Angiotensin II: Role in Skeletal Muscle Atrophy

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Angiotensin II: Role in Skeletal Muscle Atrophy

Claudio Cabello-Verrugio1,*, Gonzalo Córdova2 and José Diego Salas1

1Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biológicas, Facultad de Ciencias

Biológicas & Facultad de Medicina, Universidad Andrés Bello, Santiago, Chile; 2Centro de Regulación Celular y Pa-

tología (CRCP), Centro de Regeneración y Envejecimiento (CARE), Departamento de Biología Celular y Molecular,

Pontificia Universidad Católica de Chile, Santiago, Chile

Abstract: Skeletal muscle, the main protein reservoir in the body, is a tissue that exhibits high plasticity when exposed to changes. Muscle proteins can be mobilized into free amino acids when skeletal muscle wasting occurs, a process called skeletal muscle atrophy. This wasting is an important systemic or local manifestation under disuse conditions (e.g., bed rest or immobilization), in starvation, in older adults, and in several diseases. The molecular mechanisms involved in muscle wasting imply the activation of specific signaling pathways which ultimately manage muscle responses to modu-late biological events such as increases in protein catabolism, oxidative stress, and cell death by apoptosis. Many factors have been involved in the generation and maintenance of atrophy in skeletal muscle, among them angiotensin II (Ang-II), the main peptide of renin-angiotensin system (RAS). Together with Ang-II, the angiotensin–converting enzyme (ACE) and the Ang-II receptor type 1 (AT-1 receptor) are expressed in skeletal muscle, forming an important local axis that can regulate its function. In many of the conditions that lead to muscle wasting, there is an impairment of RAS in a global or local fashion. At this point, there are several pieces of evidence that suggest the participation of Ang-II, ACE, and AT-1 receptor in the generation of skeletal muscle atrophy. Interestingly, the Ang-II participation in muscle atrophy is strongly ligated to the regulation of hypertrophic activity of factors such as insulin-like growth factor 1 (IGF-1). In this article, we reviewed the current state of Ang-II and RAS function on skeletal muscle wasting and its possible use as a therapeutic tar-get to improve skeletal muscle function under atrophic conditions.

Keywords: angiotensin II, skeletal muscle atrophy, angiotensin–converting enzyme (ACE), angiotensin II receptor type 1 (AT-1), AT-1 receptor blocker (ARB), atrogin-1, MuRF-1.

INTRODUCTION

Skeletal muscle atrophy corresponds to the loss of mus-cle mass produced by muscle wasting concomitantly with a decrease of muscle strength associated with some pathologi-cal conditions. This wasting is an important systemic or local manifestation under acute pathological conditions, such as disuse by immobilization, post-operatory recovering process, microgravity, and starvation, or under chronic conditions, such as aging, a sedentary lifestyle, or several diseases (can-cer, diabetes, AIDS, and cardiac, lung, or renal failure). All of them correspond to an increasing problem in our society [1, 2]. Under these conditions, the catabolism of proteins is exaggerated and the oxidative stress are increased, leading to a decrease in muscle mass [3].

One of the modulators of skeletal muscle function is the renin-angiotensin system (RAS) axis. The main effector of RAS is angiotensin II (Ang-II), a peptide that participates in the control of blood pressure, sodium balance, fluids volume, and some other hemodynamic features. In addition, Ang-II plays a key role in the regulation of skeletal muscle function

*Address correspondence to this author at the Laboratorio de Biología y Fisiopatología Molecular, Departamento de Ciencias Biológicas, Facultad de Ciencias Biológicas & Facultad de Medicina, Universidad Andres Bello, Santiago, Chile. Av. Republica 239, Postal Code 8370146, Santiago, Chile; E-mail: [email protected]

by modulating the damage and contractile activity in muscle disease, such as Duchenne muscular dystrophy [4, 5]. How-ever, the main deleterious effect of Ang-II on skeletal muscle is that by inducing changes in enzyme activation, cell oxida-tive state, and gene expression, loss of muscle mass results. All of these changes alter the normal muscle remodeling process, leading to skeletal muscle wasting. Many of the conditions that contribute to skeletal muscle atrophy, such as chronic heart failure (CHF) and chronic kidney disease (CKD), are accompanied by an increase in the activation of the RAS axis, hence promoting an increase in the circulating Ang-II, while the loss of muscle mass worsens [6]. In this review, we address some of the main topics in relation with systemic or local muscle-RAS axis, skeletal muscle atrophy, and the cellular and molecular mechanisms underlying this process.

