Testosterone exerts significant effect on muscle cells, and abnormalities of plasma concentrations can cause both skeletal muscle and cardiovascular diseases. Low levels are known to be associated with hypogonadism and have recently been linked to sarcopenia and metabolic syndrome; high levels are associated with hypertrophy. However, most evidence of the link between testosterone and metabolic actions is observational. Studies targeted to establish the mechanisms for such effects at the cell level and their correlation with
1.1. Physiology of the androgens
Anabolic/androgenic steroid hormones are part of the male reproductive endocrine axis. Androgens are the male sex hormones responsible for development of the male reproductive system. Testosterone is the main androgen circulating in the blood and it is secreted from the testes, while other androgens, such as androstenedione and dehydroepiandrostenedione (DHEA) come mainly from the adrenal gland. In some tissues the androgen actions require that testosterone can be converted to dihydrotestosterone by action of 5α-reductase, and in other tissues, including adipose tissue, testosterone can also be converted into estradiol by aromatization of the androgen ring.
Endocrine actions of testosterone are under control of the hypothalamus-pituitary-gonad axis. The hypothalamus secretes gonadotropin-releasing hormone (GnRH), which stimulates the secretion of luteinizing hormone (LH) from the anterior pituitary (adenohypophysis). In the Leydig cells of the testes, the binding of LH to its receptor activates the uptake of circulating cholesterol, the steroid precursor for biosynthesis of all androgens. In the last step of testosterone biosynthesis, androstenedione is converted to testosterone, which is the main secreted component (95% of circulating androgens). In some cases testosterone acts directly on the cells of the target organ, but in others the active hormone is formed within the cells of the target organ by reduction of testosterone at position 5 of the steroid ring to yield the more active dihydrotestosterone. Androgens are responsible for primary and secondary sexual characteristics in men and also for the development of skeletal muscle mass and strength, erythropoiesis, and bone density, amongst other functions.
The divergent effects that androgens have between the sexes can be explained by differences in concentration, metabolism, and receptor expression. Male sex hormones are also known to fluctuate along the day and throughout life. Testosterone levels are usually low in males before puberty. However, after puberty, the testosterone level increases and reaches its peak around the age of 20–25 in men. As aging occurs, testosterone levels decline.
From total circulating levels of testosterone, only the free fraction of testosterone, the part dissolved in the plasma, is biologically active. In blood, free circulating testosterone is around a 2%, while the rest of the hormone is bound in different proportions to sex hormone binding globulin (SHBG) and albumin. However, the bio-available bound testosterone can be released on demand, as the albumin binding is weak. Thus, a higher apparent concentration of free testosterone is available to act in specific tissues.
The androgens have a variety of peripheral actions. They are anabolic throughout the body. That is, they stimulate protein synthesis. It is for this reason that the male body composition is generally larger and more muscular than the female. Androgen axis alterations are due mainly to deficiency or excess of testosterone, and the final effect will depend on whether the imbalance occurs before or after puberty. Before puberty, it can lead to delayed activation or never reached puberty (hypogonadism). If in excess, the hormone will have the opposite effect promoting early puberty accompanied by growth problems characterized by bone epiphysis alterations. Testosterone deficiency during embryonic development will condition a feminization of the external genitalia in men. After puberty, given the role of the male sex hormone on spermatogenesis, testosterone deficiency can induce infertility. Exogenously induced elevated testosterone concentrations cause hypertrophy in several tissues, with the effects on skeletal and cardiac muscle being critical.
In men, plasma testosterone concentrations range from 300 to 1000 ng/dL, whereas in women circulating levels of testosterone are about 10% of those observed in men [2, 3]. The body composition of men is regulated by testosterone concentrations [4, 5]. Pharmacological suppression of endogenous testosterone levels in healthy young subjects increased fat mass and decreased fat free mass and protein synthesis in muscle, suggesting a direct effect of androgens on body metabolism of lipids and proteins . Healthy young subjects suppressed of endogenous testosterone levels and supplemented with different testosterone doses (from 25 mg to 600 mg testosterone enanthate/week) for 20 weeks increased the volume of the quadriceps muscle in a dose dependent manner, as determined by nuclear magnetic resonance. At the histological level, this increase was explained by an increase in the area of type I and II muscle fibers . In bone tissue, testosterone deficiency is associated with decreased bone density with increasing tissue turnover markers. Thus, hormone replacement therapy in patients with hypogonadism has been established as effective to increase bone density . Although testosterone and its derivatives are well known for their androgenic properties and anabolic effects, so far the effects of androgens on muscle remain incompletely understood.
