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Cited by 16Histone Deacetylase Inhibitors ResearchMuscle Physiology and DisordersMetabolism, Diabetes, and Cancer

Class IIa HDACs inhibit cell death pathways and protect muscle integrity in response to lipotoxicity

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Martin, Sheree D., Connor, Timothy, Sanigorski, Andrew, McEwen, Kevin A., Henstridge, Darren C., Nijagal, Brunda, De Souza, David, Tull, Dedreia L. +8 more·2023·Cell Death & Disease
DOI 10.1038/s41419-023-06319-5PMC PMC10692215

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Abstract

Lipotoxicity, the accumulation of lipids in non-adipose tissues, alters the metabolic transcriptome and mitochondrial metabolism in skeletal muscle. The mechanisms involved remain poorly understood. Here we show that lipotoxicity increased histone deacetylase 4 (HDAC4) and histone deacetylase 5 (HDAC5), which reduced the expression of metabolic genes and oxidative metabolism in skeletal muscle, resulting in increased non-oxidative glucose metabolism. This metabolic reprogramming was also associated with impaired apoptosis and ferroptosis responses, and preserved muscle cell viability in response to lipotoxicity. Mechanistically, increased HDAC4 and 5 decreased acetylation of p53 at K120, a modification required for transcriptional activation of apoptosis. Redox drivers of ferroptosis derived from oxidative metabolism were also reduced. The relevance of this pathway was demonstrated by overexpression of loss-of-function HDAC4 and HDAC5 mutants in skeletal muscle of obese db/db mice, which enhanced oxidative metabolic capacity, increased apoptosis and ferroptosis and reduced muscle mass. This study identifies HDAC4 and HDAC5 as repressors of skeletal muscle oxidative metabolism, which is linked to inhibition of cell death pathways and preservation of muscle integrity in response to lipotoxicity.

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  • The contribution of HDAC4 to ferroptosis in different diseases seems to be context-dependent.

    “which indicates that the contribution of HDAC4 to ferroptosis in different diseases seems to be context-dependent.”

    From An HDAC4-specific PROTAC degrader achieves radiation sensitization by enhancing ferroptosis in lung cancer (2026) · cites this paper as [52]

    The Results section reports that HDAC4 and HDAC5 suppress ferroptosis-related processes in myoblasts and skeletal muscle under lipotoxic conditions. The paper does not compare HDAC4’s effects across different diseases, and its experiments assess HDAC4 together with HDAC5, so it does not establish the claimed cross-disease context dependence. (LLM, conf=0.83)

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Cited by

Sorted by citations

Authors
Martin, S. D., Connor, T., Sanigorski, A., McEwen, K. A., Henstridge, D. C., Nijagal, B., De Souza, D., Tull, D. L., Meikle, P. J., Kowalski, G. M., Bruce, C. R., Gregorevic, P., Febbraio, M. A., Collier, F. M., Walder, K. R., & McGee, S. L.
Affiliations
  • Deakin University (AU)
  • University of Tasmania (AU)
  • The University of Melbourne (AU)
  • Baker Heart and Diabetes Institute (AU)
  • Monash University (AU)
  • Barwon Health (AU)
Corresponding author
McGee, Sean L.
ORCID
Venue
Cell Death & Disease
Publisher
Springer Science and Business Media LLC
Published
2023-12-01
Volume
14
Issue
12
Pages
787-787
ISSN
2041-4889 (ISSN-L)
DOI
10.1038/s41419-023-06319-5
PMC
PMC10692215
OpenAlex
W4389245202
Cited by
16
References
5
Citations by year
2026: 5 · 2025: 9 · 2024: 2
FWCI
1.42
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Death and Disease (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
Department of Health | National Health and Medical Research Council (APP1027227, APP1030474, APP1127059)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Histone Deacetylase Inhibitors Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
lipotoxicity, HDAC4, HDAC5, class IIa histone deacetylases, skeletal muscle, oxidative metabolism, p53 acetylation, apoptosis, ferroptosis, muscle integrity, metabolic reprogramming, mitochondrial metabolism, db/db mice, obesity
MeSH terms
Animals, Histone Deacetylases, Protein Processing, Post-Translational, Cell Death, Muscle, Skeletal, Muscle Cells, Mice

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