EXPRESSION OF RENIN-ANGIOTENSIN SYSTEM

COMPONENTS IN SKELETAL MUSCLE

The identification of the local RAS axis has been de-scribed in several tissues [7]. In addition to Ang-II, the local RAS axis is composed of the angiotensin–converting enzyme (ACE) and two membrane receptors for Ang-II called Ang-II receptors type 1 (AT-1) and type 2 (AT-2) [8]. This section reviewed the evidence that support the expression of RAS components in skeletal muscle.

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ACE

ACE is the enzyme responsible to produce Ang-II from angiotensin I. The levels and activity of ACE are directly related to the circulating Ang-II levels or to the tissues of these levels.

ACE activity has been reported in skeletal muscle and cell lines from skeletal muscle [9-13]. Thus, there is evi-dence that de novo synthesis of angiotensin I (Ang-I) and angiotensin II occurs in skeletal muscle, suggesting the pres-ence of ACE activity in an indirect way [14]. Other in vivo experiments gave similar results, suggesting the presence of functional ACE [15]. The Ang-II production has been asso-ciated with ACE expressed in the capillaries from skeletal muscle, showing a close relationship between capillary den-sity and the number of ACE transcripts [16]. This evidence suggests that the activation of ACE from capillaries has an impact on skeletal muscle physiology [17-20]. This evi-dence, in addition to a short half life of Ang-II (14.8 +/- 2.5 seconds under physiological conditions), suggests that in skeletal muscle could exist a local paracrine/autocrine signal-ing of Ang-II in which the relation muscle - vessels would be is essential [21]. Examples in other tissues in which Ang II can act through local RAS are heart and kidneys [22]. In addition, the existence of local paracrine/autocrine Ang-II signaling in the rat epididymis has been reported [23]. Fur-thermore, in cardiac muscle there is a loop initiated by the heart contraction and induces the secretion of Ang II which led to an increase in force contraction through an autocrine/paracrine signaling [24]. Thus, a possible mecha-nism of Ang-II activity in skeletal muscle is through a paracrine/autocrine action.

Interestingly, there is evidence that ACE is also ex-pressed in the neuromuscular junction [20]. Moreover, ACE is expressed in skeletal muscle fibers, which is supported by studies in vitro, which suggests that ACE is expressed in skeletal muscle cells [12, 13, 25, 26].

Together, these data indicate that ACE is expressed both in muscle fibers and vessels associated with skeletal muscle.

AT Receptors

The main receptors for Ang-II are AT-1 and AT-2 recep-tors [7]. These receptors mediate the majority of Ang-II-dependent effects in vitro and in vivo [27]. However, there is contrasting evidence about the expression of the AT recep-tors and their direct contribution to the Ang-II-dependent effects on skeletal muscle. Some studies have reported that skeletal muscle does not express the Ang-II receptors [28]. However, there is increasing evidence that indicate the ex-pression of AT receptors in skeletal muscle. Thus, it has been reported that Ang-II acts directly on myotubes to in-crease protein degradation or on skeletal muscle cells to pro-duce an increase in extracellular matrix protein levels and reactive oxygen species, which suggests that Ang-II-dependent effects are mediated by receptors located in the muscle surface [29-31]. A more direct evidence has been demonstrated in primary human skeletal myoblasts, which suggests the presence of AT-1 and AT-2 receptors, with AT-1 predominantly expressed, as observed from an analysis of Ang-II binding in the presence of selective inhibitors of AT-

1 and AT-2 receptors and western blot analysis [32]. In addi-tion, studies from whole skeletal muscle, primary and C2C12 myoblasts, and C2C12-derived myotubes showed differen-tially the expression of RAS members, including AT-1 and AT-2 receptors. The AT-2 receptors are distributed with a heterogeneous staining pattern in comparison with AT-1 receptors, which colocalized with the actin cytoskeleton in many areas and were detected in the nucleus [26]. Evidence from our group and others strongly suggest that AT-1 and AT-2 receptors are both expressed in normal and dystrophic skeletal muscle, in myoblasts, and in C2C12-derived myo-tubes [4, 5, 20].

