Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function
Year: 2022
Type: article
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 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.
Source: eLife
DOI: 10.7554/elife.82951
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $2,500
Funders: Sir Edward ‘Weary’ Dunlop Medical Research Foundation, ALS Association, University of Sydney, University of Melbourne, National Institutes of Health, Medical Research Council, National Health and Medical Research Council, National Institute on Aging, National Heart, Lung, and Blood Institute, National Institute of General Medical Sciences, National Institute of Diabetes and Digestive and Kidney Diseases
Awards: Systems genetics approach to inflammatory mechanisms in atherosclerosis, Development of a strategy for endocrine axis discovery, Pharmacogenomics of Statin Therapy, Systems-based approaches for investigating tissue communication during exercise, Bioengineered skeletal muscle to discover therapies for age-related muscle weakness , Genetic regulation of signal transduction and metabolic flexibility, Targeting skeletal muscle for the treatment of insulin resistance, Developing a novel class of therapeutics for muscle wasting and frailty, Copper-ATSM and follistatin: A nerve-muscle combination therapy strategy, A strategy for discovery of endocrine interactions, G9000275154, G9000295956, G9000306216, Systems Genetics Dissection of Non-alcoholic Steatohepatitis, Integrative approaches to dissection of endocrine communication, dkNET Coordinating Unit: Harnessing the Power of AI and Data Science forCollaborative Discovery and Sharing in the DK Community
OpenAlex ID: W4310778801