1.2. Androgen mechanisms of action
Androgens exert most of their effects through direct binding to specific intracellular receptors acting as transcriptional activators . Intracellular androgen receptors have been described in skeletal and cardiac muscle cells in addition to other tissues [9, 10]. The intracellular receptor mediates the “classic” genomic response to testosterone and is characterized as a 110-kDa protein with domains for androgen binding, nuclear localization, DNA binding, and transactivation. The conserved domain structure has 3 major functional regions, an NH-terminal transactivation domain, a centrally located DNA binding domain (DBD), and a COOH-terminal hormone-binding domain (HBD). The COOH-terminus contains an additional activation domain and a hinge region connecting the HBD and the DBD. Upon ligand binding, the nuclear receptors translocate to the nucleus, where they dimerize and bind to regulatory DNA sequences on target genes to either activate or repress transcription . These effects are slow, with a latency period before onset, but they are also long lasting, remaining active for several hours after hormone stimulation. Several co-regulatory proteins that bind and regulate the activity of receptors have been identified. These include both co-activators that positively regulate transcriptional effects of intracellular receptors after ligand binding and co-repressors that negatively regulate receptor activity. In addition to this transcriptional or genomic mode of action, increasing evidence suggests that androgens can exert rapid, non-genomic effects. The time course of these responses is not compatible with the classic genomic mechanism for the action of steroids, since they have a rapid onset without an apparent latency period. Common to these early effects is a fast increase in intracellular Ca2+ and activation of Ca2+-dependent pathways and second messenger cascades [12, 13]. Second messenger induction by non-genomic steroid action is insensitive to inhibitors of either transcription or translation. Little is known about these non-genomic effects in cardiac and skeletal muscle cells other than the generation of different patterns of Ca2+ signals and also the activation of complementary Ca2+-dependent pathways involved in these responses. An interesting hypothesis is that these second messenger cascades may ultimately serve to modulate the transcriptional activity of the intracellular androgen receptor and its associated global response [14-16].
2. Musculoskeletal conditions related to androgens
Emerging syndromes and new approaches to classic diseases are now being linked to androgens. The androgen-associated diseases that will be discussed in this section include hypogonadism of the elderly (late onset hypogonadism [LOH]), sarcopenia, and the “metabolic syndrome.” The interrelation between these diseases and decreased androgen levels is complex in the sense that these diseases are not only androgen dependent but that many other factors intervene in their development. Figure 1 shows the relationship between each of these diseases with the others, demonstrating that they are not “pure” androgen-dependent syndromes. With exception of LOH, which has implicit the concept of low androgen levels, neither sarcopenia nor metabolic syndrome are solely androgen-dependent diseases. It is important to bear this characteristic in mind when considering sarcopenia and metabolic syndrome, as there are numerous causes that may be behind the same clinical presentation. Further, the role of each of the hypothesized components may be very different from one patient to the other. The fourth disease that will be discussed here is Kennedy’s disease, a hereditary X-linked neurodegenerative disease that affects mainly the androgen receptor function. In this sense, the pathophysiology of this disease is somewhat different from the 3 previously considered syndromes.
We will review the current definition of each syndrome, the epidemiology, the pathophysiology, and the effects that testosterone supplementation has demonstrated upon the evolution of the disease. After presenting these syndromes, we will highlight the differences observed among clinical studies in relation to age of populations analyzed, type of study, and expected outcome. This issue is important because it may affect the obtained results and therefore the subsequent conclusions.
2.1. Late onset hypogonadism (LOH)
The normal reference levels for total testosterone in adult males vary from 300–1000 ng/dL. Morning levels (before 10 AM) below 250 ng/dL will make the diagnosis highly probable. A second total testosterone measurement is required to confirm the diagnosis. These tests should generally be followed by studies that help in determining the anatomical level of the endocrine failure, in order to confirm the cause of hypogonadism (primary, secondary, or mixed) [19, 20].
