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

Jeffrey Molendijk; Ronnie Blazev; Richard J Mills; Yaan-Kit Ng; Kevin I Watt; Daryn Chau; Paul Gregorevic; Peter J Crouch; James B W Hilton; Leszek Lisowski; Peixiang Zhang; Karen Reue; Aldons J Lusis; James E Hudson; David E James; Marcus M Seldin; Benjamin L Parker

doi:10.7554/eLife.82951

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

Elife. 2022 Dec 6:11:e82951. doi: 10.7554/eLife.82951.

Authors

Jeffrey Molendijk^{1

2}, Ronnie Blazev^{1

2}, Richard J Mills³, Yaan-Kit Ng^{1

2}, Kevin I Watt^{1

2}, Daryn Chau⁴, Paul Gregorevic^{1

2}, Peter J Crouch⁵, James B W Hilton⁵, Leszek Lisowski^{6

7}, Peixiang Zhang⁸, Karen Reue⁸, Aldons J Lusis^{8

9}, James E Hudson³, David E James¹⁰, Marcus M Seldin⁴, Benjamin L Parker^{1

2}

Affiliations

¹ Department of Anatomy and Physiology, University of Melbourne, Melbourne, Australia.
² Centre for Muscle Research, University of Melbourne, Melbourne, Australia.
³ QIMR Berghofer Medical Research Institute, Brisbane, Australia.
⁴ Department of Biological Chemistry and Center for Epigenetics and Metabolism, University of California, Irvine, Irvine, United States.
⁵ Department of Biochemistry and Pharmacology, University of Melbourne, Melbourne, Australia.
⁶ Children's Medical Research Institute, University of Sydney, Sydney, Australia.
⁷ Military Institute of Medicine, Warszawa, Poland.
⁸ Department of Human Genetics/Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, United States.
⁹ Department of Microbiology, Immunology and Molecular Genetics, University of California, Los Angeles, Los Angeles, United States.
¹⁰ Charles Perkins Centre, School of Life and Environmental Science, School of Medical Science, University of Sydney, Sydney, Australia.

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.

Keywords: UFMylation; computational biology; human; mouse; proteomics; skeletal muscle; systems biology; systems genetics.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Humans
Mice
Muscle, Skeletal / metabolism
Phenotype
Proteome* / metabolism
Proteomics*
Quality of Life

Substances

Proteome

Abstract

Publication types

MeSH terms

Substances

Grants and funding