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This Article Abstract Full Text (PDF) All Versions of this Article: 90/5/755    most recent expphysiol.2005.030908v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Burniston, J. G Articles by Goldspink, D. F Search for Related Content PubMed PubMed Citation Articles by Burniston, J. G Articles by Goldspink, D. F Related Collections Muscle

¹ Research Institute for Sport & Exercise Sciences, Liverpool John Moores University, Webster Street, Liverpool L3 2ET, UK ² Academic Unit of Molecular Vascular Medicine, University of Leeds, Leeds General Infirmary, Leeds LS2 9JT, UK

	Abstract

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Our previous work has established that angiotensin II is cardiotoxic. Here we sought to investigate whether skeletal muscle is similarly susceptible to damage. Male Wistar rats were either given a single subcutaneous injection of angiotensin II (range 1 µg kg^–1 to 10 mg kg^–1) or only the vehicle and killed 7 h later, or implanted with preconditioned osmotic pumps dispensing 1 mg kg^–1 day^–1 angiotensin II and killed 9 or 18 h later. Apoptotic (caspase 3 positive) myocytes were counted on cryosections of the heart, soleus, tibialis anterior and diaphragm muscle. Single injections of 100 µg kg^–1 to 10 mg kg^–1 angiotensin II induced significant (P < 0.05) myocyte apoptosis (per 10⁴ viable myocytes) in the heart and this was heterogeneously distributed, peaking (5.7 ± 0.6; P < 0.05) at a point 6 mm from the apex, i.e. approximately three-quarters of the way towards the base. The slow-twitch soleus muscle was also damaged significantly (peak = 2.6 ± 0.4; P < 0.05), while only the administration of 1 mg kg^–1 induced significant (P < 0.05) apoptosis in the fast-twitch tibialis anterior muscle (peak = 1.2 ± 0.3). Infusion of 1 mg kg^–1 day^–1 angiotensin II induced more myocyte apoptosis than a single bolus administration of the same dose, and in general there was a higher incidence of apoptosis in muscles harvested after 18 than after 9 h. Infusion of 1 mg kg^–1 day^–1 angiotensin II over 18 h induced significant (P < 0.05) myocyte apoptosis in the heart (3.3 ± 0.4), soleus (3.9 ± 1), tibialis anterior (5.9 ± 0.4) and diaphragm (19.8 ± 5.6) muscle. Depending on the muscle type, angiotensin II induces myocyte apoptosis in skeletal muscle to a similar or greater extent as in cardiac muscle, supporting the hypothesis that angiotensin II is generally toxic to all striated muscles.

(Received 14 May 2005; accepted after revision 28 June 2005; first published online 29 June 2005)
Corresponding author J. G. Burniston, Research Institute for Sports and Exercise Sciences, Liverpool John Moores University, Webster Street, Liverpool L3 2ET, UK. Email: j.burniston{at}livjm.ac.uk

	Introduction

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Excess catecholamines (Ng et al. 2002), angiotensin II (Tan et al. 1991) and aldosterone (De Angelis et al. 2002; Burniston et al. 2005b) all induce cardiomyocyte death in vivo. A cumulative attrition of myocytes from the heart, as induced by the chronic elevation of these hormones, will reduce its reserve capacity (Goldspink et al. 2003) and propagate a vicious cycle of cell death and neurohormonal activation, resulting in earlier fatalities (Tan et al. 2003b).

Skeletal muscle wasting is associated with heart failure (Anker et al. 1997b) and can be correlated with the degree of compensatory hormonal over-activation (Anker et al. 1997a). This loss of muscle mass reduces the heart failure patients' tolerance to exercise (Minotti et al. 1991; Mancini et al. 1994) and is associated with an increased risk of mortality (Anker et al. 1997b), due to the importance of muscle metabolism. Similar to the situation in the heart (Goldspink et al. 2003), myocyte apoptosis may also contribute to the development of the skeletal myopathy in heart failure. For example, Vescovo et al. (2000) reported both fibre atrophy and an increased expression of caspase 3 and terminal deoxynucleotidyl transferase mediated dUTP nick end labelling (TUNEL)-positive nuclei in muscle biopsy samples from patients with congestive heart failure. Importantly, both the degree of muscle atrophy and the incidence of apoptosis correlated with the severity of the disease.