The mechanisms behind this age-associated decline in male hormone levels are still unclear. Various alterations have been described in the elderly men that can lead to LOH. The main points where the physiology of androgens has been found to be affected by age are the testes, the hypothalamus, and the transport protein, SHBG. Primary testicular changes play an important role in age-associated testosterone decline. Leydig cells in the elderly have demonstrated a reduced secretory capacity in response to stimulation with recombinant LH . This decrease has been related to a reduction in the number of Leydig cells. In addition to the decline in testicular reserve seen in the elderly, an altered neuroendocrine regulation, mainly at a hypothalamic level, has been suggested. Moderate increases of basal gonadotropin levels have been observed in response to the decline in testosterone levels, but not all studies agree with this observation . The increases in GnRH as well as LH are thought to be abnormally low in response to the testosterone decline induced by the aforementioned Leydig cell alterations, implying a failure at some point in the neuroendocrine axis. It has been shown that the anterior pituitary has a preserved LH response to exogenous pulsate GnRH stimulation , suggesting, in line with other studies, the role played by the hypothalamus and the deficit of GnRH. Finally, increases in SHBG binding capacity have also been related to LOH. This change would result in an even greater decrease of free and bioavailable (albumin-bound) testosterone levels. The cause for this increase in SHBG binding capacity is still unknown.
In conclusion, testosterone decline in the elderly appears to have multiple causes, involving the testicular, hypothalamic, and transport levels. These alterations may be present in different proportions in different patients, making LOH a difficult syndrome both to understand and to treat.
Finally, one of the most recognized concerns about testosterone replacement therapy is the risk of developing prostate cancer. It has long been postulated that exogenous androgens can have a causative role in prostate cancer. On the other hand, androgen deprivation therapy has demonstrated a clear role for endogenous androgens in an already settled prostatic cancer. Therefore, the question remains open whether subclinical, “occult,” prostatic lesions could develop into a neoplasia due to exogenous androgen administration. At the level of the prostate tissue, 6 months of testosterone replacement therapy in men with LOH showed no differences with placebo when considering prostate histology, tissue biomarkers, gene expression, and incidence or severity of prostate cancer . Other studies that analyzed the association between testosterone treatment and prostate cancer did not find convincing evidence for this relationship [32, 33]. Nevertheless a meta-analysis  has shown a higher risk of detection of prostate events (incidence of prostate cancer, elevated prostatic-specific antigen, prostate biopsies) and increases in International Prostate Symptom Score (IPSS) in treated
In conclusion, benefits of testosterone replacement in LOH men have been established, but functional studies that demonstrate a significant improvement in large population samples are scarce and clinical studies of the risks of testosterone replacement therapy are still contradictory. Larger longitudinal, randomized placebo controlled studies are needed to draw definitive conclusions. At present, treatment is recommended for men diagnosed with LOH with appropriate monitoring of the prostate and the cardiovascular and hematological systems.
The prevalence of sarcopenia generally increases with age. Baumgartner et al.  observed an increase in the prevalence of sarcopenia after 80 years that reached >50% of individuals. Iannuzzi-Sucich et al.  also described an increase in the prevalence of sarcopenia in a subgroup of the studied population (80 years or older), reaching 31% in women and 52.9% in men. In reference to the relationship between testosterone levels and physical performance in older men, the Framingham Offspring study  described a significant association between serum free testosterone levels, walking speed, and short performance physical battery (SPPB) results. Men with low baseline free testosterone had 57% higher odds of reporting incident mobility limitation and 68% higher odds of worsening mobility limitations. Total testosterone and SHBG were not significantly associated with mobility limitation, subjective health, or physical performance measures.
The prevalence of sarcopenia varies from one study to another and these differences can be explained by different definitions of sarcopenia, differences in the studied populations and their reference (control) populations, sample sizes, and methods used to measure skeletal muscle mass. The unification of criteria to diagnose sarcopenia as well as the methods used to assess it will certainly aid in a better knowledge of the prevalence of this syndrome.
