BCL6 coordinates muscle mass homeostasis with nutritional states

• 成果类型: Article
• 署名作者: Wang, Hui J.; Fan, Weiwei; Liu, Sihao; Kim, Kyeongkyu; Matsushima, Ayami; Ogawa, Satoshi; Kang, Hyun Gyu; Zhu, Jonathan; Estepa, Gabriela; He, Mingxiao; Crossley, Lillian; Liddle, Christopher; Kim, Minseok S.; Truitt, Morgan L.; Yu, Ruth T.; Atkins, Annette R.; Downes, Michael; Evans, Ronald M.
• 署名单位: Salk Institute; Kyushu University; University of Sydney; Westmead Institute for Medical Research; University of Sydney; Daegu Gyeongbuk Institute of Science & Technology (DGIST)
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-14823
• DOI: 10.1073/pnas.24088961221
• 发表日期: 2025-01-28
• 关键词: growth-hormone secretagogue; skeletal-muscle; gene-expression; ghrelin; hypertrophy; sensitivity; deficiency; suppressor; sarcopenia; mechanism

摘要

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 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 Bcl6 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.