Previous work from our laboratory has investigated the myotoxic effects in the heart of the natural catecholamines, noradrenaline and adrenaline (Goldspink et al. 2003), and the synthetic analogue of adrenaline, isoprenaline (Tan et al. 2003a). We have also shown that this myotoxicity extends to the skeletal muscle (Ng et al. 2002). Dalla Libera et al. (2001) also reported significant skeletal muscle apoptosis in monocrotaline-treated rats. This apoptosis and fibre atrophy was accompanied by increased (4-fold) plasma concentrations of angiotensin II. Furthermore, administration of the angiotensin II type 1 (AT₁) receptor blocker, irbesartan, effectively protected the skeletal muscles from this damage. The over-activation of the renin–angiotensin–aldosterone system may therefore contribute to skeletal muscle myopathy, since skeletal myocytes are known to express AT₁ receptors (van Kats et al. 1997).

The present work tests the hypothesis that angiotensin II exerts a direct toxic affect on skeletal, as well as cardiac, myocytes.

	Methods

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All experimental procedures were carried out under the auspices of the Animals (Scientific Procedures) Act 1986 and were performed in accordance with local Ethics Committee guidelines. Wistar rats (weighing 310 ± 10 g; mean ± S.D.) were purchased from a commercial supplier (Bantin & Kingman, Hull, UK) and allowed a period of 4 days prior to experimental procedures. Animals were housed in controlled conditions of 20°C, 45% relative humidity, and a 12 h light (06.00–18.00), 12 h dark cycle, with water and food (containing 18.5% protein) available ad libitum.

Hormone administration

The dose dependency (1 µg kg^–1 to 10 mg kg^–1) of angiotensin II-induced apoptosis was investigated using independent groups of animals (n = 5 in each group). Angiotensin II (Sigma) was freshly prepared in a 154 mmol NaCl vehicle immediately prior to administration. Animals received a single subcutaneous injection of this hormone or the vehicle only and were killed 7 h later. In a separate experiment, angiotensin II or the vehicle only was infused subcutaneously via osmotic pumps (Alzet^TM model 1003D, Cupertino, CA, USA) that had been primed prior to implantation by incubation in sterile saline at 37°C. General anaesthesia was induced with 4% isoflurane in medical oxygen at a flow rate of 0.8 l min^–1, using an induction chamber. Anaesthesia was maintained with 1.5% isoflurane via a nosepiece with combined scavenger. Pumps were implanted in a subcutaneous pocket opened on the animal's flank. Independent groups of control or angiotensin II-treated animals (n = 5 in each group) were humanely killed either 9 or 18 h after implantation.

Tissue harvesting

After the respective experimental procedures, rats were killed by cervical dislocation. The atria and great vessels were removed from the heart, and the ventricles mounted apex uppermost on a piece of cork. A standardized segment of the diaphragm and a segment from the mid-belly of the soleus and tibialis anterior was mounted in transverse section and supported with a piece of liver to ensure that the muscle remained in the correct orientation when cryosectioning. Muscles were then snap-frozen in supercooled isopentane and stored at –80°C, prior to cryo-sectioning (5 µm) and storage at –20°C.

