Sex Steroids and Apoptosis In Skeletal Muscle: Molecular Mechanisms

Andrea A. Vasconsuelo

• Publisher: Bentham Science Publishers
• Year: 2019
• Print ISBN:
  9789811412356
• eBook ISBN:
  9789811412363
• Topic: Scienze biologiche
• Subtopic: Biochimica

This monograph focuses on the actions exerted by sex hormones, 17?-estradiol and testosterone, in skeletal muscle tissue. An important consideration of this volume is the fact that both estrogen receptors (ERs) and androgen receptors (ARs) are ubiquitously expressed and, as a result, steroid hormones affect growth and different cell functions in several organs. Moreover, ERs and ARs may have a non-classical pattern of intracellular localizations, raising complexity to the functional roles of estradiol and testosterone. Readers will find key information about the role of sex hormones in mitochondrial physiology and their relation with ageing, apoptosis, and sarcopenia. Chapters integrate important points with the latest information on the subject, including work of leading researchers studying the cellular and molecular mechanisms underlying the age-linked changes in muscle tissue while highlighting the role of satellite cells. Furthermore, the book presents a chapter about phytoestrogens (compounds which are structurally very similar to estrogen 17?-estradiol) and their selective action on sex steroid receptors (specifically, they have a higher affinity for ER? receptors than ER? receptors). The book is recommended reading for scientists and clinicians involved in the field of medical and health sciences as well as for scholarly readers (students of biochemistry and medicine) who are interested in the molecular mechanism of cellular apoptosis regulated by steroid hormones.

Subcellular Localization and Physiological Roles of Androgen Receptor

Lucía Pronsato^*

Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR CONICET-UNS), 8000 Bahía Blanca, Argentina

Abstract

Androgens, such as testosterone and Dihydrotestosterone (DHT), exert their actions through the Androgen Receptor (AR), a ligand-dependent nuclear transcription factor that belongs to the steroid hormone nuclear receptor superfamily. The actions of androgens can be mediated through the AR in a DNA binding-dependent manner to modulate the transcription of target genes, or in a manner independent of DNA binding, to trigger rapid cellular events such as the activation of the second messenger signaling pathway. The AR is expressed ubiquitously and it has a wide variety of biological actions comprising significant roles in the development and maintenance of the reproductive, skeletal muscle, cardiovascular, immune, neural and haemopoietic systems, exerting a diversity of roles in many physiological and pathological processes. Studies with AR Knockout (ARKO) mouse models, specifically the cell type- or tissue-specific ARKO models, have revealed many cell type- or tissue-specific pathophysiological roles of AR in mice. Because of the huge amount of information about androgens and the AR, this chapter is not presented as an extensive review of all of it, but rather as an overview of the expression and biological function of AR as well as its significant role in clinical medicine.

Keywords: Androgens, Androgen Receptor, Biological Action, Tissue Distribution.

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^* Corresponding author Lucía Pronsato: Instituto de Investigaciones Biológicas y Biomédicas del Sur (INBIOSUR CONICET-UNS) 8000, Bahía Blanca, Argentina; Tel: [phone]x4337; E-mail: [email protected]

INTRODUCTION

Adequate regulation of androgens action is essential for a variety of developmental and physiological processes, mainly male sexual development and maturation, male reproductive organs maintenance and spermatogenesis [1^-4]. Similarly, androgens are central in the functioning of several other organs and tissues. The major physiological androgens, Testosterone (T) and its metabolite

5α-dihydrotestosterone (DHT), mainly mediate their biological actions through binding to the androgen receptor (AR).

AR is a member of the nuclear receptors (NR) superfamily, a group of transcription factors that trigger the transcription of their target genes in response to specific ligands [5, 6]. They are implicated in a biological process such as development, differentiation, reproduction and homeostasis of eukaryotic organisms. NRs have been preserved during evolution [7], and can be divided into three classes: type I receptors are steroid receptors that include the AR, estrogen receptor (ER), progesterone receptor (PR), mineralocorticoids receptor (MR) and glucocorticoids receptor (GR), classically defined as ligand-dependent, that homodimerize to exert their function. The type II nuclear receptors are known as the retinoid-thyroid family, and consist of the receptors for vitamin D (VDR), thyroid hormone (TR), retinoic acid (RAR), and the peroxisome proliferator-activated receptors (PPAR); they are ligand-independent with potential to both homodimerize and heterodimerize [8]. Finally, the receptors of the third class, named Orfan, comprise a group of proteins that share sequences with significant homologies, whose ligands have not been characterized [9, 10]. The comparative functional and structural analyzes of the NRs revealed that they contain a similar structural organization and can be divided into four functional domains: the carboxyl-terminal ligand binding domain (LBD) is connected by a hinge region (H) to a highly conserved DNA-binding domain (DBD). The LBD includes a hormone-dependent coactivator interface named activation function 2 (AF2). The amino-terminal domain (NTD) contains a hormone-independent coactivator interface, AF1. It is the least conserved domain and has little intrinsic structure. The binding to the DNA or the interaction with other proteins leads to a more ordered structure [11, 12]. The NTD encloses the majority of phosphorylation sites, many of which have serine-proline motifs (Ser-Pro) which can be recognized by the peptidyl-prolyl isomerase, Pin1 [13]. Therefore, phosphorylation of these sites can lead to the isomerization and thus, alteration of the structure of the receptor.

