Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function
2022
Jeffrey Molendijk | Ronnie Blazev | Richard J Mills | Yaan-Kit Ng | Kevin I Watt | Daryn Chau | Paul Gregorevic | Peter J Crouch | James BW Hilton | Leszek Lisowski | Peixiang Zhang | Karen Reue | Aldons J Lusis | James E Hudson | David E James | Marcus M Seldin | Benjamin L Parker
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 previously acquired 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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