Oral Presentation ANZBMS-MEPSA-ANZORS 2022

A multi-scale mechanobiological model of skeletal muscle regeneration in typical and pathological conditions (#111)

Stephanie Khuu 1 , Justin W Fernandez 1 2 , Geoffrey G Handsfield 1
  1. Auckland Bioengineering Institute, Auckland, New Zealand
  2. Department of Engineering Science, The University of Auckland, Auckland, New Zealand

Skeletal muscle is an adaptable tissue with the potential to repair in response to injury. Muscle fibres and surrounding cells carry the repair process within and around skeletal muscle fibres. The cytokine and chemokine environment in skeletal muscle and surrounding extracellular matrix are crucial to guiding cell activity for efficient repair. Exercise can induce focal or segmental muscle fibre damage and elicits the muscle repair cascade. Surrounding cells migrate towards the damage and begin the repair process that results in well-organised contractile units that form muscle fibres[1]. While this complex process is essential for understanding muscle regeneration and repair in disease, post-surgery, and regenerative medicine applications; few models exist that integrate mechanical and physiological cues to simulate skeletal muscle regeneration. Here we use agent-based modelling to explore the role of the molecular and mechanical environment in typical and pathological skeletal muscle repair following simulated exercise-induced muscle damage.

 

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Agent-based modelling is well-positioned to connect macroscale muscle adaptation to its cellular level causes [2]. To investigate the cellular level interactions that give rise to muscle degeneration in pathological scenarios, we created a mechanically coupled agent-based model (Figure 1) that aims to explore cycles of muscle regeneration and degeneration in typically developing muscle and muscle affected by cerebral palsy or inflammatory myopathies, over time. We created a finite element (FE) model of a muscle fibre bundle with active contraction using FEBio, and models of cytokine and chemokine behaviour to represent the effect of HGF, IGF-1, TNF-α, IL-10, IL-6, IL-15 and TGF-β levels on muscle repair. The FE model was used to determine locations of high strain following active muscle lengthening, which indicate locations of mechanical damage (Figure 2). The molecular models acted as bottom-up cell-guidance cues. These in silico models may be used in the future for regenerative medicine and modelling post-surgery outcomes.

  1. [1] M. N. Wosczyna and T. A. Rando, A Muscle Stem Cell Support Group: Coordinated Cellular Responses in Muscle Regeneration, vol. 46, no. 2. Cell Press, 2018, pp. 135–143. doi: 10.1016/j.devcel.2018.06.018.
  2. [2] T. E. Gorochowski, “Agent-based modelling in synthetic biology,” Essays In Biochemistry, vol. 60, no. 4, pp. 325–336, 2016, doi: 10.1042/EBC20160037.