Evidence that the hypertrophic action of clenbuterol on denervated rat muscle is not propranolol-sensitive.

1. The effect of propranolol on the clenbuterol-induced protein anabolism in innervated and denervated soleus and plantaris muscles of the rat was studied. 2. The response to the beta-agonist, clenbuterol, in both innervated and denervated muscles, was not significantly inhibited by the beta-antagonist, propranolol. 3. The results provide further evidence to suggest that the action of clenbuterol on skeletal muscle protein accretion may not be directly mediated by beta-adrenoceptors.     

Effect of the beta-adrenoceptor agonist clenbuterol and phytohaemagglutinin on growth, protein synthesis and polyamine metabolism of tissues of the rat.

1. The kidney bean lectin, phytohaemagglutinin (PHA), induced a marked atrophy of skeletal muscle which was evident from the changes in tissue composition (protein, RNA, DNA and polyamine content) and from the reduction in weight and protein synthesis of hind leg muscles of rats fed on kidney bean-diets for four days. The beta-adrenoceptor agonist, clenbuterol, induced skeletal muscle hypertrophy by transiently stimulating protein synthesis. As a consequence, the muscle loss caused by a short exposure to PHA was, in part, ameliorated by clenbuterol treatment. 2. Cardiac muscle was affected to a lesser extent than skeletal muscle by both clenbuterol and the lectin. However, there was evidence that protein synthesis in heart was reduced by PHA. 3. PHA had opposite effects on the gut, the lectin-induced hyperplasia of the jejunum was accompanied by a large increase in protein synthesis. Clenbuterol alone had no effect on the jejunum whereas a combination of PHA and clenbuterol appeared to exacerbate the effect of the lectin on gut. 4. Both the lectin-induced gut growth and the hypertrophy of skeletal muscle caused by clenbuterol were preceded by the accumulation of polyamines in the respective tissues. Of particular note was the observation that a significant increase in the proportion of the intraperitoneally injected 14C-labelled spermidine or putrescine taken up by the growing tissues could be detected by the second day. Therefore, the measurement of uptake of labelled polyamines may be used as a sensitive indicator of early alterations in tissue metabolism.     

Year-long clenbuterol treatment of mice increases mass, but not specific force or normalized power, of skeletal muscles

1. Clenbuterol has been proposed for the treatment of muscle wasting disorders, but its long-term effects on skeletal muscle function have not been tested rigorously. We tested the hypothesis that year-long treatment of young (6 months) mice with clenbuterol would increase skeletal muscle mass and in vitro measurements of specific force (Po) and power output. 2. Male mice (C57BL/10ScSn) were divided into treated (n = 6) or untreated (n = 8) groups. Treated mice received clenbuterol (1.5-2 mg/kg per day) in their drinking water for 52 weeks, following a staggered 3 day on/3 day off schedule to attenuate the response to clenbuterol. 3. Clenbuterol treatment increased the absolute mass of each muscle tested: the heart by 28%, extensor digitorum longus (EDL) by 16%, soleus by 22% and tibialis anterior by 17%. For treated compared with untreated mice, absolute Po (mN) was greater in soleus muscles but not different in EDL muscles. Absolute power output (mW) of the EDL and soleus muscles was not different and no differences were observed for the specific Po (kN/m2) or normalized power output (W/kg) of EDL muscles, soleus muscles or diaphragm muscle strips. 4. We conclude that, following year-long treatment of mice with clenbuterol, the mass of the heart and both fast and slow skeletal muscles is increased, but the lack of any change in normalized Po or power output indicates that clenbuterol has little therapeutic effect on the functional properties of skeletal muscle.     

Transforming growth factor betas are upregulated in the rat masseter muscle hypertrophied by clenbuterol, a beta2 adrenergic agonist