Muscle mass is determined by a balance between protein synthesis and breakdown. It has been established that with advancing age, there is a decrease in whole body protein turnover . In contrast to what happens in cachexia, where both skeletal muscle mass and fat mass are decreased, in the elderly the loss of muscle mass is accompanied by gains in fat mass . Examination of the synthesis rate of particular proteins in skeletal muscle has shown that there is a particular synthesis rate, at least for each cell compartment in the skeletal muscle. The synthesis rate of mitochondrial and myosin heavy chain (MHC) proteins declines with age, whereas the synthesis rate of the sarcoplasmic protein pool was unchanged . Ferrington et al. (1998)  have shown changes in other key skeletal muscle compartments, such as the sarcoplasmic reticulum, in aged rats. The turnover rate of SERCA pumps and ryanodine receptors decreased, whereas calsequestrin showed no changes. Studies about other key contractile elements in aging muscle, such as the α-actin protein, are recently available , and it was shown that in the vastus lateralis muscles of middle-aged
In addition to changes in skeletal muscle mass, there are changes in the motor units innervating the muscles. In humans, there is a decrease in the number of functional motor units with age. These changes have been confirmed in aged rats, where a reduction in the number of muscle fibers innervated per motor axon  was evident. These changes will lead to a decreased skeletal muscle fiber/motor neuron interaction that can further explain the decline in coordinated muscle action.
Other elements involved in the development of sarcopenia may be the loss of anabolic factors including neural growth factors, growth hormone, androgens and estrogens, and physical activity. An increase in oxidative stress and inflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α), and a decrease in food intake with aging have also been implicated [41, 48]. Cross-sectional and longitudinal studies have demonstrated that testosterone levels decrease with normal aging. Serum testosterone levels below the lower limit of normal, has a prevalence of 5% in healthy young men, up to 20% in the sixth decade, and increasing to 40–90% in men over 80 years . Epidemiologic studies have demonstrated a relationship between levels of bioavailable testosterone and fat-free mass as well as muscle strength [49, 50]. These data correlated with physical performance tests. In the Framingham Offspring Study, men with low baseline of free testosterone concentrations showed a higher risk of incident or worsening mobility limitations . In a study conducted in healthy young men to further elucidate the role of testosterone in the maintenance of skeletal muscle mass reported by Mauras et al. , a transient pharmacological hypogonadism was induced, decreasing fat-free mass, muscle strength, and fractional muscle protein synthesis in the volunteers. Despite this evidence, there are other studies, mainly that by Travison et al. , that have failed to show a clear association between testosterone concentration and physical function. This might be explained by certain aspects of the design of the study, including the selection of a younger population, a basal high physical activity level, mainly normal testosterone concentrations, and minimally demanding physical tests .
In short, testosterone has shown a tight association with skeletal muscle mass and a reasonable relationship with muscle strength, but no clear association with physical performance [50, 52]. The pathophysiology of sarcopenia appears, in conclusion, to be explained in part by intrinsic skeletal muscle changes associated with aging, but extrinsic causes also exist, and there are factors that aid in the development of sarcopenia or influence the degree of the attrition in skeletal muscle mass seen in the elderly.
Physical activity is always associated with a general well being outcome that stimulates cardiovascular, respiratory, and skeletal muscle systems. Endurance and resistance exercise has been shown to improve the rate of decline in muscle mass and strength that occurs with age, although resistance exercise have proven to be more effective increasing muscle mass and strength in older men . There is controversy in the literature regarding the extent of the muscle response induced by exercise in the elderly. Some authors indicate that resistance exercise in older people produces smaller strength increases in absolute terms, but similar in relative terms, to younger people . On the other hand, similar increases in percent muscle strength were found in healthy older individuals and in young people in a prospective investigation that also assessed changes at the satellite cell level following a heavy resistance strength training period .
It seems that a key feature of skeletal muscle, its plasticity, is retained even in very old individuals. Muscle cross sectional area, muscle strength, and physical performance have been shown to improve in very old nursing home residents  and in community residents  engaged in progressive resistance exercise training. The intensity of the resistance exercise required to obtain positive changes is also still under debate. The majority of studies suggest that a high intensity resistance exercise (70–90% of 1 repetition maximum) is needed in order to obtain the desired improvements in muscle mass and strength . As little as 1 resistance training session per week has demonstrated positive strength changes . This recent issue may be an interesting point to explore in order to attract interest of more individuals to participate in strength training programs that will aid in the prevention and treatment of sarcopenia.
In conclusion, understanding sarcopenia as a multifactorial syndrome also involves the potential discovery of a great number of therapeutic targets. So far, testosterone, but more clearly, exercise, have been the more successful therapeutic options. More studies with the newest therapies and/or improved exercise and hormone replacement therapies should be performed in order to gain advances against this quality of life (QOL)-threatening syndrome.
