BCL6 coordinates muscle mass homeostasis with nutritional states
Nutritional status is a determining factor for growth during development and homeostatic maintenance in adulthood. In the context of muscle, growth hormone (GH) coordinates growth with nutritional status; however, the detailed mechanisms remain to be fully elucidated. Here, we show that the transcriptional repressor B cell lymphoma 6 (BCL6) maintains muscle mass by sustaining GH action. Muscle-specific genetic deletion of BCL6 at either perinatal or adult stages profoundly reduces muscle mass and compromises muscle strength. Conversely, muscle-directed viral overexpression of BCL6 significantly reverses the loss of muscle mass and strength. Mechanistically, we show that BCL6 transcriptionally represses the suppressor of cytokine signaling 2 to sustain the anabolic actions of GH in muscle. Additionally, we find that GH itself transcriptionally inhibits BCL6 through the Janus kinase and signal transducer and activator of transcription 5 (JAK/STAT5) pathway. Supporting the physiologic relevance of this feedback regulation, we show the coordinated suppression of muscle <i>Bcl6</i> expression with the induction of GH in the fasted state. These findings reveal the complexity of the feedback controls modulating GH signaling and identify BCL6 as a key homeostatic regulator coordinating muscle mass with nutrient availability. Moreover, these studies open avenues for targeted therapeutic strategies to combat muscle-wasting conditions.
Authors
- Minseok S. Kim (ORCID: https://orcid.org/0000-0002-4268-6886)
- Morgan Truitt (ORCID: https://orcid.org/0000-0001-7012-1228)
- Satoshi Ogawa (ORCID: https://orcid.org/0000-0002-4790-546X)
- Jonathan J. H. Zhu (ORCID: https://orcid.org/0000-0001-6173-6941)
- Christopher Liddle (ORCID: https://orcid.org/0000-0003-3936-6790)
- Gabriela Estepa (ORCID: https://orcid.org/0000-0002-8380-1596)
- Kyeongkyu Kim (ORCID: https://orcid.org/0000-0002-9533-6142)
- Ruth T. Yu (ORCID: https://orcid.org/0000-0002-9527-9627)
- Hyun Gyu Kang
- Annette R. Atkins (ORCID: https://orcid.org/0000-0003-3583-4091)
- Ayami Matsushima (ORCID: https://orcid.org/0000-0001-9751-577X)
- Ronald M. Evans (ORCID: https://orcid.org/0000-0002-9986-5965)
- Michael Downes (ORCID: https://orcid.org/0000-0002-6351-9585)
- Hui Wang
- Ming‐Xiao He
- Weiwei Fan (ORCID: https://orcid.org/0000-0002-1347-7321)
- Sihao Liu (ORCID: https://orcid.org/0000-0003-0937-2460)
- Lillian Crossley
Institutions
- The University of Sydney (AU)
- Salk Institute for Biological Studies (US)
- Kyushu University (JP)
- Daegu Gyeongbuk Institute of Science and Technology (KR)
- Westmead Institute for Medical Research (AU)
Publication Details
- Journal
- Proceedings of the National Academy of Sciences
- Published
- 2025-01-22
- DOI
- https://doi.org/10.1073/pnas.2408896122
- Citations
- 4
- Primary Topic
- Immune Cell Function and Interaction
- Type
- article
- Field-Weighted Citation Impact
- 3.19
Funders
- March of Dimes Foundation
- American Heart Association
- Larry L. Hillblom Foundation
- NOMIS Stiftung
- National Institutes of Health
- National Heart, Lung, and Blood Institute
- Office of Naval Research
- National Cancer Institute
- Division of Diabetes, Endocrinology, and Metabolic Diseases