In addition, there are several results that suggest that AT-1 and AT-2 receptors are expressed also in skeletal muscle microvasculature, where one of its possible roles is to regu-late basal muscle microvascular perfusion [33].

To summarize, all the composing elements of the RAS are expressed in skeletal muscle, with differences in their densities and location.

ANGIOTENSIN II IS AN ATROPHIC FACTOR IN SKELETAL MUSCLE

Ang-II levels are increased in diseases such as CHF and CKD, which are characterized by significant skeletal muscle wasting that negatively impacts mortality and morbidity [34, 35]. Thus, several studies in vivo strongly support the par-ticipation of Ang-II in muscle wasting. Delafontaine et al. have described that Ang-II infusion in rats caused a signifi-cant decrease in the animals’ weight by a reduction in food intake through a pressure-independent mechanism [36]. Fur-ther studies based on pair-feeding experiments in rats dem-onstrated that an anorexigenic effect produces the Ang-II-dependent weight loss, which is directly related to the de-crease of skeletal muscle mass [37]. This study indicated that the main mechanism of Ang-II-induced loss of muscle mass involves an increase in protein breakdown and a decrease in the IGF-1 levels and signaling, which is the main anabolic pathway in skeletal muscle [37]. Recently it was demon-strated that Ang-II infusion produces waste in the diaphragm muscle, which could explain respiratory muscle dysfunction in CHF and CKD patients [38]. In addition, there is evidence that suggests the treatment with AT-1 receptor blockers and ACE inhibitors may improve weight loss in CHF, indirectly supporting the participation of Ang-II in this pathological process [39, 40]. Moreover, several studies in vitro indicate the catabolic role of Ang-II on skeletal muscle. In myotubes from C2C12 cells, Ang-II decreases the total amount of muscle proteins [30, 31, 41]. The mechanism in this process involves the increased protein catabolism, although an in-hibitory component on protein synthesis has also been re-ported [42].

Protein Degradation

Ang-II-dependent loss in skeletal muscle mass is caused by enhancing protein degradation through the activation of the ubiquitin-proteasome pathway (UPP) [31, 38].

Briefly, ubiquitin-conjugated proteins are recognized and subsequently degraded by the 26S proteasome, a multicata-lytic enzyme complex. UPP activity depends upon coordi-

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nated interactions among several enzyme families (Fig. 2). First, ubiquitin monomers are activated by the ubiquitin-activating enzyme known as E1. This is an ATP-dependent step in which ubiquitin is linked to E1. Second, activated ubiquitin is transferred to an ubiquitin carrier protein (E2). Third, the E2 interacts with one of several hundred ubiquitin ligases (E3s) to transfer activated ubiquitin to the substrate. This begins an iterative process by which E2/E3 partners attach multiple ubiquitin monomers to form polyubiquitin chains, marking the protein substrate for degradation. Fi-nally, the marked protein is degraded by the 26S proteasome complex [43-45]. The 26S proteasome complex is formed by a 20S core complex, the catalytic subunit, and one or two 19S regulatory complexes in charge of substrate recognition (see Fig. 1) [46, 47]. In skeletal muscle, there are E3 ubiq-uitin ligases called muscle atrophy F-box (MAFbx), or atrogin-1, and muscle RING finger 1 (MuRF-1). These mus-cle-specific E3-ligases are upregulated in skeletal muscle atrophy, essential to produce muscle waste [48, 49]. More interestingly, levels of both proteins increase after Ang-II treatment in skeletal muscle (see Fig. 1) [50].

It has been described that in skeletal muscle atrophy, the levels and activity of the proteasome components are in-creased [51]. Among them is the increase of mRNA levels of several subunits from the 20S core complex (Psma1, Psma5, Psmb3, and Psmb4) and the 19S regulator complex (Psmc4, Psmd8, and Psmd11) of the 26S proteasome in atrophied muscles from different causes including Ang-II treatment (see Fig. 1) [52].

In summary, Ang-II is involved directly in the process of muscle degradation by stimulating expression and activity of several components of the ubiquitin-proteasome pathway.

