RESEARCH

The MyoLab’s research focuses primarily on skeletal muscle function – structure, metabolism and contraction. Although the research fields overlap, we can divide it into four main categories, each with unique projects answering specific questions. These are: Nature or Nurture, Obesity, lifestyle and insulin resistance, Muscle weakness and Exercise-induced myopathies.

Scientists have been looking for that key gene for decades. But each time a new gene shows an association with some performance measure, the hypothesis gets thwarted by another. However, there is no doubt that your genetic makeup plays a significant role in sporting performance. By merely looking at the different mammalian species, one sees a diversity of fast runners, runners with endurance, or those with brut strength. Even within species, there are vast differences: certain horse breeds are fast sprinters, some again known for their endurance ability. The same can be said about the various dog breeds – a grey hound vs. a bull dog. There is something inherent that brings these attributes to the surface, but this is still unknown.

Current projects in Nature or Nurture

  • Markers of exercise performance between animal species
  • Performance markers within human populations

Question: Mother Nature has some pretty fast, strong and scary animals. Humans actually fall into the category of being the slowest and weakest. Species are formed as a result of small genetic differences. Mammals share a number of genes that are similar, with only very small differences in their genetic code. Comparatively, there are vast differences between land mammals on a morphological level. But, given the vast number of animal species, their muscles are very poorly studied – only 0.9% of the 5500 mammal species have been studied on a muscular level.

Research: The Myolab has already made some significant headway in studying muscle contractility, metabolism and structure of some African wildlife species. For starters, the cat species (lion, caracal and cheetah) have more than 50% type IIX muscle fibres, whereas the same muscle in humans contain between 5 – 20%. The prey of these wild cats, that includes the springbok, kudu, mountain reedbuck, blesbok and fallow deer, also has more than 50% type IIX fibres. In fact, one type IIX single fibre from either the caracal or lion can produce three times the amount of power to that of the human equivalent! To produce this exceptional power, these animals must rely on efficient and an abundance of ATP generated from their muscle metabolism. Collectively, the cats and antelopes have a very high capacity to burn carbohydrates in the form of glycogen and blood glucose. However, this is where the prey has the advantage: they all have many more mitochondria in their muscle. In essence, the prey have speed and endurance whereas the cats only have speed. These findings confirm why cats need to stalk their prey and kill quickly. Once the antelope gets away and starts running, the odds of catching it becomes very poor.

Question: Although a very sensitive topic, science has observed that specific populations seem to perform better in sports than others. It also holds true for certain diseases, such as sickle cell anaemia and even most recently, susceptibility to diabetes. Kenyan and Ethiopian runners dominate the world of endurance running, whereas Jamaican and African-American runners dominate the short sprinting events. There has been lots of speculation surrounding the performance advantage, being it genetics or environmental, but thus far, no genetic marker(s) can explain these advantages in sporting success. Nevertheless, the human body can very easily and relatively quickly adapt to various forms of exercise, such as altered training loads and the environment. Thus, just because one group excels in a specific sport, does not necessarily mean that their success is genetic. Exposure to the sport, training volume and intensity, and motivation are factors that can significantly influence performance. However, to what extent these factors can push the human body to its limits and bring about the physiological adaptations, are still unclear and must be investigated.

Research: There are only a handful of studies that have investigated the physiology between athletes, in particular endurance runners. The overall consensus thus far is that African runners exhibit lower blood lactate at the same running intensity than their European counterparts. Secondly, it appears that African runners have a larger proportion of type IIA muscle fibres. Combined, these two factors should theoretically result in greater force output and a longer time to fatigue. However, whether improved performance is indeed as a result of these two factors needs to be further investigated.

Obesity, lifestyle and insulin resistance

Humans today are leading a more sedentary lifestyle, consuming the typical urbanised diet rich in refined sugars and processed foods. Our lifestyle choices have led to an obesity epidemic, that is causing the dramatic rise in insulin resistance and type II diabetes. Furthermore, it appears that animals, domestic and wild, are also at risk of developing diabetes.