2.3. Metabolic syndrome
Testosterone regulates the deposition of triglycerides in the abdominal fat tissue by lipoprotein lipase enzymes and a hormone sensitive lipase. Testosterone has an anticoagulant and profibrinolytic action, and by decreasing fibrinogen and PAI-1, it also has a pro-aggregatory effect through decreased platelet cyclooxygenase activity. During eugonadism, testosterone stimulates hormone-sensitive lipase and lipolysis. Thus, in testosterone deficiency, lipolysis is inhibited, favoring the accumulation of adipose tissue , which is reversed by testosterone administration. In addition, it has been reported that in hypogonadal patients, the deposition of visceral adipose tissue leads in turn to a further decrease in testosterone concentrations via conversion to estradiol by the aromatase. This leads to further abdominal fat deposition and a higher testosterone deficiency [4, 66]. In parallel, hyperinsulinemia is associated with decreased SHBG production, which decreases plasma total testosterone . To date, the question of whether hypogonadism influences insulin resistance by increased abdominal obesity or whether obesity favors the reduction of plasma testosterone concentrations is still debated. However, insulin resistance leads to increased risk factors including increased triglycerides, lower HDL, and predominance of LDL-C. To these lipoprotein factors are added intolerance to carbohydrates, high blood pressure, and pro-coagulant and antifibrinolytic states . Clinical studies show that men exhibit higher susceptibility to atherosclerosis than pre-menopausal women. The available data indicate that the evolution of atherosclerosis is more rapid in males, independent of dyslipidemia or evidence of endothelial damage, than in females . The actual evidence indicates that low androgen concentrations are strongly associated with increases in cardiovascular risks including atherogenic lipid profile, insulin resistance, obesity, and metabolic syndrome [70, 71].
2.4. Considerations regarding clinical studies dealing with testosterone supplementation in sarcopenia and metabolic syndrome
Figure 2 emphasizes some of the determinants that should be considered when analyzing clinical studies working with androgen replacement therapy in sarcopenia and metabolic syndrome. It is important to bear in mind the level of testosterone that is sought with the proposed treatment and from this starting point, other important considerations must be made, including age of the individuals, in order to place the conclusions in an adequate context according to the population seeking treatment.
2.5. Spinal and bulbar muscular atrophy (Kennedy’s disease)
3. Molecular basis of influence of high levels of testosterone on skeletal and cardiac muscle
High blood levels of androgens, above the physiological range, are produced by exogenous administration of testosterone or its synthetic derivatives. These hormones have been used by athletes to improve performance by increasing muscle mass and strength. Hypertrophy is the more recognized among the numerous documented hormonal effects of long-term use of androgens.
Muscle mass is regulated by the normal balance between synthesis and degradation of muscle proteins. There is consensus that the use of testosterone leads to hypertrophy by increasing net protein synthesis over protein degradation, however the pathways responsible for this effect, and this dependence of intracellular androgen receptor, have not been fully described to date. Moreover, testosterone activates skeletal muscle satellite cell and mesenchymal stem cell differentiation, which also accounts for the clinical effect of this hormone on body composition [103, 104]. Side effects related to use of anabolic steroids are focused especially on the cardiovascular system . It is known that there are increases in blood pressure and peripheral arterial resistance [105-108], and there are also effects on the heart muscle, primarily left ventricular hypertrophy with restricted diastolic function [109-111]. Severe cardiac complications (heart failure, atrial fibrillation, myocardial infarction or sudden cardiac death) in strength athletes with acute anabolic/androgenic steroid abuse have also been reported [112, 113].
The anabolic actions of androgens enhance muscle strength and increase muscle size clinically [6, 7, 114].
As noted, hypertrophy processes involve changes in gene expression controlled by intracellular androgen receptor-mediated pathways, and recent studies have demonstrated an alternative rapid intracellular androgen receptor-independent mode of testosterone action. The establishment of the testosterone-androgen receptor complex acts as a transcriptional factor for the expression of different genes and proteins necessary for protein synthesis, energy production, and cell growth, which are also crucial for hypertrophic growth. Now, aside from the classical action mechanism of testosterone, non-classical effects have also been implicated in the growth of the muscle cell. Hypertrophy in both skeletal and cardiac muscle is an adaptive response of the cell to increase force and contractile activity. Although initially beneficial, the prolonged activation of muscle cells by hypertrophic stimuli may produce detrimental effects. Unlike that in cardiac muscle, hypertrophy of skeletal muscle cell is a reversible process.