Protein Synthesis

The catabolic effects of Ang-II to produce muscle waste have been associated with changes in IGF-1 levels and its signaling pathway. IGF-1 has been described as an inductor of protein synthesis and an inhibitor of protein degradation [53]. Briefly, IGF-1 binds to its transducer receptor (IGF-1R) which in turn phosphorylates insulin receptor substrate 1 (IRS-1) and activates PI3kinase and AKT. Subsequently, AKT phosphorylates FOXO3 and mTOR proteins. Phos-phorylated FOXO3 is kept in the cytoplasm, preventing its nuclear translocation to activate the transcription of atro-genes, such as atrogín-1, whereas phosphorylated mTOR favors the signaling involved in the protein synthesis, with the participation of S6 kinase and translational machinery (see Fig. 2).

Delafontaine’s group showed that the infusion of Ang-II in rats decreased the levels of circulating IGF-1 and its bind-ing proteins, IGFBP-2 and IGFBP-3, which regulate PI3K/AKT signaling [36]. Moreover, they further demon-strated that Ang-II infused to rats has an inhibitory effect on the autocrine IGF-1 system in skeletal muscle. This becomes more important than the decrease in circulating IGF-1 [37]. Since IGF-1 levels were strongly diminished in Ang-II-induced wasting, further studies to strengthen the Ang-II/IGF-1 relation showed that the muscle-specific overex-

Fig. (1). The Ubiquitin Proteasome Pathway (UPP) is involved in the Ang-II-induced skeletal muscle atrophy.

The ubiquitination machinery is composed of E1 ubiquitin activation proteins, E2 ubiquitin conjugation enzymes, and E3 ubiquitin ligation proteins, which catalyze the polyubiquitination (U) of substrate proteins (S). The proteasome 26S complex is formed by the 20S catalytic subunit and at least one 19S regulatory complex. Ang-II specifically stimulates the expression of two E3 ubiquitin ligases, atrogin-1, and MuRF-1. In addition, Ang-II that has been implicated in the expression increased in several components of the 20S and 19S subunits of the proteasome.

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pression of IGF-1 blocked the Ang-II-induced deleterious effects, producing a protective effect on skeletal muscle against Ang-II [54].

Ang-II produces muscle atrophy by inhibition of protein synthesis [42]. This effect involves proteins that are part of the translation machinery, such as the alpha subunit of eu-karyotic initiation factor 2 (eIF2 ), the elongation factor 2 (eEF2), and the initiation factor 4E-binding protein (4E-BP1). Eley et al. showed that the treatment of myotubes with Ang-II increases the eIF2 phosphorylation and concomi-tantly the inhibition of protein synthesis. This effect was sensitive to a dsRNA-dependent protein kinase (dsPKR) inhibitor [55]. Moreover, they later showed that Ang-II in-creased the phosphorylation of dsPKR, eEF2, and 4E-BP1. All these effects lead to a decrease in protein synthesis [56].

In summary, one of the mechanisms that participates in the Ang-II-dependent atrophic effect is the impairment of the IGF-1 signaling, which is directly involved in the protein synthesis.

REGULATORY MECHANISMS AND SIGNALING

PATHWAYS INVOLVED IN THE ANGIOTENSIN II–

DEPENDENT SKELETAL MUSCLE ATROPHY

Ang-II levels are essential in the atrophic effect on skele-tal muscle in CHF and CKD [34, 35]. The main factor that modulates the Ang-II levels is the ACE activity. Studies of the ACE gene demonstrated that a polymorphism exists,

which modulates the ACE activity. This polymorphism con-sists of an insertion (I) or a deletion (D) of a 287-base pairs sequence in the 16th intron of ACE gene which is located in the chromosome 17 [57]. One possible explanation about how the polymorphism affects the ACE expression is the proximity of the 16th intron with Alu regions of the gene. Because of this proximity it is possible that the I or D geno-type affects the regulation of the expression in charge of Alu regions [58]. The different possible genotypes (I/I), (I/D), and (D/D) account for around half of the enzyme levels in plasma. The D/D alleles are associated with higher concen-trations of serum ACE, while the I/D and the I/I alleles are ligated to lower ones [59]. This suggests that persons with D/D allele would present a higher circulating Ang-II amount than persons with the other two alleles. The D allele variant correlates with a major risk of CHF. Furthermore, there are contradictory results among ethnic groups in relation with CKD and the different polymorphisms [60]. The D/D allele was correlated with a higher risk of nephropathies and a faster decrease in renal function particularly in Asian indi-viduals with type II diabetes while the data for other ethnic groups was inconsistent [61].

Thus, the ACE polymorphism can be considered as a genetic factor that could modulate the development of Ang-II-dependent skeletal muscle atrophy.