  • Investigating diabetes in urban baboons
  • Devolopment of insulin resistance in domestic cats and dogs
  • Metabolic syndrome in captive felids
  • Effect of glycine supplementation on captive cheetahs

Question: Observations of baboons in the Cape Peninsula within the City of Cape Town have hinted that some individuals may in fact be suffering the consequences of poor diet, just as humans are. Baboon monitors (humans that act as baboon police) have even gone as far as to report that some of these regular raiders are becoming overweight and lethargic, and some showing signs of hair- and teeth-loss. Apart from the physical symptoms observed, these baboons that are consuming processed foods high in sugar and fat may also run the risk of developing insulin resistance and type II diabetes.

Research: This project investigated whether Cape Towns’ urban baboons are eating their way towards developing insulin resistance and type II diabetes. To do this, we compared the results with baboons that were never exposed or had access to human foods (i.e. rural baboons). We specifically measured the glucose transport and insulin signalling complex within skeletal muscle, as these pathways easily become resistant to insulin. It was found that the urban Cape Peninsula baboons were heavier, had more teeth problems and had lower active insulin receptor complexes than their rural counterparts. To conclude, the consumption of foods high in sugar and fat may put the Cape Peninsula baboons at risk of developing insulin resistance and diabetes. This project is still ongoing with the City of Cape Town and Cape Nature.

Question: The rate of diabetes has increased in domestic animal populations. Dogs are believed to develop a form of diabetes that is similar to type 1 diabetes in humans. Breed seems to be a risk factor for diabetes with various breeds showing different predispositions to the disease, e.g. it seems that Samoyeds, Swedish Elkhound, Lapphund, Fox Terriers, Australian Terriers, Pugs and Poodles are at a higher risk for developing diabetes. While Golden Retrievers, German Shepherds, Cocker Spaniels, Collies and Boxers are at a lower risk for developing the disease. Cats are believed to have a form of diabetes similar to type 2 diabetes in humans, with obesity being a major risk factor. It appears that the breed of your cat or dog may be a risk factor in developing diabetes, but what causes this predisposition is still unknown. With the vital role of skeletal muscle in glucose regulation, and the link between fibre type and insulin sensitivity, could the answer lie in the muscle?

Research: Skeletal muscle morphology (fibre type distribution and cross sectional area) and metabolic activity have been investigated in 16 breeds of healthy domestic dogs. It was found that dogs have a high oxidative capacity (which aligns to the literature), although a high variation was seen across breeds. This study is still ongoing, with further investigation required into domestic cats and diabetic populations.

Question: The captivity of wild animals is a practice implemented for a number of reasons, but primarily for the protection and conservation of endangered species. The dietary needs of felids are not yet well understood and may predispose these animals to metabolic diseases. In a group of captive lions in the North West Province in South Africa, body weight was found to be highly skewed as the lions were greatly overweight. Furthermore, as a result of routine feeding, the need for behavioural activities of hunting and chasing prey have been removed, causing these lions to become inactive and lethargic. Along with lions, there are various other felid species, such as caracals, cheetahs, leopards and lynxes, that reside in captivity. Each of these species differ in their biochemical and genetic makeup, and therefore may have different nutritional needs.

Research: We have collected muscle samples from 87 lions, with 7 being wild and the rest from sanctuaries. Additionally, we also collected samples from 36 cheetahs. The samples are being processed for: fibre morphology, fat content, metabolism, insulin signalling pathway and glucose transport.

Question: Gastritis is a chronic disease that affects more than 90% of cheetahs in captivity. Recent pilot data suggests that a dietary glycine deficiency could play a role in the pathogenesis of this disease. Glycine is a simple amino acid that plays a key role in various tissue metabolic pathways. However, it is not known whether the addition of this simple amino acid to the diet of captive cheetahs will have an effect on these various tissues and the overall metabolism of cheetahs.

Research: The effect of glycine supplementation on the metabolism of skeletal muscle, blood and urine in cheetahs will be investigated in 10 captive cheetahs. The study is a cross-over design with cheetahs being supplemented with glycine for four weeks, and samples being collected before and after the intervention. We will use a number of techniques to determine the mechanism of how a simple molecule like glycine has such an enormous effect on the health of cheetahs, primarily focused on whole body metabolism (through metabolomics analyses) and skeletal muscle. This study was done in collaboration with Cango Wildlife Ranch in Oudtshoorn, Western Cape.