Immunohistochemical detection of myocyte-specific apoptosis

Apoptosis was detected on muscle cryosections in vitro using an anti-caspase 3 antibody (Ab). Briefly, cryosections were incubated with the primary rabbit anti-caspase 3 antibody (R & D Systems, Minneapolis, MN, USA) overnight at 4°C. Primary Ab binding was detected using a horseradish peroxidase-conjugated goat anti-rabbit antibody (Vector Laboratories, Burlingame, CA, USA) and visualized by development with 3,3'-diaminobenzidine (DAB; Sigma). All cryosections were counterstained with Haematoxylin. Previous work from our laboratory (Goldspink et al. 2004) and others (De Angelis et al. 2002) has shown that caspase 3 activity colocalizes with dUTP nick-end labelling on cryosections in vitro, and with annexin V-biotin detection of phosphatidylserine externalization in vivo (Burniston et al. 2005c), confirming the identification of apoptosis.

To quantify the incidence of apoptosis in cardiac and skeletal muscle, the number of positively stained myocytes is reported relative to the total number of viable myocytes in each muscle cross-section. Values (means ± S.D.) of the total number of myocytes per cross-section were: heart 11 362 ± 442; soleus 2436 ± 147; tibialis anterior 4250 ± 211; and diaphragm 815 ± 73. For clarity, all data have been normalized and expressed as the number of apoptotic myocytes per 10⁴ viable myocytes.

Statistical analyses

Unless otherwise stated, all data are presented as means ± S.E.M. To accommodate the zero baseline in the vehicle control group, data were analysed using Kruskal–Wallis one-way analysis of variance by ranks. Post hoc comparisons were conducted on pairs of independent groups using the Mann–Whitney U test, and P < 0.05 was accepted as statistically significant.

	Results

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Myocyte apoptosis was clearly discernible in the hearts and skeletal muscles (Fig. 1A and B) of animals that received angiotensin II. In marked contrast, no apoptosis was detected in the muscles of control animals that had received only the saline vehicle (Fig. 1C and D). Angiotensin II induced more apoptosis in the slow-contracting heart and soleus muscles than the in fast-twitch tibialis anterior of the same animals (Fig. 2). Apoptosis was first detected in the heart and soleus muscle after the administration of just 1 µg kg^–1 angiotensin II (Fig. 2A and B). In contrast, a higher dose of 10 µg kg^–1 was required to induce apoptosis in the tibialis anterior (Fig. 2C). Administration of 1 mg kg^–1 angiotensin II induced the greatest incidence of apoptosis, this being statistically significant (P < 0.05) compared with the baseline of zero myocyte apoptosis in the control animals (Fig. 2).

View larger version (174K): [in this window] [in a new window]   Figure 1.  Immunohistochemical detection of myocyte apoptosis in cardiac and skeletal muscle Myocyte apoptosis was detected using an anti-caspase 3 Ab on cryosections (5 µm) of the heart (A) and skeletal muscle (soleus; B) 7 h after the administration of 1 mg kg–1 angiotensin II. No myocyte apoptosis was detected on cryosections of the heart (C) or skeletal muscle (D) from animals that had received only the saline vehicle. Brown (DAB) staining (arrowheads) represents Ab binding, contrasted against a blue (Haematoxylin) background. All images are x400 magnification.

View larger version (14K): [in this window] [in a new window]   Figure 2.  Dose-dependent angiotensin II-induced myocyte apoptosis Myocyte apoptosis was quantified in the heart (A), soleus (B) and tibialis anterior muscle (C) after administration of angiotensin II. Independent groups (n = 5 in each group) of animals were administered a single subcutaneous injection of angiotensin II and were killed 7 h later. Data are presented as means ± S.E.M. *P < 0.05 denotes significant differences from saline vehicle control; P < 0.05 denotes significant differences from the incidence of apoptosis induced by 100 µg or 10 mg kg–1 angiotensin II.

View larger version (16K): [in this window] [in a new window]   Figure 3.  Myocyte apoptosis induced by infusion of angiotensin II Independent groups (n = 5 in each group) of animals were infused with either 1 mg kg–1 day–1 angiotensin II or saline and were killed either 9 or 18 h after pump implantation and the heart (A), soleus (B), tibialis anterior (C) and diaphragm muscles (D) isolated. Data are presented as means ± S.E.M. *P < 0.05 denotes significant differences from saline vehicle control; P < 0.05 denotes significant differences from the incidence of apoptosis after infusion of angiotensin II for 9 h.

