Explaining the ageing of skeletal muscle fibres through a novel evolutionary mechanism

Lead Research Organisation: Imperial College London
Department Name: Dept of Mathematics


The expansion of deleted mitochondrial DNA (mtDNA) molecules has been linked to ageing, particularly in muscle fibres, where it leads to sarcopenia. Despite three years of research, the mechanism underlying muscle fibre ageing has remained unclear. Previous accounts have assigned a selective advantage to the deleted mitochondrial DNA, but, in fact, cells can selectively remove disadvantageous mtDNA.

In this project we have been exploring how spatially extended models with a combination of enhanced density for mutants and stochasticity satisfactorily reproduce the expansion and its speed, that we have estimated estimate form experimental data. We have found evidence that the expansion takes place in a wavelike fashion and we have found an empirical formula for the wavespeed. Notably, these models permit a selective disadvantage for the mutants while nonetheless yielding spreading waves. We introduce the mechanism of stochastic survival of the densest, and we are exploring its plausibility as an alternative to conventional evolutionary theory based survival of the fittest. Muscle fibre ageing is thus a candidate exemplar for the role of noise and spatial structure in yielding novel evolutionary phenomena.

Our understanding of muscle ageing, based on the novel mechanism we propose, suggests the relevance of existing drugs for slowing waves of mutants. Based on our empirical formula for the expansion speed, we plan to explore the relevance of possible pharmaceutical interventions that could slow down the spreading of mutants.

The tools used in this project are a combination of analytical and computational techniques. We are using stochastic calculus to gain analytical insight in our model and the Gillespie algorithm to simulate it. Additionally, we use statistical techniques to compare the predictions of ours and competing models to experimental data.


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Studentship Projects

Project Reference Relationship Related To Start End Student Name
EP/N509486/1 01/10/2016 31/03/2022
2032993 Studentship EP/N509486/1 01/10/2017 05/11/2021 Ferdinando Insalata
Description We have found that ageing in skeletal muscle fibres can take place through a novel evolutionary mechanism.
Exploitation Route Our model and the resulting understanding of muscle ageing can pave the way for therapeutic interventions.
Sectors Healthcare

URL https://scholar.google.com/scholar?cluster=4234389864288178971&hl=en&oi=scholarr
Description Collaboration with the Mitochondrial Biology Unit, University of Cambridge 
Organisation University of Cambridge
Department Cambridge Neuroscience
Country United Kingdom 
Sector Academic/University 
PI Contribution Provided mathematical models to describe previously unexplained phenomena in mitochondrial biology. Provided predictions for model of mitochondrial DNA control by the nucleus.
Collaborator Contribution Provided more in-depth knowledge of mitochondrial biology, started experiments to validate our model
Impact No outcome yet
Start Year 2017