FibReGen: Modelling Myofibre Regeneration

In young individuals, myofibres are capable of altering their profile in response to perturbation, but plasticity of ageing skeletal muscle is less clearly understood. The age-related loss of muscle mass in sarcopenia is mediated by a reduction in the total number of myofibres, a decrease in size of fast-twitch myosin heavy chain fibres and altered morphology. These maladaptations create negative metabolic and functional implications that impede healthy ageing.

Despite modern advances, Duchenne muscular dystrophy (DMD) remains fatal and incurable. Muscle is extensively replaced by adipose tissue, and heart failure often results. We propose to model for the molecular pathogenesis centred around the increased susceptibility of glycolytic fibres to degeneration in DMD and connect the histological findings of hypercontracted fibres, segmental necrosis and grouped necrosis to glycolytic fibres and investigate recent evidence from animal models suggesting that oxidative fibre type switching may ameliorate the effects of the disease.

Early physiological changes often start at the cellular or fascicular level, which is beyond the capabilities of conventional MRI. Histology, requiring invasive biopsies, is necessary to assess early treatment and training effects. Diffusion tensor imaging (DTI) provides a sensitive noninvasive readout of early physiological changes in tissue microstructure. DTI can also be applied for in vivo quantification and 3D visualisation of the macroscopic muscle fibre architecture.

The aim of FibReGen is to develop subject-specific and patient-specific computational models of skeletal and cardiac muscle entirely from MRI data. These computational models will integrate anatomical, functional, metabolic and mechanical data, and will characterise fibre type proportion and interconversion in a wide-ranging spectrum of subjects including elite athletes, those with age-related sarcopenia and patients with DMD.