View larger version (10K): [in this window] [in a new window]   Figure 4.  Distribution of cardiomyocyte apoptosis along the longitudinal axis of the heart Animals (n = 5) were killed 7 h after a single subcutaneous injection of 1 mg kg–1 angiotensin II. Hearts were cryosectioned along their entire length, from the apex to the base, and apoptosis detected using caspase 3 immunohistochemistry on cryosections taken at 2 mm intervals. Data are presented as means ± S.E.M. *P < 0.05 denotes significant differences from the incidence of apoptosis measured at 2, 4 and 8 mm.

	Discussion

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Our observations support previous research, both in vivo (De Angelis et al. 2002) and in vitro (Kajstura et al. 1997), describing cardiomyocyte apoptosis in response to angiotensin II. However, in this study, the cardiomyocyte apoptosis induced by angiotensin II was not homogeneously distributed throughout the ventricles (Fig. 4). Rather, the incidence of cardiomyocyte apoptosis was significantly greater 6 mm from the apex, i.e. approximately two-thirds of the way towards the base. Using the same approach, we have previously shown (Goldspink et al. 2004) that catecholamine-induced cardiomyocyte death is more prevalent closer (2 mm) to the apex of the heart. These differences may be explained by differences in receptor density throughout the myocardium. Unfortunately, the distribution of the angiotensin II receptors in the heart is currently unknown. However, these findings (Fig. 4) warn against either randomly isolating myocytes without regard for their origin within the myocardium or using whole tissue homogenates to investigate cardiomyocyte death.

Either bolus administration of 1 mg kg^–1 angiotensin II or continuous infusion of 1 mg kg^–1 angiotensin II induced significant myocyte apoptosis in the heart and skeletal muscle. Previously, we have shown (Tan et al. 1991) that infusion of this dose results in a plasma angiotensin II concentration of 70.6 ± 6.4 pg ml^–1, this being similar to that (56.7 ± 21.9 pg ml^–1) induced by abdominal aorta banding. These values agree closely with those (87 ± 8 pg ml^–1) observed in the monocrotaline model of heart failure (Dalla Libera et al. 2001) and are comparable to those observed during hypertension (60 pg ml^–1; Sim & Qui, 2003) and heart failure (30 pg ml^–1; McKelvie et al. 1999). After our infusion of 1 mg kg^–1 day^–1 angiotensin II for 9 h, the incidence of cardiomyocyte apoptosis (2.27 ± 0.2 per 10⁴ viable myocytes; P < 0.05) was similar to that (1.76 ± 0.5 in situ dUTP nick-end labelled cardiomyocytes per 10⁴ nuclei) reported by De Angelis et al. (2002) using the same dose. Notably, this amount of cardiomyocyte apoptosis is also comparable to that (2.3 per 10⁴ nuclei) measured in a transgenic model of constitutive caspase activation that resulted in lethal dilated cardiomyopathy after 8 weeks (Wencker et al. 2003). The functional consequences of the apoptosis measured in the present study remain to be investigated. Other work from our laboratory has shown that apoptotic myocytes in the heart and skeletal muscles often lyse in vivo and become necrotic (Goldspink et al. 2004; Burniston et al. 2005a). We know from our previous work (Tan et al. 1991) that infusion of 1 mg kg^–1 angiotensin II over a longer period of time (14 days) also induces necrosis, microscopic scarring and fibroblast proliferation in the myocardium, suggesting that the cardiomyocyte apoptosis measured in the present study is associated with long-term cumulative damage.

