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.
Show 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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