Fig. 1

Non-transcriptional and transcriptional events activated by AR in skeletal muscle cells. It illustrates the key partners of the androgen receptor (AR) identified in skeletal muscle cells and mediating transcriptional or non-transcriptional androgen actions. (A) Upon crossing the plasma membrane, androgens bind to AR in cytoplasm of skeletal muscle cells. This event leads to the assembly of a binary complex made up of AR and Filamin A (FlnA), triggering the activation of downstream signaling pathways, including Focal Adhesion Kinase (FAK), paxillin, and Rac1. Additionally, androgen stimulation allows AR to interact with p85, the regulatory subunit of PI3K, leading to its activation. PI3K activation may also occur via a FAK-mediated mechanism. The downstream mediators of IGF-1 signaling, insulin receptor substrates 1 and 2 (IRS-1 and IRS-2) further contribute to PI3K activation. Whatever the upstream mechanism, activated PI3K, in turn, phosphorylates and activates Akt. This event results in increased protein synthesis and anabolic effects via mTOR and S6K1 phosphorylation, on one hand. On the other, Akt suppresses catabolic effects by phosphorylating FoxO3a, thereby inhibiting its transcriptional activity. (B) Upon ligand binding, AR enters the nuclei, where it interacts with co-activators such as paxillin, gelsolin, supervillin, and ARA55. AR then binds to androgen-responsive elements (AREs) to regulate the transcription of genes involved in muscle development (MEF2) as well as glycolysis, oxidative metabolism, muscle contraction and polyamine biosynthesis. (C) Myostatin binds to its receptor, thus inducing receptor tetramerization and the subsequent phosphorylation of cytoplasmic SMAD proteins. Once phosphorylated, SMAD4 translocates to the nucleus, where it inhibits the transcription of genes essential for myoblast proliferation and differentiation. (B, C). By activating IGF-1 axis (as depicted in A), androgens, positively influence the expression of follistatin. By preventing the binding of myostatin to the receptor and, consequently, its activation, follistatin counteracts the activity of myostatin, thus promoting oxidative metabolism and skeletal muscle contraction. (D) Androgen binding to GPCRs at the plasma membrane triggers adenylate cyclase (AC), leading to increased intracellular levels of inositol triphosphate (IP3) and calcium (Ca²⁺). This pathway also promotes AMP-activated protein kinase (AMPK) activation, which modulates the PI3K/Akt circuit. Akt might also modulate AMPK activity, further integrating the androgen signaling activation in skeletal muscle cells