Muscle Weakness

Myopathy literally means “muscle disease”. Any condition that negatively affects muscle performance can be seen as a myopathy. In humans and animals, they can arise from a wide variety of hereditary and/or acquired causes. These include abnormalities in i) structural proteins (e.g. muscular dystrophies), ii) impaired muscle metabolism (e.g. disorders of carbohydrate or fat metabolism) or iii) immune-mediated inflammation (e.g. polymyositis, dermatomyositis). The primary feature of all these different abnormalities is that of muscle weakness that affects predominantly large muscle groups like the hip, thigh or shoulder muscles.

  • Understanding inflammatory myopathies and weakness
  • Establishing the single fibre in vitro contracture test in Africa
  • Muscle function in metabolic myopathies

Question: Idiopathic inflammatory myopathies (IIMs) are a group of muscle disorders caused by an immune-mediated attack on skeletal muscle tissue, and consist of polymyositis (PM), dermatomyositis (DM), inclusion body myositis (IBM), non-specific inflammatory myopathy (NIM) and necrotising autoimmune myopathy (NAM). All these myopathies present with some level of weakness. The exact mechanism of weakness in IIMs is still unknown, but may theoretically be from a decrease in the actual number of muscle fibres, decreased contractility (performance) of the individual muscle fibres, or both. To date, it has been assumed this weakness result from a decrease in the number of muscle fibres as a result of necrosis. It is due to this assumption that the fibre contractility has been poorly studied. Only one study has looked at the muscle fibres’ function in untreated DM and IBM. However, this study had a number of flaws. Also, a number of observations argue against necrosis as the only factor contributing to the weakness. These include:

☆ a lack of correlation between weakness and the degree of inflammation in muscle,
☆ the relatively small amount of necrotic fibres on muscle histology as compared to the degree of weakness, and
☆ how quickly patients respond to the treatment with corticosteroids.

Research: We are currently comparing the contractile properties of single muscle fibres from patients with untreated IIMs to those of healthy volunteers. Apart from the functional single fibre tests, we are also assessing a number of proteins in the muscle. We have recently performed the first training study on a participant with advanced stage inclusion body myositis (IBM) and the data has made us very excited.

Question: Malignant hyperthermia (MH) is a fatal condition triggered by volatile anaesthetic agents. Once a patient is subjected to the anaesthetic (e.g. halothane), symptoms of MH appear within minutes. The most prominent symptoms are involuntary muscle contractions and elevated body temperatures (>40˚C), the latter due to increased skeletal muscle metabolism. The cause of MH is due to mutations in the ryanodine receptors located in the sarcoplasmic reticulum. These receptors form part of the channels that release calcium into the cytosol to initiate contraction. The mutation causes the ryanodine receptors to be highly sensitive to caffeine and certain anaesthetics (e.g. halothane). The increased sensitivity triggers the release of calcium, leading to involuntary muscle contraction. Treatment is usually a large dose of dantrolene, which blocks the release of calcium from the sarcoplasmic reticulum.

A number of ryanodine receptor mutations have already been identified. Patients who have a reaction during anaesthesia would be genetically screened from a blood sample. However, an unknown mutation can easily go undetected. The only sure way to establish whether an individual is susceptible to MH, is to perform a muscle biopsy and subject it to the In Vitro Contracture Test (IVCT). This test requires a large muscle sample (approximately 30 mm in length and 3 – 5 mm thick), rendering the process very invasive. Most patients complain about severe pain during the healing process, and are usually left with significant scaring. The IVCT test itself involves the muscle to be bathed in a solution containing various amounts of caffeine and halothane. If muscle contraction starts before the recommended threshold, the patient is usually classified as MH susceptible and confirmed with a genetic screening test. Muscle testing on the rest of the family will also be required.

Research: Technology has since evolved so that contracture tests may be performed on single isolated muscle fibres. The upside of this technology is that a very small muscle biopsy may be sufficient (5 mm in length) and could be obtained using a muscle biopsy needle. To confirm the validity of using the single fibre method to assist in diagnosing MH, and because there is no IVCT facility available in Africa, the MyoLab has embarked on developing, establishing and validating a single fibre technique to assist in diagnosing MH. This research heavily relies on small muscle biopsy samples from individuals that have previously been diagnosed with MH.

