Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function
- University of Melbourne, Australia
- QIMR Berghofer Medical Research Institute, Australia
- University of California, Irvine, United States
- University of Sydney, Australia
- University of California, Los Angeles, United States
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.
Data availability
The proteomics data generated in this study are deposited to the ProteomeXchange Consortium via the PRIDE (Perez-Riverol et al., 2019) under the identifiers PXD032729, PXD034913 and PXD035170. The code used for downstream analysis of proteomic data can be found at: https://github.com/JeffreyMolendijk/skeletal_muscle.
Article and author information
Author details
Funding
National Health and Medical Research Council (APP1184363)
- Karen Reue
- Marcus M Seldin
- Benjamin L Parker
National Institute of Health (HL147883)
- Aldons J Lusis
National Institute of Health (DK117850)
- Aldons J Lusis
Weary Dunlop Foundation (NA)
- Benjamin L Parker
The ALS Association (21-DDC-574)
- Paul Gregorevic
- Peter J Crouch
National Health and Medical Research Council (APP2009642)
- Benjamin L Parker
National Health and Medical Research Council (APP2013189)
- Richard J Mills
National Health and Medical Research Council (APP1156562)
- Paul Gregorevic
- Benjamin L Parker
National Institute of Health (HL138193)
- Marcus M Seldin
National Institute of Health (DK130640)
- Marcus M Seldin
National Institute of Health (DK097771)
- Marcus M Seldin
National Institute of Health (GM115318)
- Karen Reue
National Institute of Health (AG070959)
- Aldons J Lusis
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Charles Farber, University of Virginia, United States
Ethics
Animal experimentation: All rAAV6 intramuscular injection mouse experiments were approved by The University of Melbourne Animal Ethics Committee (AEC ID1914940) and conformed to the National Health and Medical Research Council of Australia guidelines regarding the care and use of experimental animals. All studies involving the use of SOD1G37R mice and non-transgenic littermates were approved by a University of Melbourne Animal Experimentation Ethics Committee (approval #2015124) and conformed with guidelines of the Australian National Health and Medical Research Council.
Version history
- Preprint posted: August 22, 2022 (view preprint)
- Received: August 24, 2022
- Accepted: November 29, 2022
- Accepted Manuscript published: December 6, 2022 (version 1)
- Version of Record published: January 11, 2023 (version 2)
Copyright
© 2022, Molendijk et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function
eLife 11:e82951.
https://doi.org/10.7554/eLife.82951
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Runs-of-homozygosity (ROH) segments, contiguous homozygous regions in a genome were traditionally linked to families and inbred populations. However, a growing literature suggests that ROHs are ubiquitous in outbred populations. Still, most existing genetic studies of ROH in populations are limited to aggregated ROH content across the genome, which does not offer the resolution for mapping causal loci. This limitation is mainly due to a lack of methods for the efficient identification of shared ROH diplotypes. Here, we present a new method, ROH-DICE (runs-of-homozygous diplotype cluster enumerator), to find large ROH diplotype clusters, sufficiently long ROHs shared by a sufficient number of individuals, in large cohorts. ROH-DICE identified over 1 million ROH diplotypes that span over 100 single nucleotide polymorphisms (SNPs) and are shared by more than 100 UK Biobank participants. Moreover, we found significant associations of clustered ROH diplotypes across the genome with various self-reported diseases, with the strongest associations found between the extended human leukocyte antigen (HLA) region and autoimmune disorders. We found an association between a diplotype covering the homeostatic iron regulator (HFE) gene and hemochromatosis, even though the well-known causal SNP was not directly genotyped or imputed. Using a genome-wide scan, we identified a putative association between carriers of an ROH diplotype in chromosome 4 and an increase in mortality among COVID-19 patients (p-value = 1.82 × 10−11). In summary, our ROH-DICE method, by calling out large ROH diplotypes in a large outbred population, enables further population genetics into the demographic history of large populations. More importantly, our method enables a new genome-wide mapping approach for finding disease-causing loci with multi-marker recessive effects at a population scale.
