Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis
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Arginine methylation is a protein posttranslational modification important for the development of skeletal muscle mass and function. Despite this, our understanding of the regulation of arginine methylation under settings of health and disease remains largely undefined. Here, we investigated the regulation of arginine methylation in skeletal muscles in response to exercise and hypertrophic growth, and in diseases involving metabolic dysfunction and atrophy. We report a limited regulation of arginine methylation under physiological settings that promote muscle health, such as during growth and acute exercise, nor in disease models of insulin resistance. In contrast, we saw a significant remodeling of asymmetric dimethylation in models of atrophy characterized by the loss of innervation, including in muscle biopsies from patients with myotrophic lateral sclerosis (ALS). Mass spectrometry-based quantification of the proteome and asymmetric arginine dimethylome of skeletal muscle from individuals with ALS revealed the largest compendium of protein changes with the identification of 793 regulated proteins, and novel site-specific changes in asymmetric dimethyl arginine (aDMA) of key sarcomeric and cytoskeletal proteins. Finally, we show that in vivo overexpression of PRMT1 and aDMA resulted in increased fatigue resistance and functional recovery in mice. Our study provides evidence for asymmetric dimethylation as a regulator of muscle pathophysiology and presents a valuable proteomics resource and rationale for numerous methylated and nonmethylated proteins, including PRMT1, to be pursued for therapeutic development in ALS.
| Originalsprog | Engelsk |
|---|---|
| Artikelnummer | e23647 |
| Tidsskrift | FASEB Journal |
| Vol/bind | 38 |
| Udgave nummer | 10 |
| ISSN | 0892-6638 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:
We thank Nicholas Williamson, Ching-Seng Ang, Shuai Nie, Swati Varshney, and Michael Leeming for instrument support in the Bio21 Mass Spectrometry and Proteomics Facility. We thank all patients with ALS and control individuals who participated in this study, and Dr Zara Ioannides, Dr Diana Lucia, Zoe Castles, Jordana Sheahan, and Cory Holdom for their assistance with data collection. This research was supported by access to the Melbourne Mouse Metabolic Phenotyping Platform at The University of Melbourne. This work was funded by an NHMRC Emerging Leader Investigator Grant (APP2009642) and a University of Melbourne Driving Research Momentum Grant to B.L.P., a Motor Neurone Disease Research Australia Charcot Grant and NHMRC Ideas Grant 1185427 to F.J.S. and S.T.N., and the Scott Sullivan MND Research Fellowship (University of Queensland, Royal Brisbane & Women's Hospital, and the MND and Me Foundation) to S.T.N. This work was also supported by a Department of Anatomy and Physiology (The University of Melbourne) ECR Seeding Grant to R.B. Y.-K.N. is a recipient of a School of Biomedical Science Postgraduate Award.
Funding Information:
We thank Nicholas Williamson, Ching\u2010Seng Ang, Shuai Nie, Swati Varshney, and Michael Leeming for instrument support in the Bio21 Mass Spectrometry and Proteomics Facility. We thank all patients with ALS and control individuals who participated in this study, and Dr Zara Ioannides, Dr Diana Lucia, Zoe Castles, Jordana Sheahan, and Cory Holdom for their assistance with data collection. This research was supported by access to the Melbourne Mouse Metabolic Phenotyping Platform at The University of Melbourne. This work was funded by an NHMRC Emerging Leader Investigator Grant (APP2009642) and a University of Melbourne Driving Research Momentum Grant to B.L.P., a Motor Neurone Disease Research Australia Charcot Grant and NHMRC Ideas Grant 1185427 to F.J.S. and S.T.N., and the Scott Sullivan MND Research Fellowship (University of Queensland, Royal Brisbane & Women's Hospital, and the MND and Me Foundation) to S.T.N. This work was also supported by a Department of Anatomy and Physiology (The University of Melbourne) ECR Seeding Grant to R.B. Y.\u2010K.N. is a recipient of a School of Biomedical Science Postgraduate Award.
Publisher Copyright:
© 2024 Federation of American Societies for Experimental Biology.
ID: 393508151