1. The regulatory mechanism for the hypertrophy of skeletal muscles induced by clenbuterol is unclear. The purpose of the present study was to determine the extent to which transforming growth factor betas (TGFbetas), fibroblast growth factors (FGFs), hepatocyte growth factor (HGF), and platelet-derived growth factors (PDGFs) are involved in the hypertrophy of rat masseter muscle induced by clenbuterol. 2. We measured the mRNA expression levels for TGFbetas, FGFs, HGF, and PDGFs in rat masseter muscle hypertrophied by oral administration of clenbuterol for 3 weeks and determined correlations between the weight of masseter muscle and mRNA expression levels by regression analysis. We determined immunolocalizations of TGFbetas and their receptors (TGFbetaRs). 3. The mRNA expression levels for TGFbeta1, 2, and 3, and for PDGF-B demonstrated clenbuterol-induced elevations and positive correlations with the weight of masseter muscle. In particular, TGFbeta1, 2, and 3 showed strong positive correlations (correlation coefficients >0.6). The mRNA expression levels for PDGF-A, FGF-1 and 2, and HGF showed no significant differences between the control and clenbuterol groups, and no significant correlations. TGFbeta1, 2, and 3 were principally localized in the connective tissues interspaced among myofibers, and TGFbetaRI and II were localized in the periphery and sarcoplasm of the myofibers. 4. These results suggest that paracrine actions of TGFbeta1, 2, and 3 via TGFbetaRI and II could be involved in the hypertrophy of rat masseter muscle induced by clenbuterol. This is the first study to document the involvement of TGFbetas in the hypertrophy of skeletal muscles induced by clenbuterol.     

Systemic administration of beta2-adrenoceptor agonists, formoterol and salmeterol, elicit skeletal muscle hypertrophy in rats at micromolar doses

beta(2)-Adrenoceptor agonists provide a potential therapy for muscle wasting and weakness, but their use may be limited by adverse effects on the heart, mediated in part, by beta(1)-adrenoceptor activation. Two beta(2)-agonists, formoterol and salmeterol, are approved for treating asthma and have an extended duration of action and increased safety, associated with greater beta(2)-adrenoceptor selectivity. The pharmacological profiles of formoterol and salmeterol and their effects on skeletal and cardiac muscle mass were investigated in 12-week-old, male F344 rats. Formoterol and salmeterol were each administered via daily i.p. injection at one of seven doses (ranging from 1 to 2,000 microg kg(-1) day(-1)), for 4 weeks. Rats were anaesthetised and the EDL and soleus muscles and the heart were excised and weighed. Dose-response curves were constructed based on skeletal and cardiac muscle hypertrophy. Formoterol was more potent than salmeterol, with a significantly lower ED(50) in EDL muscles (1 and 130 microg kg(-1) day(-1), P <0.05), whereas salmeterol had greater intrinsic activity than formoterol in both EDL and soleus muscles (12% greater hypertrophy than formoterol). The drugs had similar potency and intrinsic activity in the heart, with a smaller leftward shift for formoterol than seen in skeletal muscle. A dose of 25 microg kg(-1) day(-1) of formoterol elicited greater EDL and soleus hypertrophy than salmeterol, but resulted in similar beta-adrenoceptor downregulation. These results show that doses as low as 1 microg kg(-1) day(-1) of formoterol can elicit significant muscle hypertrophy with minimal cardiac hypertrophy and provide important information regarding the potential therapeutic use of formoterol and salmeterol for muscle wasting.     

Studies on the mechanisms by which clenbuterol, a beta-adrenoceptor agonist, enhances 5-HT-mediated behaviour and increases metabolism of 5-HT in the brain of the rat

The head twitch response in mice produced by injection of 5-hydroxytryptophan (100 mg/kg i.p.) and carbidopa (25 mg/kg i.p.) was enhanced by administration of clenbuterol (0.5 mg/kg i.p.), a beta-adrenoceptor agonist. Clenbuterol also enhanced the hyperactivity syndrome in rats produced by quipazine (25 mg/kg i.p.), a 5-hydroxytryptamine (5-HT) agonist. This enhancement was not prevented by depletion of 5-HT in brain with p-chlorophenylalanine or after pretreatment with prazosin. The behavioural responses of the rats to administration of the alpha 2-adrenoceptor agonist, clonidine, was unaltered by acute or longer-term administration of clenbuterol. Following chronic administration of clenbuterol (5 mg/kg daily for 14 days), a procedure resulting in down-regulation of central beta-adrenoceptors, a larger dose of clenbuterol was necessary to enhance the quipazine-induced hyperactivity, suggesting that the mechanism of enhancement involved central post-synaptic beta-adrenoceptors. Further evidence for this conclusion was that a lesion of central noradrenaline pathways produced by 6-hydroxydopamine did not abolish the clenbuterol-induced enhancement of the quipazine-mediated behaviour. The binding characteristics of 5-HT2-receptors were unchanged by acute or chronic administration of clenbuterol. Clenbuterol (5 mg/kg) increased the percentage of plasma free (non-albumin bound) tryptophan, plasma free fatty acid concentration and the concentration of tryptophan and 5-hydroxyindoleacetic acid (5-HIAA) in the brain. The increase in 5-HT turnover in brain was prevented by pretreatment with the beta 1-adrenoceptor antagonist atenolol, which enters the brain poorly. It is therefore suggested that the clenbuterol-induced increase in 5-HT metabolism results from the increase in the concentration of plasma free fatty acid which increases plasma free tryptophan and thus increases the concentration of tryptophan in brain and 5-HT synthesis in brain. The clenbuterol-induced enhancement of 5-HT-mediated behaviour is therefore not associated with its effect on 5-HT metabolism. The data are discussed in relation to that obtained after administration of antidepressant drugs.     

