pursue new treatments best based on a centralised database. In Switzerland, we gather information from our individual datasets and I see from my experience of working in different cultures that despite the possibilities for innovation provided by the latter approach, it sometimes lacks effective power for translation on a large scale. We need a solution to direct preventive and curative treatments in a more individual and economically viable manner to the entire spectra of the population. But to do so, we should combine a well-informed population-based approach with the innovative powers of an individualized approach, possibly by changing the organization of the health care system.”
Professor Dr Martin Fluck
Laboratory for Muscle Plasticity
Balgrist University Hospital
Tel: +41 44 510 7350
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