CORR Insights®: Does a Reduced Number of Muscle Stem Cells Impair the Addition of Sarcomeres and Recovery from a Skeletal Muscle Contracture? A Transgenic Mouse Model (2020)

Where Are We Now? Cerebral palsy is a nonprogressive motor disorder that is most commonly spastic in nature (75%) [10, 13]. Muscle contractures are a frequent complication in patients with spastic cerebral palsy [10]. In addition to muscle shortening, contractures are characterized by reduced muscle volume. Patients with cerebral palsy who are able to walk still exhibit a 45% diminution in muscle volume compared to typically developing children [11]. The pathogenesis of muscle contractures involves an interplay between muscle spasticity [10] and the aberrant orientation of collagen fibers in the extracellular matrix [2, 5, 7, 8]. Furthermore, recent studies suggest an imbalance in skeletal muscle fiber plasticity that contributes to the progression of the contracture. Within healthy skeletal muscles, stretched fibers maintain constant sarcomere length by increasing the serial sarcomere number; an effect mediated by the regenerative capacity of the satellite cells [1, 6, 15]. This adaptive function explains the normalization of muscle fiber histology (sarcomere length) after limb lengthening [15]. Alternatively, muscles with contractures exhibit overstretched sarcomeres despite the reduced overall muscle length [4, 6]. The diminished number of satellite cells found in the affected muscles suggests that bone growth cannot be matched by an increase in muscle segments in the affected muscle, a function of the satellite cells. Therefore, a net elongation of individual sarcomeres is evident despite the shortened muscle overall length of muscle fibers [6]. In the current study, Dayanidhi and colleagues [3] showed diminished recovery from immobilization-induced plantar flexion contractures within a transgenic mouse model treated with tamoxifen to decrease the satellite cell count and activity. In addition, the authors highlighted a reduced number of serial sarcomeres within the satellite cell depleted cohort. There was a strong inverse correlation between the contracture severity and the number of serial sarcomeres which the authors attributed to the reduced satellite cell number with a subsequently impaired serial sarcomere addition [3]. In contrast to previous reports [14] associating contractures with deranged collagen content in the extracellular matrix, the authors did not find collagen content to be significantly correlated with the severity of contractures [3]. Where Do We Need to Go? Like any good study, Dayanidhi and colleagues [3] leave some important questions for the next report to answer. While the tamoxifen-induced satellite cell deficiency was associated with diminished recovery from the reversible immobilization contractures, the translation of this finding to progressive muscle contractures in patients with cerebral palsy requires further investigation. Similarly, the variation in the pathogenesis of muscle contractures among disuse atrophy, denervation atrophy, myopathic conditions and spastic derangements of muscle need to be explored. Muscle contractures in patients with spastic cerebral palsy exhibit fewer satellite cells. However, a correlation between contracture severity and the number of satellite cells in spastic patients with cerebral palsy has not been established [6]. Similarly, it is controversial whether a causal relationship exists between muscle contractures and satellite cell deficiency in these patients. Investigating the role of satellite cells in the development of contractures has the potential to identify therapeutic interventions targeting the original pathology. The progression of microstructural changes in muscle contractures requires evaluation at multiple time points. The current study outlines a lack of substantial association between collagen content and the severity of muscle contractures [3], in contrast to previous reports associating the high collagen content in the extracellular matrix with the progression of muscle contractures [2, 5, 7, 8]. This finding raises questions regarding what the minimum required follow-up period in animal models should be in order to attain an accurate reflection of the chronic findings associated with cerebral palsy in humans. Likewise, the discrepancy in the rate of development of muscle contractures, their severity, and variability between different muscle groups in patients with cerebral palsy require further investigation [12]. How Do We Get There? The pathogenesis as well as the prevention of muscle contractures need further basic and clinical research, given the implications of this problem on patients’ quality of life and the role this finding plays in surgical decision making. Laboratory science studies should investigate what biochemical markers may have prolific potential in satellite and mesenchymal stem cells, both in normal muscles and muscles with contractures. This might begin in animal models, and promising avenues would get further attention in human studies among patients with cerebral palsy. I believe that animal models with induced upper motor neuron lesions might better reflect the pathogenesis in cerebral palsy than immobilization-induced contractures. This can be done by reproducing the rehabilitation programs and surgical interventions performed in patients with cerebral palsy within the animal models followed by the histological and biochemical assessment of the affected muscle groups at multiple follow-up periods. Moreover, translating the basic science findings into clinical practice is a pressing topic; there may be a role for orthobiologics in the management of contractures in patients with cerebral palsy, though as of now this is speculative. Unfortunately, these treatments are being promoted to the public before sufficient high-quality evidence is available in support of their use; I agree with the recent editorial in this journal [9] urging caution on this front. Future studies involving stem cells should be encouraged on a basic science level, before shifting to a limited nonprofit clinical trials that are mindful of ethics, safety, and long-term effects. Indeed, the scientific community needs a better understanding of stem cells before using them on our patients.