Of the skeletal muscles investigated, the greatest incidence of apoptosis was measured in the diaphragm (Fig. 3D). The diaphragm muscle is inextricably linked to respiration and damage in this muscle may decrease its ability to provide adequate negative intrathoracic pressure and impact on an individual's capacity for exercise, as observed in heart failure patients with cachexia (Mancini et al. 1994). Indeed, the breathlessness associated with heart failure may be partly attributed to respiratory muscle dysfunction (Carmo et al. 2001). Interestingly, angiotensin-converting enzyme inhibitor therapy is able to improve respiratory muscle function of heart failure patients (Coirault et al. 2001). Our discovery that elevated levels angiotensin II, similar to those seen in heart failure, induce myocyte death in the diaphragm provides a possible mechanism for the beneficial effects of angiotensin-converting enzyme inhibition on the respiratory muscle dysfunction.

Angiotensin II-induced cardiomyocyte apoptosis is mediated through the AT₁ receptor (Kajstura et al. 1997; Diep et al. 2002). Dalla Libera et al. (2001) reported that irbesartan, an AT₁ receptor blocker, reduced the skeletal myocyte apoptosis in an animal model of congestive heart failure, suggesting that angiotensin II-induced skeletal myocyte apoptosis too is mediated by the AT₁ receptor. Angiotensin II, acting via the AT₁ receptor, also stimulates the secretion of aldosterone from the adrenal cortex (Bassett et al. 2004). The cardiotoxic effects of over-activation of the renin–angiotensin–aldosterone system are recognized (Tan et al. 1991; Tan & Hall, 1994). However, there is uncertainty about the relative potencies of angiotensin II and aldosterone in inducing cardiomyocyte death and whether it is more efficacious to block the effects of angiotensin II or aldosterone (Tan et al. 2004). For example, the mineralocorticoid receptor antagonist, spironolactone, partly protects the myocardium from angiotensin II-induced apoptosis (De Angelis et al. 2002).

Previous work from our laboratory (Burniston et al. 2002, 2005a,c; Ng et al. 2002; Goldspink et al. 2004) has described the myotoxic effects of ß-adrenergic receptor (ß-AR) stimulation in both the heart (ß₁-AR-mediated effect) and skeletal muscles (ß₂-AR-mediated effect). While little is know about the mechanisms that mediate ß₂-AR-induced myocyte death (Burniston et al. 2005c), the postreceptor signalling pathways mediating ß₁-AR-induced cardiomyocyte death have been studied extensively and have been shown to involve a calcineurin-dependent pathway (Saito et al. 2000; Xiao et al. 2004). Angiotensin II also signals through increased intracellular calcium to induce cardiomyocyte death (Cigola et al. 1997; Kajstura et al. 1997) and can signal through calcineurin to induce gene expression (Finckenberg et al. 2003). Furthermore, inhibition of calcineurin had a beneficial effect in Dahl salt-sensitive rats (Sakata et al. 2000), a model in which angiotensin II signalling is know to be important (Tojo et al. 2002). Similar mechanisms might also mediate the skeletal myocyte apoptosis induced by angiotensin II.

In the present work, angiotensin II induced significant myocyte apoptosis in vivo in skeletal, as well as cardiac, muscle of normal rats. While not a model of heart failure, these experiments provide further evidence to support the concept that heart failure should be treated as a generalized, rather than cardiac specific, myopathy (Coats, 1996; Filippatos et al. 2003). In the light of these findings, more investigations should include skeletal, as well as cardiac, muscle and pharmacological therapies should be aimed at preventing myocyte death in all striated muscles.

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	Acknowledgements

 
J.G.B. is a British Heart Foundation Post-Doctoral Research Fellow (FS/04/028).

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This Article Abstract Full Text (PDF) All Versions of this Article: 90/5/755    most recent expphysiol.2005.030908v1 Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Burniston, J. G Articles by Goldspink, D. F Search for Related Content PubMed PubMed Citation Articles by Burniston, J. G Articles by Goldspink, D. F Related Collections Muscle