Close
Supervisor: Francesco Muntoni, Massimo Ganassi
Project Description:
Background
Skeletal muscles constitute approximately one-third of total body weight in humans and serve multiple functions: generates force for movement, provides skeletal support, thermoregulation, and supports metabolism. Hence, diseases affecting muscle maintenance and function significantly reduce quality of life.
The fibres composing each muscle are formed during embryonic development in a process called myogenesis, involving proliferation and differentiation of muscle progenitor cells, that finally fuse together to generate strong multinucleated muscle fibres. Due to persistent life-long exposure to mechanical stress, fibres can be damaged and must rely on their ability to be locally repaired and regenerate. Such tissue plasticity is sustained by resident muscle stem cells that activate following injury at underneath muscle fibres, rapidly proliferate to generate a new population of muscle cells which then differentiate and either fuse into damaged fibres, or together to form new ones, resembling embryonic muscle development.
Since stem cells ensure life-time muscle plasticity, it is crucial to study and model their function to develop tailored therapies to improve tissue regeneration and so maintain muscle function. Importantly, many genes regulating the regenerative capacity of muscle stem cells are inactivated in several muscle illnesses such as muscular dystrophies and myopathies1,2 indicating that specific therapies targetting stem cell activity are promising novel therapeutics to tackle declining muscle function in those pathogenic conditions.
Aim of the project
The project is aimed at unveiling the cellular and molecular processes underlying the regenerative capacity of muscle stem cells for the development of novel tailored therapies to ameliorate muscle regeneration and rescue muscle performance in muscular dystrophies and myopathies.
This project will exploit and integrate:
- in-depth comparative transcriptomic and epigenetic analysis on both cultured muscle cells and human muscle biospies from a range of dystrophies and myopathies and healthy controls to highlight deregulated mechanism for further experimental validation. Complex bioinformatics will be performed in collaboration with experts, with possibility of expanded training.
- In vitro modelling of muscle formation and regeneration through use of genetic manipulation (eg siRNA, AOs, CRISPRi/a, splicing modulation, lentiviral transduction), cell-based assays (fluorescent-based reporters, immunolabelling) and drug (activator/inhibitor) treatment(s) to study the molecular regulation of muscle plasticity.
- Use of refined in vitro models (eg iPSCs) from specific muscle conditions or use of in vivo models (zebrafish/rodents) of defective/disease myogenesis will be integrated for additional validation of identified druggable targets and further promote translational development.
References
1) Ganassi M, Muntoni F, Zammit PS. Defining and identifying satellite cell-opathies within muscular dystrophies and myopathies. Exp Cell Res. 2022 Feb 1;411(1):112906. doi: 10.1016/j.yexcr.2021.112906. Epub 2021 Nov 3. PMID: 34740639; PMCID: PMC8784828.
2) Ganassi M, Zammit PS. Involvement of muscle satellite cell dysfunction in neuromuscular disorders: Expanding the portfolio of satellite cell-opathies. Eur J Transl Myol. 2022 Mar 18;32(1):10064. doi: 10.4081/ejtm.2022.10064. PMID: 35302338; PMCID: PMC8992676.
Contact Information:
f.muntoni@ucl.ac.uk; massimo.ganassi@kcl.ac.uk