Sex Steroids and Apoptosis In Skeletal Muscle: Molecular Mechanisms

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.

It is well established that estrogens elicit a variety of rapid effects in many tissues in addition to their actions on gene expression in the cell nucleus after Estrogen Receptors (ERs) dimerization and DNA-binding through their EREs. In this chapter we describe tissue distribution, subcellular localization, targets and roles of classical and non-classical ERs.

Mitochondrial localization of estrogen and androgen receptors and hormone-responsive elements (EREs) was reported in different cell lines and indicated that these steroid hormones have specific actions on the mitochondrial gene expression and functions. Both steroids act through a complex molecular mechanism that involves crosstalk between plasma membrane, mitochondria and nucleus. One of the results of these interactions is mitochondrial protection. Here, we discuss studies that describe the estrogen- and testosterone-dependent actions on the mitochondrial and their implications.

Apoptosis is a physiologic process that take place during development and in the progression of specific diseases. In skeletal muscle, this process is poorly explored. Skeletal muscle represents an exceptional tissue regards apoptosis, by its multinucleated structure and its variable mitochondrial content. On the other hand, apoptosis of skeletal muscle tissue could have a wide spectrum of effects on organism since it is now well established that skeletal muscle not only generates force and movement; other functions are associated to this tissue. Skeletal muscle contributes to basal energy metabolism, in the storing for substrates such as amino acids and carbohydrates, in the keep of core temperature and blood glucose levels, and in the use of oxygen and energy during movement. Also, skeletal muscle acts as an endocrine organ, thus could be regulated by owning or no own hormones. This chapter summarizes the generalities of skeletal muscle at the molecular/structural and functional level and basic concepts of apoptosis, for a better understanding of the following chapters of this ebook. Which it focuses specifically, at a molecular level involving genomic regulation, on the actions of 17β-Estradiol and Testosterone in the homeo- stasis of skeletal muscle tissue in physiological and pathological conditions, converging in the relationship of muscle apoptosis and sexual hormones.

As it was mentioned before, estrogens and androgens acts on different tissues, also estrogens and androgens receptors are ubiquitously expressed and have shown not only nuclear, but also non-classical intracellular sites like plasma membrane, mitochondria, golgi and endoplasmic reticulum, making increasing this properties a more complex function to the classical roles of estrogens and androgens (regulation of gene expression). E2 and T can trigger different pathways by a non-genomic mechanism through proteins that have the ability to interact with the steroid hormones (structural similar or different from known steroid receptors). So the hormones can regulate apoptotic events through those different signaling pathways. In mitochondria, a control point of apoptosis, it was demonstrated not only the presence of ER and AR but also an steroid protective action against different injuries that results in antiapoptotic effect. Here we summarize the molecular events, modulated by E2 and/or T in several tissues, during programmed cell death.

The cytoskeleton is composed of intracellular structures that maintain cell shape, interconnect organelles to each other, often attached to the cell membrane and is involved in signaling pathways. Sex steroids are effective regulators of cell morphology and recent evidence indicates that it is obtained through the regulation of the actin cytoskeleton. Intriguingly, evidence implicates the actin cytoskeleton as both a sensor and mediator of apoptosis. Since it has been shown that sex hormones affect/regulate the cellular cytoskeleton, the aim of the present chapter is to discuss the molecular mechanism and targets, related to cytoskeleton, where sex steroids act and modulate the apoptotic process and in consequence the cellular lifespan.

The muscle mass declines with age, affecting the independence in the elderly. This process known as sarcopenia and the acceleration of myocytes loss through apoptosis might signify the main causative. Skeletal muscle tissue increases its size and shows a notable capacity to adapt to injury, due the existence of an undifferentiated group of myogenic-specific precursor cells, called satellite cells. The knowledge of mechanism that driven the apoptosis in satellite cells represents an important base to understand the etiology of sarcopenia. This chapter centers on the potential impact that the estrogen- and testosteroneregulation of satellite cell function has in elderly skeletal muscle, highlighting in the role that both steroids have on apoptotic signaling in myoblasts.

Phytoestrogens are polyphenolic nonsteroidal plant compounds with have estrogen-like biological activity. According to their chemical structures, phytoestrogens might be organised into three central groups: flavonoids, lignans and stilbenes. Isoflavonoids, a subgroup of flavonoids, are the most studied ones for their biological activities, and they are present in many foods, such as soybeans. The most representative isoflavonoids are genistein and daidzein. Due to the fact that phytoestrogens are considerably similar in structure to estrogen17β-estradiol, they may display selective estrogen receptors (ERs) modulating activities; having a higher affinity for ERβ than for ERα. Several studies conducted in animals and humans have indicated that one of the main functions of phytoestrogens involves having a protective effect on certain conditions which are estrogen-dependent, such as symptoms related to menopause, and on estrogen-dependent diseases including prostate and breast cancer, osteoporosis and heart disease. However, phytoestrogens have also anti-estrogenic properties, which have raised concerns since they might cause adverse health effects. At the moment, the existing data are not enough to support a more sophisticated semiquantitative risk-benefit analysis. Hence, phytoestrogens are currently being studied for their role in human health.