An overview on androgen

Fig. 1. Genomic and non-genomic androgen-mediated signaling pathways. Genomic signaling is mediated by ligand (e.g. dihydrotestosterone, DHT) entry in the cell through the cytoplasmic membrane. Upon ligand binding to the androgen receptor (AR), the AR-heat-shock protein complex (HSP) retaining AR in the cytoplasm dissociates. AR bound to its ligand translocates to the nucleus as a homodimer, and exerts its transcriptional activity by binding androgen response elements (AREs), in association with coactivators and other transcription factors. Non-genomic signaling is characterized by ligand binding to a membranal AR (mAR). Consequently, secondary messengers induce a cascade of intracellular signaling such as protein kinase A (PKA), protein kinase C (PKC), phospholipase C (PLC), phosphoinositide 3-kinases (PI3Ks) or mitogen-activated protein kinases (MAPKs). These latter will promote processes such as transcriptional and translational activities, structural protein and signaling enzyme synthesis, and other signaling pathways such as calcium mediated signaling. The figure was created with BioRender.com (www.biorender.com).

Fig. 2. Regulation of satellite cell homeostasis by androgen signaling. A. Androgen-mediated stemness regulation. Satellite cell stemness is maintained by various factors such as molecular signaling and mechanical stimuli. In the absence of androgen signaling, they highly express NOTCH, and are in direct cell-to-cell contact through intracellular domain of Notch (NICD) with myofibers expressing ligands Delta-like 4 (DLL4). This maintains the expression of paired box 7 (Pax7) and inhibits that of mind bomb 1 (Mib1), and consequently myogenic differentiation factors such as myogenic determination protein 1 (Myod1) and myogenin (Myog), preserving satellite cells in a quiescent state. B. Androgen-mediated proliferation and differentiation. In response to androgen signaling, ligand-receptor interactions between satellite cells and myoblasts trigger NICD intramembrane proteolysis, and release of the NICD into the cytoplasm. The latter translocates into the nucleus where it forms a complex with Recombination Signal Binding Protein for Immunoglobulin Kappa J Region (RBPJ), and members of the coactivator Mastermind-like (MAML) family. This represses the expression of paired box 7 (Pax7), and activates the transcription of mind bomb 1 (Mib1), which subsequently inhibits their NOTCH signaling and onsets the expression of myogenic differentiation factors such as myogenic determination protein 1 (Myod1) and myogenin (Myog). The figure was created with BioRender.com (www.biorender.com).

Fig. 3. Regulation of myofiber functions by androgen signaling. Androgen signaling in myofibers mainly control fours main aspects. (A) First, it modulates contraction and force generation by inducing the expression of calcium (Ca2+) channels and of various components of the contractile and non-contractile cytoskeleton. (B) In addition, they prevent the emergence of type-2 diabetes by increasing the expression of hexokinase (Hk2), thus facilitating glucose entry, catabolism and storage within the myofiber. (C) AR limits fatty acid import to the myofiber by the modulation of CD36 expression. It also promotes the expression of Pgc1a and Nrf1, as well as the import of fatty acids to the mitochondria, thereby activating their oxidation. (D) Finally, the absence of AR in myofibers promotes the branched chain amino acids (BCAA) catabolism to generate acetyl-CoA. The figure was created with BioRender.com (www.biorender.com).

Fig. 4. Regulation of adipocyte physiology by androgen signaling. Androgens influence several aspects of physiology in adipose tissues, and while most of the observations discussed in literature are specific to the model organism, sex, and fat depot, a general consensus can still be drawn from them, keeping in mind that this necessitates further studies to be significant. Androgens (testosterone in this figure) interact through AR to mediate the following processes in adipocytes: (A) proliferation of mesenchymal stem cells and other adipose precursors along with adipogenesis. (B) the adipokine repertoire from adipocytes. (C) Insulin sensitivity, glucose uptake and glucose tolerance (D) body fat distribution (yellow depots: white adipose tissue; brown depots: brown/beige adipose tissue) (E) Lipogenesis and lipolysis. Adipose tissue is drawn in the center with other cells from SVF including macrophages, T cells and neutrophils. Red arrows indicate repressive effects and green arrows indicate beneficial/promoting effects. AR: androgen receptor; T: testosterone; GLUT4: glucose transporter type 4; Myf5: myogenic factor 5; TNFα: tumor necrosis factor alpha; RBP4: retinol binding protein 4; MCP-1: monocyte chemoattractant protein-1; SAA: serum amyloid A; IL-6: interleukin 6; PAI-1: plasminogen activator inhibitor-1; ACE: angiotensin converting enzyme; VEGF: vascular endothelial growth factor. The figure was created with BioRender.com (www.biorender.com).

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