A high-throughput tissue engineered model for investigating age-related muscle diseases

Muscle plays an important structural role in the body and has a significant impact on our general health. For example, when muscle mass decreases, the risk of diseases increase including sarcopenia (age-related muscle loss), chronic obstructive pulmonary disease and diabetes1; However, the cellular and molecular mechanisms associated with muscle loss remain unclear. Understanding these mechanisms is paramount to create informed therapeutic interventions with the potential to benefit millions of people worldwide. In an attempt to tap into the underpinning cellular and molecular mechanisms, our collaborators at Karolinska Institutet (KI), Sweden used severe disuse or unloading human model including bed rest to show that there are certain transcription factors (e.g., MEF2) that appear to be master regulators of skeletal muscle deconditioning during unloading2. In addition, they performed one of the most comprehensive bed rest transcriptomic studies to date3. Furthermore, they developed muscle models derived from muscle cells from young and older donors and were quite successful in profiling the transcriptome of both4; However, cell culture in monolayer has significant limitations in reconstructing the native microenvironment of muscle because it cannot maintain its structural integrity over long periods or mimic cell-cell matrix interactions5,6. The proposed solution is using tissue engineering muscle (TEM). TEM is typically generated from muscle cells encapsulated in a hydrogel designed to look and contract like a native muscle. Since TEM contains the genetics of human tissue and looks and contracts like a native muscle, it is considered physiologically relevant. In recent years, TEM has gained considerable attention in basic and clinical research due to its ability to better mimic complex microenvironments and for being contractile; However, no high-throughput model depicting the phenotypic traits of age-related muscle loss or sarcopenia exists. This project aims to generate TEM showing traits of sarcopenia in a high-throughput manner using a patented technology (No. PCT/GB2023/053038) available from Nottingham Trent University (NTU), UK with cells from sarcopenic patients currently available from KI. To achieve this aim the following objectives (O) will be pursued: To transfer technology and cell culture protocols between NTU to KI enabling KI to develop TEM with traits of sarcopenia To transfer expertise and data between KI to NTU regarding the development and characterisation of the TEM with traits of sarcopenia To utilise pilot data generated at both institutions in support of future EU, UK or Swedish Research Council grant applications The proposed technology will be applied to develop a TEM showing traits of sarcopenic muscle. This will help to unravel the molecular mechanism underpinning this disease, improve drug discovery and reduce reliance on animal models in this area. Thus, there is a strong scope to benefit sarcopenic patients and animal welfare. In addition, there is a strong potential to boost the economy via commercialisation. This is highly likely since the proposed technology is patented as detailed above and falls into the market of non-animal alternative testing, which is predicted to grow with a compound annual growth of 10.3% - an increase from $1.7 billion in 2022 to $4.5 billion in 2032. Furthermore, obtained data can be used to improve recruitment strategies and health management of astronauts (due to the microgravity/unloading environment) during missions and to better manage patients at risk of suffering exaggerated dysfunction due to long-term hospitalisation resulting in savings for the health care systems.