The multifaceted roles of BAF60 subunits in muscle: regulation of differentiation, reprogramming, and metabolic homeostasis

Abstract

Muscle development and metabolic homeostasis are critical aspects of human health. As a key component of the SWI/SNF chromatin remodeling complex, the BAF60 subunit plays a widespread and crucial role in the differentiation, reprogramming, and metabolic regulation of skeletal, cardiac, and smooth muscle. Recent studies reveal that BAF60c promotes skeletal muscle differentiation and regeneration by interacting with MyoD, while also driving cardiac-specific gene expression and cooperating with transcription factors such as NKX2.5 and GATA Binding Protein 4 (GATA4) during heart development and remodeling. In smooth muscle, BAF60c interacts with serum response factor to maintain contractility and homeostasis by reducing inflammation and apoptosis. In contrast, BAF60a promotes inflammatory responses and extracellular matrix degradation, contributing to vascular diseases such as abdominal aortic aneurysm and atherosclerosis. Importantly, different BAF60 isoforms exhibit antagonistic, synergistic, or mutually exclusive effects in different muscle types, highlighting their complexity. This review provides a comprehensive overview of BAF60 isoforms' regulatory roles, with an emphasis on their potential as therapeutic targets for muscle-related metabolic and vascular diseases.

Keywords: BAF60 subunit; BAF60a; BAF60b; Baf60c; differentiation; metabolic homeostasis; muscle; reprogramming.

FIGURE 1

Role of BAF60c in skeletal muscle glucose metabolism and regeneration. BAF60c promotes glycolytic metabolism and muscle regeneration by activating the Deptor–AKT signaling pathway and suppressing Dkk3-mediated inhibitory signals. Its function is regulated by glucose sensing, sulfonylurea action, and ERK signaling in metabolic disease states. The figure is based on illustrations from Wang et al. (2018) and Meng et al. (2017), with modifications to incorporate additional pathways and findings relevant to this study. VDCC, Voltage-Dependent Calcium Channel; KATP, ATP-Sensitive Potassium Channel; CaMKII, Calcium/Calmodulin-Dependent Protein Kinase II; HDAC5, Histone Deacetylase 5; SWI/SNF, SWItch/Sucrose Non-Fermentable; AKT, Protein Kinase B; Deptor, DEP Domain-Containing MTOR-Interacting Protein; ERK, Extracellular Signal-Regulated Kinase; Dkk3, Dickkopf-3; T2D, Type 2 Diabetes; ECM, Extracellular Matrix.

FIGURE 2

BAF60c-mediated chromatin remodeling in cardiac hypertrophy and heart failure. (A) In hypertensive hearts, SWI/SNF subunits including BAF60c are upregulated and activate fetal cardiac genes. (B) MAPK–MSK signaling induces H3S28 phosphorylation, facilitating recruitment of SWI/SNF and activation of immediate early genes. (C) In heart failure, elevated BAF60c suppresses oxidative metabolism via PGC1α/PPARα/mTOR inhibition, promoting glycolysis and cardiomyocyte apoptosis. SWI/SNF, SWItch/Sucrose Non-Fermentable; MAPK, Mitogen-Activated Protein Kinase; MSK, Mitogen- and Stress-activated Kinase; H3S28, Histone H3 Serine 28; ANP, Atrial Natriuretic Peptide; BNP, Brain Natriuretic Peptide; PGC1α, Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-Alpha; PPARα, Peroxisome Proliferator-Activated Receptor Alpha; mTOR, Mechanistic Target of Rapamycin; ROS, Reactive Oxygen Species; HTN, Hypertension; c-Fos, FBJ murine osteosarcoma viral oncogene homolog; c-Jun, Jun proto-oncogene.

FIGURE 3

Opposing roles of BAF60c promotes the contractile phenotype, inhibits apoptosis via KLF5-BCL2, and reduces inflammation via HDAC1-mediated NF-κB suppression, thereby protecting against AAA. In contrast, BAF60a activates NF-κB, promotes vascular inflammation, upregulates MMPs and CTSS, enhances ECM degradation, and contributes to AAA and atherosclerosis progression. The figure is based on illustrations from Zhao et al. (2022) and includes content derived from Chang et al. (2020) and Jiang et al. (2022). SRF, Serum Response Factor; ECM, Extracellular Matrix; NF-κB, Nuclear Factor-kappa B; MMPs, Matrix Metalloproteinases; CTSS, Cathepsin S; AAA, Abdominal Aortic Aneurysm.