Journal article
PARP1 mediated PARylation contributes to myogenic progression and glucocorticoid transcriptional response
- Abstract:
- The ADP-ribosyltransferase, PARP1 enzymatically generates and applies the post-translational modification, ADP-Ribose (ADPR). PARP1 roles in genome maintenance are well described, but recent work highlights roles in many fundamental processes including cellular identity and energy homeostasis. Herein, we show in both mouse and human skeletal muscle cells that PARP1-mediated PARylation is a regulator of the myogenic program and the muscle transcriptional response to steroid hormones. Chemical PARP1 modulation impacts the expression of major myocellular proteins, including troponins, key in dictating muscle contractile force. Whilst PARP1 in absence of DNA damage is often assumed to be basally inactive, we show PARylation to be acutely sensitive to extracellular glucose concentrations and the steroid hormone class, glucocorticoids which exert considerable authority over muscle tissue mass. Specifically, we find during myogenesis, a transient and significant rise in PAR. This early-stage differentiation event, if blocked with PARP1 inhibition, reduced the abundance of important muscle proteins in the fully differentiated myotubes. This suggests that PAR targets during early-stage differentiation are central to the proper development of the muscle contractile unit. We also show that reduced PARP1 in myoblasts impacts a variety of metabolic pathways in line with the recorded actions of glucocorticoids. Currently, as both regulators of myogenesis and muscle mass loss, glucocorticoids represent a clinical conundrum. Our work goes on to identify that PARP1 influences transcriptional activation by glucocorticoids of a subset of genes critical to human skeletal muscle pathology. These genes may therefore signify a regulatory battery of targets through which selective glucocorticoid modulation could be achieved. Collectively, our data provide clear links between PARP1-mediated PARylation and skeletal muscle homeostatic mechanisms crucial to tissue mass maintenance and endocrine response.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 4.9MB, Terms of use)
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(Supplementary materials, zip, 10.6MB, Terms of use)
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- Publisher copy:
- 10.1038/s41420-023-01420-2
Authors
- Publisher:
- Springer Nature [academic journals on nature.com]
- Journal:
- Cell Death Discovery More from this journal
- Volume:
- 9
- Issue:
- 1
- Pages:
- 133
- Article number:
- 133
- Place of publication:
- United States
- Publication date:
- 2023-04-22
- Acceptance date:
- 2023-03-29
- DOI:
- EISSN:
-
2058-7716
- ISSN:
-
2058-7716
- Pmid:
-
37087471
- Language:
-
English
- Keywords:
- Pubs id:
-
2409676
- Local pid:
-
pubs:2409676
- Source identifiers:
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W4366769160
- Deposit date:
-
2026-04-21
- ARK identifier:
Terms of use
- Copyright holder:
- Tan et al.
- Copyright date:
- 2023
- Rights statement:
- © The Author(s) 2023. Open Access. This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.
- Licence:
- CC Attribution (CC BY)
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