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Published August 3, 2023 | v3
Journal Article Open

Skeletal muscle cell protein dysregulation highlights the pathogenesis mechanism of myopathy-associated p97/VCP R155H mutations

  • 1. ROR icon California Institute of Technology


p97/VCP, a hexametric member of the AAA-ATPase superfamily, has been associated with a wide range of cellular protein pathways, such as proteasomal degradation, the unfolding of polyubiquitinated proteins, and autophagosome maturation. Autosomal dominant p97/VCP mutations cause a rare hereditary multisystem disorder called IBMPFD/ALS (Inclusion Body Myopathy with Paget's Disease and Frontotemporal Dementia/Amyotrophic Lateral Sclerosis), characterized by progressive weakness and subsequent atrophy of skeletal muscles, and impacting bones and brains, such as Parkinson's disease, Lewy body disease, Huntington's disease, and amyotrophic lateral ALS. Among all disease-causing mutations, Arginine 155 to Histidine (R155H/+) was reported to be the most common one, affecting over 50% of IBMPFD patients, resulting in disabling muscle weakness, which might eventually be life-threatening due to cardiac and respiratory muscle involvement. Induced pluripotent stem cells (iPSCs) offer an unlimited resource of cells to study pathology's underlying molecular mechanism, perform drug screening, and investigate regeneration. Using R155H/+ patients' fibroblasts, we generated IPS cells and corrected the mutation (Histidine to Arginine, H155R) to generate isogenic control cells before differentiating them into myotubes. The further proteomic analysis allowed us to identify differentially expressed proteins associated with the R155H mutation. Our results showed that R155H/+ cells were associated with dysregulated expression of several proteins involved in skeletal muscle function, cytoskeleton organization, cell signaling, intracellular organelles organization and function, cell junction, and cell adhesion. Our findings provide molecular evidence of dysfunctional protein expression in R155H/+ myotubes and offer new therapeutic targets for treating IBMPFD/ALS.

Copyright and License

© 2023 Luzzi, Wang, Li, Iacovino and Chou. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.


The acknowledgments are for Michael Kyba Ph.D., and Rita Perlingeiro Ph.D., of Minneapolis University, MN, for providing the plasmids to transfect the iPSCs for skeletal muscle differentiation.


This work was supported by funds from the National Institute of Neurological Disorders and Stroke (NINDS), R01NS102279.


AL, MI, and T-FC wrote the main manuscript. AL prepared Figures 14, Supplementary Figures S1–S5, and Table 1. FW and SL analyzed Figures 3, ,44 and the Supplementary Figures S3, S4. All authors contributed to the article and approved the submitted version.

Data Availability

The original contributions presented in the study are publicly available. This data can be found in PRIDE under the accession number PXD044004: https://www.ebi.ac.uk/pride/archive/projects/PXD044004.

Conflict of Interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


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Additional details

November 10, 2023
January 9, 2024