A platform to investigate multi-tissue crosstalk mediated by exercise induced soluble factors released from human skeletal muscle

The benefits of exercise are well documented, whereby people regularly undertaking some form of physical activity score highly in measures of fitness, health and mental wellbeing. Exercise is also known to reduce the likelihood of developing a number of diseases including (but not limited to): type 2 diabetes, dementia and cancer. Participation in exercise does not cause severe side effects, and in many cases is considered as effective as some prescribed medical interventions in the cure and reduction of symptoms. However, despite these clear advantages, exercise is rarely used as a clinical intervention. One reason for its infrequent use is that individuals respond differently to the same exercise intervention, with some people not responding at all. Additionally, a specific exercise intervention may improve one health outcome but not another, an effect that is increasingly variable between patients. This makes exercise prescription challenging. To overcome this, we need new methods of determining whether exercise interventions are effective for the specific organ/tissue (e.g. liver or muscle) being targeted, and whether each unique patient is responsive to that mode of treatment.

As skeletal muscle adapts to exercise it also communicates with other organs and tissues both directly (e.g. bone) and indirectly (e.g. pancreas). This phenomenon is termed crosstalk. Our current understanding of this crosstalk is that biological materials (named exerkines) are released as we exercise and are able to travel between tissue/organs. Latest studies suggest that this crosstalk may be responsible for many of the health benefits associated with exercise. These current studies have been conducted in both humans and animals during exercise. However, the biological complexity of animals and humans makes it difficult to model crosstalk associated with a single tissue, as the rest of the bodily functions mask these signals. These studies are also expensive, time consuming, and in the case of animal modelling unethical. Therefore, we need new methods (not using humans/animals) that allow us to understand more about the role of exerkines, and determine their effect on other tissues. To achieve this, this research will: a) recreate protocols that mimic skeletal muscle during exercise within lab grown tissues, b) measure and monitor the exerkines produced during this exercise c) administer these exerkines to other tissues (e.g. bones) so we can understand how they affect different parts of the body. The long-term vision of this work is that we can reduce, and ultimately replace, the animal models currently used in this research, and provide a way of modelling tissue crosstalk that allows us to assess biological crosstalk in a level of detail in which existing models cannot.

Exercise decreases both the risk and severity of numerous conditions including (but not limited to); type 2 diabetes, dementia, cardiovascular disease, and cancer. As a result, exercise is considered as (if not more) effective as pharmacological agents without inducing severe side effects. While exercise prescription is a powerful tool, it is unfortunately often neglected. This is due, in part, to humans (and tissues) exhibiting heterogenous adaptations, making appropriate exercise prescription challenging. To overcome this challenge, identification of exercise induced markers (exokines) indicative of effective (and ineffective) exercise that are not only patient, but diagnosis and tissue specific is of upmost importance. Skeletal muscle (SkM) is inherently linked to exercise-induced adaptation due to its role in facilitating locomotion. Adaptation occurs within the tissue itself, in addition to tissues directly (e.g. bone) and indirectly (e.g. pancreas) linked to SkM, believed to be mediated by exerkine secretion, often termed crosstalk. Current in vivo human and animal models are limited in their ability to determine tissue specific exerkine production in a spatio-temporal manor during exercise. Furthermore, if these models were available, they would be low throughput and expensive to run, as well as presenting ethical considerations. Bioengineering, however, provides a scalable, physiologically relevant, yet defined, environment to study crosstalk in human tissues. To overcome these aforementioned challenges, we will conceptualise a bioengineered model, in which multi-tissue interaction following exercise induced SkM exerkine release can be monitored in a spatio-temporal manor. Longer-term, our platform will allow exchange of tissue modules to study the reciprocal interactions between SkM and other tissues of interest, providing a platform that will replace the use of animal modelling for a broad range of conditions whereby exercise can be prescribed as medicine.