Transcriptional programming of translation by BCL6 controls skeletal muscle proteostasis

Krithika Ramachandran, Christopher R. Futtner, Meredith A. Sommars, Mattia Quattrocelli, Yasuhiro Omura, Ellen Fruzyna, Janice C. Wang, Nathan J. Waldeck, Madhavi D. Senagolage, Carmen G. Telles, Alexis R. Demonbreun, Erin Prendergast, Nicola Lai, Daniel Arango, Ilya R. Bederman, Elizabeth M. McNally, Grant D. Barish*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

Abstract

Skeletal muscle is dynamically controlled by the balance of protein synthesis and degradation. Here we discover an unexpected function for the transcriptional repressor B cell lymphoma 6 (BCL6) in muscle proteostasis and strength in mice. Skeletal muscle-specific Bcl6 ablation in utero or in adult mice results in over 30% decreased muscle mass and force production due to reduced protein synthesis and increased autophagy, while it promotes a shift to a slower myosin heavy chain fibre profile. Ribosome profiling reveals reduced overall translation efficiency in Bcl6-ablated muscles. Mechanistically, tandem chromatin immunoprecipitation, transcriptomic and translational analyses identify direct BCL6 repression of eukaryotic translation initiation factor 4E-binding protein 1 (Eif4ebp1) and activation of insulin-like growth factor 1 (Igf1) and androgen receptor (Ar). Together, these results uncover a bifunctional role for BCL6 in the transcriptional and translational control of muscle proteostasis.

Original languageEnglish (US)
Pages (from-to)304-322
Number of pages19
JournalNature Metabolism
Volume6
Issue number2
DOIs
StatePublished - Feb 2024

Funding

We thank N. Hay (University of Illinois Chicago), L. Goodyear (Joslin Diabetes Center, Harvard), C. He (Northwestern University), J. Bass (Northwestern University), D. Chakravarti (Northwestern University) and J. Madsen (University of Southern Denmark) for helpful advice and discussion. We thank Northwestern University’s NU-Seq Core, Comprehensive Metabolic Core and Mouse Histology and Phenotyping Laboratory (supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center) for services. This research was supported by computational resources provided by the Quest high-performance computing facility at Northwestern University. Figures , , and were created with BioRender.com . This work was funded by Merit Review Award #I01BX004898 from the United States (U.S.) Department of Veterans Affairs (to G.D.B.), National Institutes of Health (NIH) grants R01DK108987 (to G.D.B.) and T32 GM008061 (to E.F.) and Pfizer Aspire award WI183795 (to G.D.B.). M.Q. is supported by NIH grants R56HL158531, R01HL166356-01, R03DK130908-01A1 and R01AG078174-01 and CCHMC grants RIP, CCRF Endowed Scholarship and HI Translational Funds. D.A. is supported by the Searle Scholar Program (grant no. SSP-2023-102). E.M.M. is supported by NIH grants R01HL061322 and R01NS047726. The article contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government. We thank N. Hay (University of Illinois Chicago), L. Goodyear (Joslin Diabetes Center, Harvard), C. He (Northwestern University), J. Bass (Northwestern University), D. Chakravarti (Northwestern University) and J. Madsen (University of Southern Denmark) for helpful advice and discussion. We thank Northwestern University’s NU-Seq Core, Comprehensive Metabolic Core and Mouse Histology and Phenotyping Laboratory (supported by NCI P30-CA060553 awarded to the Robert H Lurie Comprehensive Cancer Center) for services. This research was supported by computational resources provided by the Quest high-performance computing facility at Northwestern University. Figures 1d, 2a, 6c and 8 were created with BioRender.com. This work was funded by Merit Review Award #I01BX004898 from the United States (U.S.) Department of Veterans Affairs (to G.D.B.), National Institutes of Health (NIH) grants R01DK108987 (to G.D.B.) and T32 GM008061 (to E.F.) and Pfizer Aspire award WI183795 (to G.D.B.). M.Q. is supported by NIH grants R56HL158531, R01HL166356-01, R03DK130908-01A1 and R01AG078174-01 and CCHMC grants RIP, CCRF Endowed Scholarship and HI Translational Funds. D.A. is supported by the Searle Scholar Program (grant no. SSP-2023-102). E.M.M. is supported by NIH grants R01HL061322 and R01NS047726. The article contents do not represent the views of the U.S. Department of Veterans Affairs or the United States Government.

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Physiology (medical)
  • Cell Biology

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