Cerebral palsy (CP) is caused by a static lesion to the brain occurring in utero or up to the first 2 years of life; it often manifests as musculoskeletal impairments and movement disorders including spasticity and contractures. Variable manifestation of the pathology across individuals, coupled with differing mechanics and treatments, leads to a heterogeneous collection of clinical phenotypes that affect muscles and individuals differently. Growth of muscles in CP deviates from typical development, evident as early as 15 months of age. Muscles in CP may be reduced in volume by as much as 40%, may be shorter in length, present longer tendons, and may have fewer sarcomeres in series that are overstretched compared to typical. Macroscale and functional deficits are likely mediated by dysfunction at the cellular level, which manifests as impaired growth. Within muscle fibres, satellite cells are decreased by as much as 40–70% and the regenerative capacity of remaining satellite cells appears compromised. Impaired muscle regeneration in CP is coupled with extracellular matrix expansion and increased pro-inflammatory gene expression; resultant muscles are smaller, stiffer, and weaker than typical muscle. These differences may contribute to individuals with CP participating in less physical activity, thus decreasing opportunities for mechanical loading, commencing a vicious cycle of muscle disuse and secondary sarcopenia. This narrative review describes the effects of CP on skeletal muscles encompassing substantive changes from whole muscle function to cell-level effects and the effects of common treatments. We discuss growth and mechanics of skeletal muscles in CP and propose areas where future work is needed to understand these interactions, particularly the link between neural insult and cell-level manifestation of CP.

Cerebral palsy is a neuromusculoskeletal disorder associated with muscle weakness, altered muscle architecture, and progressive musculoskeletal symptoms that worsen with age. Pathological changes at the level of the whole muscle have been shown; however, it is unclear why this progression of muscle impairment occurs at the cellular level. The process of muscle regeneration is complex, and the interactions between cells in the muscle milieu should be considered in the context of cerebral palsy. In this work, we built a coupled mechanobiological model of muscle damage and regeneration to explore the process of muscle regeneration in typical and cerebral palsy conditions, and whether a reduced number of satellite cells in the cerebral palsy muscle environment could cause the muscle regeneration cycle to lead to progressive degeneration of muscle. The coupled model consisted of a finite element model of a muscle fiber bundle undergoing eccentric contraction, and an agent-based model of muscle regeneration incorporating satellite cells, inflammatory cells, muscle fibers, extracellular matrix, fibroblasts, and secreted cytokines. Our coupled model simulated damage from eccentric contraction followed by 28 days of regeneration within the muscle. We simulated cyclic damage and regeneration for both cerebral palsy and typically developing muscle milieus. Here we show the nonlinear effects of altered satellite cell numbers on muscle regeneration, where muscle repair is relatively insensitive to satellite cell concentration above a threshold, but relatively sensitive below that threshold. With the coupled model, we show that the fiber bundle geometry undergoes atrophy and fibrosis with too few satellite cells and excess extracellular matrix, representative of the progression of cerebral palsy in muscle. This work uses in silico modeling to demonstrate how muscle degeneration in cerebral palsy may arise from the process of cellular regeneration and a reduced number of satellite cells.

No abstract

Healthy skeletal muscle undergoes repair in response to mechanically localised strains during activities such as exercise. The ability of cells to transduce the external stimuli into a cascade of cell signalling responses is important to the process of muscle repair and regeneration. In chronic myopathies such as Duchenne muscular dystrophy and inflammatory myopathies, muscle is often subject to chronic necrosis and inflammation that perturbs tissue homeostasis and leads to non-localised, widespread damage across the tissue. Here we present an agent-based model that simulates muscle repair in response to both localised eccentric contractions similar to what would be experienced during exercise, and non-localised widespread inflammatory damage that is present in chronic disease. Computational modelling of muscle repair allows for in silico exploration of phenomena related to muscle disease. In our model, widespread inflammation led to delayed clearance of tissue damage, and delayed repair for recovery of initial fibril counts at all damage levels. Macrophage recruitment was delayed and significantly higher in widespread compared to localised damage. At higher damage percentages of 10%, widespread damage led to impaired muscle regeneration and changes in muscle geometry that represented alterations commonly observed in chronic myopathies, such as fibrosis. This computational work offers insight into the progression and aetiology of inflammatory muscle diseases, and suggests a focus on the muscle regeneration cascade in understanding the progression of muscle damage in inflammatory myopathies.