Structural Organization of the AR Gene

The gene that encodes for AR is found on the long arm of chromosome X (Xq11.2-12), and was discovered in 1981, when it was genetically studying humans and mice that showed androgen insensitivity [14^-16]. In 1988, the AR cDNA was cloned for the first time, in spite of the difficulties to obtain enough quantities of the purified protein, to produce antibodies or partial amino acid sequences to design synthetic oligonucleotide probes [5, 17]. The AR gene size is around 90 Kb and contains 8 exons, and its structural organization is almost identical to the genes that encode for the other members of steroid hormone receptors, suggesting a common ancestral past [18, 19]. The possibility of the existence of additional AR genes, which encode for an AR with unclassical localization in the plasma membrane, has been suggested. This idea firstly arose from the observation of effects triggered by testosterone, at short times of hormonal treatment (responses within few minutes or seconds) that could not be a consequence of the transcriptional activity of the classical AR, in brain and osteoblasts [20, 21]. Although only one gene for AR has been detected in humans, two isoforms of AR mRNA were found in the male larynx of Xenopus laevis [22]. Since a second gene encoding for the estrogen receptor has been found, it is possible that other members of the steroid receptor superfamily have also multiple isoforms of the encoding gene.

Protein Structure of AR

The AR protein consists of approximately 919 amino acids and a molecular weight of 98 kDa, which are structured in 4 functional domains [23]. The N-terminal regulatory domain, encoded mainly by exon 1 (1-555 bp), mediates transcriptional activity. This domain contains the activation region of the ligand-independent transcription (AF-1), being this place a site of interaction with certain co-regulators. The DBD, encoded by exons 2 and 3 (556-623 bp), contains two zinc fingers capable of interacting specifically with small sequences named androgen response elements (AREs). The hinge region, encoded by exon 4 between 624-665 bp, is important for the receptor movement. Finally, the LBD encoded by the last exons 5, 6, 7 and 8 between 666-918 bp, is the place where the androgens bind to the receptor, and contains the activation region of the ligand-dependent transcription (AF-2) [24, 25]. The DBD and the LBD share a high grade of homology with the other steroid receptors.

Schematic representation of the human AR gene and protein. The AR gene is localized on the long arm of the X chromosome. It is encoded by 8 exons (919 amino acids) and the protein contains different structural domains: the N-terminal domain (NTD) that includes the activation function 1 (AF1) domain, the DNA binding domain (DBD), the ligand binding domain (LBD) that contains the activation function 2 (AF2) domain and the hinge region containing the KLKK motif.

Classical Mechanism of Action of AR

In the absence of ligand, AR is found in a monomeric form, making a complex with heat shock proteins (Hsp), such as Hsp90, Hsp70 and Hsp56 [26] that act as chaperones. An essential function of the Hsp heterocomplex is to enable folding of the LBD into a high-affinity steroid-binding conformation. Hsp90 modulates hormone binding affinity in vivo [27], and Hsp90s are necessary for the acquirement of active conformation in agonist-bound AR to modulate nuclear transfer, nuclear matrix binding, and transcriptional activity [28]. This complex is dynamic and can translocate between the cytoplasm and the cell nucleus, although the relative subcellular distribution in absence of ligand is mainly cytoplasmic. LBD contains ligand-dependent activation function AF-2. Agonist binding provokes a conformational modification particularly in the C-terminal AF-2, which exposes an amphipathic α-helix to interact with coactivator proteins. Several coactivators bind to a surface formed by helices 3, 4, and 12, and the relocation of helix 12 is central for this interaction. AR is unique among steroid receptors, since its N-terminal AF-1 is crucial in the transcriptional activation, and an LBD-deficient AR is constitutively active [29, 30].

Given that androgens are lipid hormones derived from cholesterol, they are able to diffuse freely through the plasma me...

Table of contents

• Table of Contents
• Title
• BENTHAM SCIENCE PUBLISHERS LTD.
• FOREWORD
• PREFACE
• List of Contributors
• Subcellular Localization and Physiological Roles of Androgen Receptor
• Subcellular Localization Of Estrogen Receptors
• Estrogens and Androgens Binding Sites in Mitochondria
• General Concepts of Skeletal Muscle and Apoptosis: Molecular Mechanisms and Regulation by Sex Steroids
• Antiapoptotic Effects of Estrogens and Androgens
• Role Of Sex Hormones In Cytoskeletal Structure: Implications In Cellular Lifespan
• Apoptosis As Cause Of Sarcopenia: Hormonal Regulation
• The Role of Phytoestrogens in Apoptosis: Chemical Structures and Actions on Specific Receptors
• Conclusions