Question: The muscle from patients with McArdle’s disease are unable to utilise their stored muscle glycogen due to a mutation in their myophosphorylase enzyme. Patients with this mutation are unable to utilise their intramuscular glycogen, and thus struggle to exercise. When they do attempt exercise it may lead to severe muscle cramps, pain, discomfort, and in some extreme cases, hospitalisation. The category of metabolic myopathies consist of mainly inherited genetic defects that affect the supply of ATP through the respective pathways. These pathways include that of fat oxidation, mitochondria and glycolysis. Studies on the functional components of affected muscle are limited and very scarce, especially on how contractility on a molecular level is affected.

Research: The MyoLab, in partnership with local and international institutions, are currently investigating how contractility is affected, at a whole muscle and single muscle fibre level, and how exercise training improves these parameters.

Exercise-induced muscle pathologies

After an exercise bout, your muscles may become stiff and sore, a typical delayed onset of muscle soreness (DOMS). This is not caused by lactate build-up (the myth has been busted), but actually by small muscle tears that cause the content of the muscle fibres to leak into the blood stream, such as creatine kinase and myoglobin. Inflammation also follows making the muscles feel tender. This response is normal for any mammal after exercise and our bodies adapt to these stresses quite quickly. Severe muscle damage and breakdown can lead to a condition collectively known as rhabdomyolysis. The danger is that this rhabdomyolysis, if untreated, can lead to kidney damage by means of the myoglobin that clogs the renal filtration apparatus and eventually leads to renal failure and death. It seems that excessive exercise is the predominant factor that causes rhabdomyolysis. We aim to study as many cases of rhabdomyolysis in humans, wild animals and horses to better our understanding of the potential causes, diagnosis and prevention thereof. Our research focuses on trying to find out why muscle breaks down under certain stressful conditions, how it can be prevented and cured. 

  • Understanding capture myopathy

Question: Capture myopathy - every wildlife rancher, wildlife translocator, veterinarian and wildlife auctioneer fear these words. This so-called condition is the Achilles heel of the wildlife industry. Horror stories range from losing one eland to loosing literally the whole truckload of animals to this condition. As can be expected, it can lead to massive financial loss. Capture myopathy or capture stress is a condition that appears primarily when wild animals are captured. The signs that animal has capture myopathy are: ☆ high body temperature (above 42°C), ☆ muscle spasms, stiffness and lameness, ☆ animals would lie down or stumble around and stop eating, and ☆ the appearance of dark coloured urine – a clear sign of muscle breakdown and that the kidneys are damaged. The survival rate of these animals, once they have progressed to the stage where the urine is dark, is very bleak.

Disturbingly, humans share a similar condition, known as exertional heatstroke. This condition is different from the classic heatstroke observed in children and the elderly resulting from extreme environmental temperatures. Compared to capture myopathy, exertional heatstroke occurs in unfit humans such as fresh military recruits or those exposed to substance abuse. To date, the exact cause of capture myopathy or exertional heatstroke are largely unknown. Arguments range from species being more susceptible, genetic mutations to nutritional deficiencies. We also know that extreme hypoxia, lack of oxygen to muscles and organs, can cause tissue breakdown. There is also no known treatment for capture myopathy. However, a book by Bothma, Game Ranch Management, mentions a technique by which antelope are “trained and tamed” in a boma to reduce capture myopathy. The question therefore is whether capture myopathy stems from being unfit. Therefore, by studying exercise training and its effects on the muscle and how it protects the muscle from degradation may hold the secret to why some animals develop capture myopathy.

Research: Our research team has come up with a research plan to combine skills, technologies and techniques from the two disciplines, veterinary and exercise science, to search for the causes of capture myopathy. Both parties have agreed that much can be learned from each other. Since 2009, we have studied the skeletal muscle of a number of species, including lion, caracal, springbok, kudu, blesbok and black wildebeest. In 2017, we conducted the first ever training study on captive blesbok. These projects are still ongoing.


sdFADF

Exercise performance in humans

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