Anatomy and Neuroscience - Research Publications

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Author: Gregorevic, Paul × Author: Molendijk, Jeffrey × Author: Parker, Benjamin × End date: 2023 × Start date: 2021 ×

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    Phosphoproteomics of three exercise modalities identifies canonical signaling and C18ORF25 as anAMPK substrate regulating skeletal muscle function
    Blazev, R ; Carl, CS ; Ng, Y-K ; Molendijk, J ; Voldstedlund, CT ; Zhao, Y ; Xiao, D ; Kueh, AJ ; Miotto, PM ; Haynes, VR ; Hardee, JP ; Chung, JD ; McNamara, JW ; Qian, H ; Gregorevic, P ; Oakhill, JS ; Herold, MJ ; Jensen, TE ; Lisowski, L ; Lynch, GS ; Dodd, GT ; Watt, MJ ; Yang, P ; Kiens, B ; Richter, EA ; Parker, BL (CELL PRESS, 2022-10-04)
    Exercise induces signaling networks to improve muscle function and confer health benefits. To identify divergent and common signaling networks during and after different exercise modalities, we performed a phosphoproteomic analysis of human skeletal muscle from a cross-over intervention of endurance, sprint, and resistance exercise. This identified 5,486 phosphosites regulated during or after at least one type of exercise modality and only 420 core phosphosites common to all exercise. One of these core phosphosites was S67 on the uncharacterized protein C18ORF25, which we validated as an AMPK substrate. Mice lacking C18ORF25 have reduced skeletal muscle fiber size, exercise capacity, and muscle contractile function, and this was associated with reduced phosphorylation of contractile and Ca2+ handling proteins. Expression of C18ORF25 S66/67D phospho-mimetic reversed the decreased muscle force production. This work defines the divergent and canonical exercise phosphoproteome across different modalities and identifies C18ORF25 as a regulator of exercise signaling and muscle function.
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    Proteome-wide systems genetics identifies UFMylation as a regulator of skeletal muscle function
    Molendijk, J ; Blazev, R ; Mills, RJ ; Ng, Y-K ; Watt, K ; Chau, D ; Gregorevic, P ; Crouch, PJ ; Hilton, JBW ; Lisowski, L ; Zhang, P ; Reue, K ; Lusis, AJ ; Hudson, JE ; James, DE ; Seldin, MM ; Parker, BL (eLIFE SCIENCES PUBL LTD, 2022-12-06)
    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.