Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function

Molendijk, J.; Blazev, R.; Mills, R.; Ng, Y.-K.; Watt, K. I.; Chau, D.; Gregorevic, P.; Crouch, P. J.; Hilton, J. B.; Lisowski, L.; Zhang, P.; Reue, K.; Lusis, A. J.; Hudson, J. E.; James, D. E.; Seldin, M. M.; Parker, B. L.

doi:10.1101/2022.08.22.504871

bioRxiv · 10.1101/2022.08.22.504871

Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function

Molendijk, J.·Blazev, R.·Mills, R.·Ng, Y.-K.·Watt, K. I.·Chau, D.·Gregorevic, P.·Crouch, P. J.·Hilton, J. B.·Lisowski, L.·Zhang, P.·Reue, K.·Lusis, A. J.·Hudson, J. E.·James, D. E.·Seldin, M. M.·Parker, B. L.

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Abstract

Improving muscle function has great potential to improve the quality of life. To identify novel regulators of skeletal muscle metabolism and function, we performed a proteomic analysis of gastrocnemius muscle from 73 genetically distinct inbred mouse strains, and integrated the data with genomics and >300 molecular/phenotypic traits via quantitative trait loci mapping and correlation network analysis. These data identified thousands of associations between protein abundance and phenotypes and can be accessed online (https://muscle.coffeeprot.com/) to identify regulators of muscle function. We used this resource to prioritize targets for a functional genomic screen in human bioengineered skeletal muscle. This identified several negative regulators of muscle function including UFC1, an E2 ligase for protein UFMylation. We show UFMylation is up-regulated in a mouse model of amyotrophic lateral sclerosis, a disease that involves muscle atrophy. Furthermore, in vivo knockdown of UFMylation increased contraction force, implicating its role as a negative regulator of skeletal muscle function.

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Molendijk, J., Blazev, R., Mills, R., Ng, Y.-K., Watt, K. I., Chau, D., Gregorevic, P., Crouch, P. J., Hilton, J. B., Lisowski, L., Zhang, P., Reue, K., Lusis, A. J., Hudson, J. E., James, D. E., Seldin, M. M., Parker, B. L.. 2022-08-22. Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function. https://doi.org/10.1101/2022.08.22.504871

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