Studies using AT-1 receptor blockers (ARB) and ACE inhibitors are among the first studies performed to identify the role of Ang-II in skeletal muscle atrophy, which resulted

Fig. (2). IGF-1-dependent anabolic pathway is modulated by Ang-II during muscle wasting.

IGF-1 is a factor that stimulates protein synthesis by activating PI3K/AKT/mTOR signaling. In addition, IGF-1 inhibits protein degradation through the PI3K/AKT/FOXO3 pathway in skeletal muscle. Ang-II decreases the levels and/or availability of IGF-1, therefore impairing PI3K/AKT signaling, which leads to the activation of FOXO3 and the expression of E3 ubiquitin ligase atrogin-1, which contributes to pro-tein degradation.

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in a decrease of skeletal muscle wasting, leading to the con-clusion that both Ang-II and the activation of the AT-1 re-ceptor could produce or exacerbate skeletal muscle atrophy by decreasing the normal protein synthesis-degradation rate [39, 62].

On the molecular level, studies from Tisdale’s group suggests that Ang-II induced the autophosphorylation of dsPKR, leading to the phosphorylation of the eukaryotic initiation factor 2 (eIF2) and inducing the decrease in protein synthesis [41, 55]. This Ang-II-dependent mechanism in-volves the transient increase of intracellular Ca(2+), which participates in the caspases-3- and caspases-8-dependent dsPKR activation, producing an increase in protein degrada-tion and a decrease in protein synthesis [63]. Moreover, the activation of caspases-3 and caspases-8 induced by Ang-II leads to the activation of p38 MAPK and to the increase in ROS formation, which is known to promote protein degrada-tion through the ubiquitin-proteasome pathway [56, 64].

In addition to dsPKR-caspase pathway, Ang-II has been described to induce the activation of nuclear factor kappa B (NF- B), increasing protein degradation by the ubiquitin-proteasome pathway [55]. This activation of NF- B requires the activity of protein kinase C (PKC) and the further inacti-vation of the NF- B inhibitor, I- B, through phosphorylation and degradation induced by the ubiquitin-proteasome path-way [30].

The ability of Ang-II to induce muscle atrophy through inhibition of protein synthesis is attenuated by insulin-like growth factor-1 (IGF-1) [50, 54]. In addition, studies show that IGF-1 prevents the catabolic effects of Ang-II, and this was mediated by AKT and FOXO3 signaling cascades, lead-ing to the inhibition of atrogin-1 and suggesting a critical role for this ubiquitin ligase in the Ang-II-induced catabolic effects [41, 50, 54]. Moreover, Ang-II was able to reduce the IGF-1/AKT/mTOR signaling cascade, preventing the normal maintenance of muscle mass [65]. Evidence shows that Ang-II can induce the expression of the ubiquitin ligases, atrogin-1 and MuRF-1, previous to the reduction in the expression of IGF-1 in the muscle, thus promoting skeletal muscle wasting [50].

The atrophic effects of Ang-II require the reactive oxy-gen species (ROS) that depends on the production of super-oxide by NADPH oxidase [66]. Interestingly, there is an increase in ROS levels and in the expression of the NADPH oxidase subunits in rats treated with an infusion of Ang-II [67]. In addition to its catabolic effect, Ang-II strongly en-hanced NADPH oxidase activity and ROS generation in myotubes from L6 cells. The incubation with ARB losartan and also the NADPH oxidase inhibitor, apocynin, blocked these effects, suggesting the participation of AT-1 receptor and ROS derived from NADPH oxidase in the Ang-II-induced catabolic effects [6, 68]. Moreover, Sukhanov et al. demonstrated an increase of mitochondria-derived superox-ides in skeletal muscle of Ang-II-infused animals, which suggests the involvement of NADPH oxidase and the mito-chondrial system in Ang-II-induced muscle atrophy [6, 66]. The treatment of murine myotubes with antioxidants, which prevented the Ang-II-induced activation of NF- B, corrobo-rated other evidence for the role of ROS in Ang-II-induced skeletal muscle atrophy [69].

