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Quantification of the skeletal muscle proteome and arginine dimethylome in human ALS

ABSTRACT: Proteomic and arginine dimethylomic analysis of skeletal muscle biopsies from control and ALS patients (n=8-9).

INSTRUMENT(S): Orbitrap Eclipse

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Skeletal Muscle

DISEASE(S): Amyotrophic Lateral Sclerosis Type 1

SUBMITTER: Benjamin Parker

LAB HEAD: Benjamin Parker

PROVIDER: PXD047184 | Pride | 2025-02-19

REPOSITORIES: pride

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			Action	DRS
	230614_Eclipse_BenParker_BP-6504_A4.raw	Raw
	230614_Eclipse_BenParker_BP-6504_A6.raw	Raw
	230614_Eclipse_BenParker_BP-6504_B5.raw	Raw
	230614_Eclipse_BenParker_BP-6504_B6.raw	Raw
	230614_Eclipse_BenParker_BP-6504_C3.raw	Raw

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1 - 5 of 33

Publications

Characterization of the skeletal muscle arginine methylome in health and disease reveals remodeling in amyotrophic lateral sclerosis.

Wong Julian P H JPH Blazev Ronnie R Ng Yaan-Kit YK Goodman Craig A CA Montgomery Magdalene K MK Watt Kevin I KI Carl Christian S CS Watt Matthew J MJ Voldstedlund Christian T CT Richter Erik A EA Crouch Peter J PJ Steyn Frederik J FJ Ngo Shyuan T ST Parker Benjamin L BL

FASEB journal : official publication of the Federation of American Societies for Experimental Biology 20240501 10

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 argi ...[more]

PMID: 38787599

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AP-MS of C18ORF25 with AMPK- and S67 phosphorylation-depedent interactions

Project description:C18ORF25 is a homolog of Arkadia (RNF111), an E3 ubiquitin ligase with SUMO-interaction motifs (SIMs) (PMID: 31417085). However, C18ORF25 lacks the entire C-terminal RING domain of RNF111 which is required for ubiquitin binding suggesting it lacks ubiquitination activity and may therefore act as an adaptor or signalling scaffold (PMID: 26283374). We have previously shown that mice lacking C18Orf25 throughout the entire body have increased adiposity, decreased lean mass, lower exercise capacity and significantly reduced ex vivo skeletal muscle force production (PMID: 35882232). Skeletal muscle isolated from C18Orf25 knockout (KO) mice have reduced cAMP-dependent protein kinase A (PKA) levels, and reduced phosphorylation of several contractile proteins and proteins involved in calcium handling. Furthermore, analysis of single muscle fibres from C18Orf25 KO mice revealed impaired SR calcium cycling in fast-twitch fibres only (PMID: 35882232). We also previously showed that the exercise-regulated phosphorylation of S67 on C18ORF25 is directly catalysed by AMPK. This phosphorylation site plays an important role in the function of C18ORF25 as re-expression of a phospho-mimetic S66/67D but not phospho-dead S66/67A in C18Orf25 KO mice is able to rescue skeletal muscle contractile defects PMID: 35882232). In the present study, we further investigated the potential molecular functions of C18ORF25. We performed affinity purification coupled to tandem mass spectrometry (AP-MS) to probe the protein:protein interaction (PPI) landscape of C18ORF25. Included in this analysis was also an investigation of potential S67 phosphorylation-dependent PPIs.

2024-01-03 | PXD045629 | Pride

AP-MS of ALPK3 in cardiomyocytes

Project description:Pathogenic mutations in alpha kinase 3 (ALPK3) cause cardiomyopathy and a range of musculoskeletal defects. How ALPK3 mutations result in disease remains unclear and little is known about this atypical kinase. Using a suite of engineered human pluripotent stem cells (hPSCs) we show that ALPK3 localizes to the sarcomere, specifically at the M-Band. Both sarcomeric organization and calcium kinetics were disrupted in ALPK3 deficient hPSC derived cardiomyocytes. Further, cardiac organoids derived from ALPK3 knockout hPSCs displayed reduced force generation. Phosphoproteomic profiling of wildtype and ALPK3 null hPSC derived cardiomyocytes revealed ALPK3-dependant phospho-peptides were enriched for proteins involved in sarcomere function and protein quality control. We demonstrate that ALPK3 binds to the selective autophagy receptor SQSTM1 (Sequestome 1) and is required for the sarcomeric localization of SQSTM1. We propose that ALPK3 is a myogenic kinase with an integral role in the intracellular signaling networks underlying sarcomere maintenance required for continued cardiac contractility.

