iPSC-derived ALS muscle model to study muscle pathology
2020
University of Central Florida, Orlando, USA
This study aimed to investigate the regenerative and functional deficits of the ALS (Amyotrophic lateral sclerosis) skeletal muscle by developing a functional in vitro phenotypic skeletal muscle model from ALS patient-derived iPSCs (ALS-iPSCs) harbouring mutations in the SOD1 gene. This patient iPSC-derived muscle model is free of other cell types such as motoneurons and allows the investigation of muscle pathology from myogenesis to functional muscle formation. With the iPSC-derived model, the authors demonstrated that ALS-iPSC myoblasts have deficits in fusion despite their expression of appropriate myogenic markers. Additionally, significant morphological and structural alterations were identified in iPSC-derived ALS myotubes that correlated with decreased contractile and metabolic function. Furthermore, a subcellular investigation revealed that ALS skeletal muscle had altered mitochondrial function, which may negatively impact metabolic pathways and energy generation. Compared to previous iPSC-derived muscle studies, this investigation provides a detailed and comprehensive view of the morphological and structural deformity of ALS muscle and demonstrates for the first time their functional defects in contractibility, as well as their metabolic dysregulation. The abnormalities revealed in these patient iPSC derived muscle models indicates that endogenous expression of the mutant SOD1 gene in muscle, independent of the influence of motoneurons, has a toxic effect on skeletal muscle regeneration and function, which supports the active role of muscle in neuromuscular junction degradation and ALS onset and/or progression. The results indicate that this model may provide a human-relevant platform for ALS research and drug development studies.
Functional skeletal muscle model derived from SOD1‑mutant ALS patient iPSCs recapitulates hallmarks of disease progression
James J. Hickman
Added on: 04-15-2021
[1] https://www.nature.com/articles/s41598-020-70510-3
