Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis
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Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis. / Wong, Julian P.H.; Blazev, Ronnie; Ng, Yaan Kit; Goodman, Craig A.; Montgomery, Magdalene K.; Watt, Kevin I.; Carl, Christian S.; Watt, Matthew J.; Voldstedlund, Christian T.; Richter, Erik A.; Crouch, Peter J.; Steyn, Frederik J.; Ngo, Shyuan T.; Parker, Benjamin L.
In: FASEB Journal, Vol. 38, No. 10, e23647, 2024.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis
AU - Wong, Julian P.H.
AU - Blazev, Ronnie
AU - Ng, Yaan Kit
AU - Goodman, Craig A.
AU - Montgomery, Magdalene K.
AU - Watt, Kevin I.
AU - Carl, Christian S.
AU - Watt, Matthew J.
AU - Voldstedlund, Christian T.
AU - Richter, Erik A.
AU - Crouch, Peter J.
AU - Steyn, Frederik J.
AU - Ngo, Shyuan T.
AU - Parker, Benjamin L.
N1 - Publisher Copyright: © 2024 Federation of American Societies for Experimental Biology.
PY - 2024
Y1 - 2024
N2 - 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.
AB - 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.
KW - amyotrophic lateral sclerosis
KW - arginine dimethylation
KW - arginine methylation
KW - proteomics
KW - skeletal muscle
U2 - 10.1096/fj.202400045R
DO - 10.1096/fj.202400045R
M3 - Journal article
C2 - 38787599
AN - SCOPUS:85194125652
VL - 38
JO - F A S E B Journal
JF - F A S E B Journal
SN - 0892-6638
IS - 10
M1 - e23647
ER -
ID: 393508151