2023-01-19 | PXD035734 | Pride

Screening in Human Cardiac Organoids Identifies a Critical Role for the Mevalonate Pathway in Cardiomyocyte Proliferation

Project description:Re-induction of endogenous proliferation is a promising regeneration strategy for post-mitotic organs. For heart regeneration, we recently discovered that dual inhibition of both GSK3 and MST1 is required for proliferation in mature human cardiac organoids1. However, the mechanisms of action are not yet understood. Here, we de-convolute the mitogenic response using proteomics and report that GSK3 inhibition activates a cell cycle network whereas MST1 inhibition drives the mevalonate pathway. Screening of an additional 105 compounds identified a p38 inhibitor, which activated a cell cycle network, as well as an inhibitor of TGFBR, which activated the mevalonate pathway; combinatorial treatment with these two inhibitors also resulted in synergistic cell cycle activation. The mevalonate pathway which was consistently activated under the most robust proliferative conditions, is down-regulated during in vivo maturation when cardiomyocyte regenerative capacity ceases and inhibition of the mevalonate pathway abolished the myocyte proliferative response to mitogens. Taken together, our findings suggest that the mevalonate pathway synergises with mitogenic agents to enable mature cardiomyocytes to re-enter the cell cycle. These findings have important ramifications for development of cardiac regenerative therapeutics.

2019-03-12 | PXD009133 | Pride

Proteomic analysis of single muscle fibres from WT and C18ORF25 KO mice

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2024-01-03 | PXD045631 | Pride

Exercise-induced molecular mechanisms for glycogen supercompensation in human skeletal muscle

Project description:A single bout of exercise followed by intake of carbohydrates leads to glycogen supercompensation in the prior exercised muscle. The molecular mechanisms underlying this well-known phenomenon remain elusive. Here we report that a single bout of exercise induces marked activation of glycogen synthase (GS) and AMP-activated protein kinase (AMPK) for several days beyond normalized muscle glycogen content in man. Acute muscle specific deletion of AMPK activity in mouse muscle abrogated the ability for glycogen supercompensation, providing genetic evidence that AMPK serves as essential driver for glycogen supercompensation. Muscle proteomic analyses revealed elevated glucose uptake capacity in the prior exercised muscle while key proteins in fat oxidation and glycolysis largely remained unchanged. The temporal order of these sustained cellular alterations induced by a single bout of exercise provide a mechanism to offset the otherwise tight feedback inhibition of glycogen synthesis and glucose uptake by glycogen, ultimately leading to muscle glycogen supercompensation.

2018-08-30 | PXD009196 | Pride

Phosphoproteomic analysis of three exercise modalities in human skeletal muscle

Project description:To characterize phosphorylation-based signaling events across different exercise modalities we subjected eight healthy young men (age, 26.3±1.3 years; BMI, 23.5±0.7 kg/m2; maximal oxygen uptake (VO2 max), 42.6±1.5 ml/kg/min) that did not perform regular physical activity apart from local bicycling to an acute bout of endurance (90 min ~60% of VO2 max), sprint (3 x 30-s all-out cycling), or resistance exercise (6 sets of 10 RM knee extensions) in the fasting state. All participants completed the three types of exercise in a randomized crossover design with 14 days washout between each exercise bout.

2022-07-18 | PXD031049 | Pride

Proteomic and phosphoproteomic of C18ORF25 KO skeletal muscle following electrical contraction

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2022-07-18 | PXD031101 | Pride

Phosphoproteomics of liver-derived extracellular vesicle treated skeletal muscle

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Phosphoproteomics of cardiac organoids derived from ALPK3 knockout hPSCs

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Proteomic anlaysis of Fabry iPSC derived cardiomyocytes treated with GLA modRNA

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