Several pro-hypertrophic stimuli activate common pathways in the muscle cell . Among pathways activated by these stimuli, key regulators are phosphatidylinositol-3 kinase (PI3K)/Akt and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK/ERK1/2) pathways [117-119]. It has also been proposed that testosterone actions involve membrane receptors that stimulated early intracellular signaling pathways through interaction with G proteins in primary cultures of skeletal muscle cells  as well as cardiac myocytes . Common to these early effects are the fast intracellular Ca2+ increase, activation of Ca2+-dependent pathways, and second-messenger cascades. Ca2+ is one of the most diverse and important intracellular second messengers as well as a key element in the excitation-contraction coupling of muscle cells. Ca2+ has been related to hypertrophy because of its ability to promote the activation of the protein phosphatase calcineurin through the establishment of a Ca2+/calmodulin complex . Calcineurin promotes translocation of the nuclear factor of activated T cells (NFAT) from cytoplasm to nucleus. NFAT family proteins are responsible for the expression of the early fetal genes, which are expressed during fetal development. These are silenced in adult stages but are re-expressed during cardiac hypertrophy, and thus are considered as hypertrophic markers [119, 121, 122].
Interlinked signaling pathways are related to hypertrophy of the muscle cells. Moreover, it has been described that testosterone induces intracellular Ca2+ increase through a non-genomic action mechanism in skeletal muscle cells [12, 13] and cardiomyocytes . Studies in cultured muscle cells show that through a nongenomic mechanism, testosterone is implicated in the activation of a membrane receptor coupled to a Gαq protein, thus resulting in the production of IP3 and release of Ca2+ from endoplasmic reticulum [12, 120]. These Ca2+ oscillations induce the activation of ERK 1/2, which in turn phosphorylates mammalian target of rapamycin (mTOR), promoting hypertrophic cardiac growth .
The PI3K/Akt pathway has been related to cell survival and proliferation in almost all cell types. However, the up-regulation of the pathway by several stimuli induces cardiac hypertrophy. One of the most common downstream targets of Akt is the protein kinase glycogen synthase kinase 3-β (GSK3-β) . Activated GSK3-β phosphorylates several members of the NFAT family, which promotes their translocation from nucleus to cytoplasm. Akt phosphorylates and inhibits GSK3-β, which increases the residence of NFAT in the nucleus. Moreover, Akt has the ability to phosphorylate mTOR, another downstream target of the PI3K/Akt pathway. In muscle cells, protein synthesis is highly regulated by mTOR, which stimulates protein translation and ribosome biosynthesis . The mTOR lies upstream of critical translation regulators such as the 40S ribosomal protein S6 kinase 1 (S6K1) and the eukaryotic initiation factor 4E-binding protein 1 (4E-BP1). Activation of the mTOR pathway is a critical step to induce cardiac hypertrophy by testosterone
Thus, considering the current information available regarding androgen actions on muscle cells, it has been proposed that muscle hypertrophy induced by testosterone requires both androgen receptor activity and signal transduction pathways to control protein synthesis.
4. Perspectives of androgen-mediated physiological and pathological responses
The role of androgens in modulating both musculoskeletal and cardiovascular function is of the highest importance, especially considering that androgen deficiency is strongly associated with several medical conditions, including sarcopenia, metabolic syndrome, obesity, diabetes, hypertension and atherosclerosis. Testosterone deficiency, as observed in LOH, further deprives muscle of important anabolic effects of androgens in human males. The action mechanism of androgens involves both androgen receptor and signal transduction pathways, so, essential for the diagnosis, clinical and pharmacological intervention studies, a detailed knowledge of these pathways is required. As cardiovascular side effects of testosterone reduce its actual therapeutic use, research in this field is badly needed to have a detailed knowledge of the effects of androgen alterations in order to elaborate safe therapeutic replacement protocols that appear to have a broad potential for high incidence pathological conditions.
This work was supported by FONDECYT (grant 1120259 to M.E. and grant 1110467 to E.J.) and by ACT 1111 (E.J.). C.B. is a CONICYT doctoral fellow (AT 24091020).
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