The other mechanism involved in the Ang-II-induced skeletal muscle wasting is mediated by the pro-inflammatory cytokine interleukin type 6 (IL-6). This cytokine has been demonstrated to be produced in the liver, together with se-rum amyloid A (SAA), in response to high levels of circulat-ing Ang-II, and then to act synergistically with SAA to im-pair IGF-1 signaling [28]. IL-6 and SAA are able to activate the suppressor of cytokine signaling 3 (SOCS-3), and as a consequence, the (IRS-1) protein levels are strongly de-creased, leading to the perturbation in the insulin/IGF-1 pathway, thus worsening the protein synthesis in skeletal muscle [28]. Interestingly, these effects are totally inhibited in IL-6-deficient mice or potentiated by an SAA-overexpressing adenovirus, suggesting that Ang-II-mediated catabolic effects on skeletal muscle can be mediated by IL-6-dependent signaling pathways [28].

In conclusion, Ang-II induces its catabolic effects through the activation of several signaling pathways, includ-ing dsPKR and NF- B, and also through the participation of ROS and the increases of expression and activity of the ubiquitin-proteasome pathway to promote the degradation of muscle proteins. On the other hand, Ang-II impairs the IGF-1/AKT/mTOR signaling cascade, decreasing the synthesis and normal maintenance of muscle proteins and contributing to skeletal muscle waste (see Fig. 3).

RENIN-ANGIOTENSIN SYSTEM AS A POSSIBLE

THERAPEUTICAL TARGET TO PREVENT SKELE-TAL MUSCLE ATROPHY

As we have characterized in this review, Ang-II is an atrophic factor that participates in the genesis of muscle wasting in several pathological conditions [34, 35]. This fact indicates that the regulation of levels or the signaling of Ang-II can be an attractive therapeutic target to decrease or prevent muscle wasting. Since ACE is the enzyme that con-verts Ang-I into Ang-II, the ACE inhibitors have been used in the modulation of muscle mass. Several clinical studies showed that patients treated with ACE inhibitors as anti-hypertensive therapy have a lower decrease in skeletal mus-cle mass and functionality as compared with the group that used different antihypertensive drugs [70-72]. Moreover, patients with chronic heart failure, which have high Ang-II levels and muscle wasting, showed that long-term therapy with the ACE inhibitors improved their respiratory muscle strength [73]. Interestingly, the treatment of older adults with ACE inhibitors produced an increase in the IGF-1 levels and IGFBP-3 [74, 75]. Since IGF-1 attenuates the Ang-II-induced skeletal muscle waste, a possible mechanism through ACE inhibitors that prevent muscle mass loss in-volves the increases in the IGF-1 levels and signaling (Table 1). Patients with congestive heart failure showed the other possible mechanism of the action of ACE inhibitors on skeletal muscle atrophy. ACE inhibition prevented the fail-ure in the sarcoplasmic reticulum Ca2+ pump and also the early fatigue and exercise intolerance, suggesting that Ang-II should have detrimental effects in skeletal muscle through the alteration of the function of the sarcoplasmic reticulum Ca2+ pump [76]. In addition to direct effects on skeletal mus-cle, patients with heart failure treated with chronic therapy involving ACE inhibitors showed an improvement in endo-thelial function and increases in the proportion of slow

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Fig. (3). Molecular mechanisms involved in Ang-II-induced skeletal muscle atrophy.

Some of the mechanisms involved in Ang-II-mediated skeletal muscle atrophy: 1. Decrease in protein synthesis is due to the inhibition of both the initiation and elongation components of translational machinery. 2. Increase in protein degradation is the effect of the increment in the levels and activation of proteasome components, such as atrogin-1 and MuRF-1.

Table 1. Strategies for Therapeutic Treatment of the Skeletal Muscle Atrophy

Target Agonist / Antagonist Effects

Renin angiotensin system

ACE ACE inhibitors

AT-1 receptor ARB

Decrease the Ang-II levels and Ang-II dependent signaling, de-

crease of apoptosis, endothelial dysfunction, ROS production andprotein degradation, increase the IGF-1 signaling

Cytokines and soluble factors

TNF-a Anti-TNF-a antibodies

Myostatin Anti-myostatin antibodies

IL-6 Anti-IL-6antibodies

Decrease the signaling pathways of these cytokines involved atro-

phy

Oxidate stress Trolox

Apocynin

Vitamin E

Attenuate the oxidative stress-induced calpain and/or caspase-

mediated cleavage of structural sarcomeric proteins

NF-kB activity Resveratrol

Thalidomide

Ibuprofen

EPA

HMB

Decrease the protein degradation by inhibiting the NF-kB activity

566 Current Protein and Peptide Science, 2012, Vol. 13, No. 6 Cabello-Verrugio et al.

(Table 1) contd….

Target Agonist / Antagonist Effects

Ubiquitin-Proteasome Bortezomib

Adenosyl-phospho-ubiquitinol

Phenylarsenoxides

MG-132

Attenuate the protein degradation by direct inhibition of ubiquitinconjugation or proteasome activity

Glucocorticoides Antagonist of receptor (RU-486) Decrease the protein degradation

Beta2 adrenergic receptor Antagonist of receptor (Clenbuterol) Decrease the protein degradation and glucocorticoid effect on mass

muscle

Deacetylase histone (HDAC) HDAC inhibitors Increase mass muscle modulating myostatin, FOXO and IGF-1

signaling

Different targets for therapeutic intervention of skeletal muscle atrophy are shown together with their antagonist or agonist and the effect observed when they are used (TNF- , tumor necrotic factor type alpha; EPA, eicosapentaenoic acid; HMB, -hydroxi- -metylbutyrate).

twitch fibers, in the oxidative capacity, and in the capillary density, thereby enhancing aerobic capacity and skeletal muscle perfusion [15, 77]. Thus, the beneficial effects of ACE inhibition on skeletal muscle atrophy can be explained by multiple mechanisms.

The other strategy to decrease the Ang-II-dependent atrophic effects is the blockade of AT-1 receptor with ARB. Early studies on rats with congestive heart failure indicate that the blockade of the AT-1 receptor reduced the apoptotic dependent atrophy and prevented changes in the myosin heavy chains (Table 1) [39]. Recently, Burks et al. demon-strated that in immobilized hind limbs of mice, the ARB losartan prevented skeletal muscle mass loss [65]. The mechanism in this antiatrophic effect of losartan involves the increase of IGF-1/AKT/mTOR signaling cascade [65].

In addition to renin angiotensin system inhibition by ACE inhibitors and ARB, there are several target to decrease skeletal muscle atrophy (See Table 1). Briefly, the use of blocking antibodies for myostatin, TNF- or IL-6 strongly decrease the protein degradation during process atrophic in the muscle [78-80]. Interestingly, Ang-II has been involved in the skeletal muscle atrophy induced by TNF- and IL-6, and myostatin has been demonstrated to increase the levels of Ang-II [28, 81-83]. Moreover, the use of antioxidant compounds such as trolox, apocynin and vitamin E indicate that oxidative stress play a key role in the skeletal muscle atrophy [84-87]. Ang-II induce ROS in vitro and in vivo and the use of ACE inhibitors or ARB can decrease the ROS-dependent effects of Ang-II. Other agents that could thera-peutically be used are inhibitors of NF- B signaling, gluco-corticoids, proteasome activity and histone deacetylase en-zymes or agonists for beta 2 adrenergic receptor (See Table 1) [88-100].

In summary, the decrease of Ang-II levels and/or signal-ing by ACE inhibitors or ARB improves the muscle function and muscle mass loss in a disease wherein high Ang-II levels have been described. Thus, the use of these antihypertensive drugs as antiatrophic treatment could be useful in the treat-ments against skeletal muscle atrophy.

CONCLUSIONS

Skeletal muscle atrophy is a muscle-wasting syndrome associated with aging, disuse, immobilization, and several pathological conditions such as AIDS, cancer, diabetes, CHF, and CKD. In this article, we reviewed the participation of one of the atrophic factors: Ang-II. We showed a vast, complex, and interlaced scenario that leads to muscle atro-phy, where Ang-II appears to be an interesting and active participant in the events that will lead to protein degradation, inhibition of protein synthesis, and muscle waste. The mechanism by which Ang-II exerts these effects includes the following: increase in the levels and activity of proteasome components, inhibition of proteins from the translational machinery, and increase of ROS through different signaling pathways. Although further information is necessary to fully elucidate the mechanisms involved in these events and the participation of RAS axis in muscle atrophy, ACE and AT-1 receptor are revealed as promising targets for muscle atrophy therapy development.

CONFLICT OF INTEREST

The author(s) confirm that this article content has no con-flicts of interest.

ACKNOWLEDGEMENT

This publication was supported by research grants from FONDECYT # 1120380, CARE PFB12/2007.

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Received: April 29, 2012 Revised: August 17, 2012 Accepted: September 07, 2012