Changes in tissue blood flow and beta-receptor density of skeletal muscle in rats treated with the beta2-adrenoceptor agonist clenbuterol.

Rats injected with the beta2-adrenoceptor agonist clenbuterol (2 mg kg-1 per day) for 18 days gained significantly more weight than controls. Tissue blood flow assessed 24 h after the last injection from the distribution of radiolabelled microspheres was increased in white (5 fold) and brown (3 fold) adipose tissue of clenbuterol-treated rats but was unaffected in kidney, brain and diaphragm, and was reduced by about 80% in skeletal muscle. Acute injection of clenbuterol one hour before measuring blood flow, increased blood flow to brown fat (20 fold) in both treated and control groups. Blood flow to skeletal muscle increased more in the rats treated chronically with clenbuterol (6 fold increase) than in control rats (2 fold increase), but absolute flow rates were still significantly lower in the rats treated chronically with clenbuterol. Skeletal muscle beta-adrenoceptor density and subtype were assessed from ligand binding and displacement studies using [3H]-dihydroalprenolol. Rats treated with clenbuterol for 18 days showed a 50% reduction in beta-receptor density, but the ratio of beta 1/beta 2-receptors was unaffected (15% beta 1/85% beta 2). The results indicate that, although clenbuterol produces acute increases in muscle blood flow, chronic treatment results in lower flow rates immediately (1 h) and 24 h after the previous injection. The attenuated response following chronic treatment is associated with a marked reduction in skeletal muscle beta-adrenoceptor density. The data suggest that any anabolic effects of clenbuterol on muscle which may require, or may be mediated by increases in blood supply, cannot be sustained by chronic treatment.(ABSTRACT TRUNCATED AT 250 WORDS)     

Biochemical Pharmacology: Polyamine-mediated Heart Hypertrophy Induced by Clenbuterol in the Mouse

The use of β-agonists as growth-promoting agents in cattle could lead to toxic side-effects in man. One such effect is the accumulation of polyamines which seem to be implicated in muscle and heart hypertrophy. We have studied the induction of cardiac hypertrophy after treatment with clenbuterol and the role of polyamines in this effect. Treatment of mice with repeated doses of clenbuterol, a specific β-adrenergic agonist, resulted in a marked increase in heart muscle weight whereas total body weight did not change significantly. Clenbuterol-linked cardiac hypertrophy could be prevented by coadministration of either the non-specific β-adrenergic antagonist, propranolol, or the irreversible inhibitor of ornithine decarboxylase, α-difluoromethylornithine. The clenbuterol-induced cardiac hypertrophy was associated with a corresponding increase in the level of the polyamines putrescine, spermidine and spermine. These observations are indicative of the role of polyamines in cardiac hypertrophy induced by clenbuterol.     

BETA-ADRENOCEPTOR-MEDIATED EFFECTS OF CLENBUTEROL (NAB 365) ON TRACHEA, HEART AND SKELETAL MUSCLE IN ANAESTHETIZED GUINEA-PIGS

1. Intravenous injection of clenbuterol (NAB 365) in anaesthetized guinea-pigs produced decreases in tracheal segment pressure and in soleus muscle contractions and a slight increase in heart rate. These responses were reduced by propranolol. 2. Clenbuterol was less potent than isoprenaline on the trachea and soleus muscle and even less potent on the heart. The maximum response to clenbuterol was the same as that to isoprenaline on the trachea and the soleus muscle but it was not more than 30% of that to isoprenaline on the heart. There was no significant difference between the potencies of clenbuterol on the trachea and the soleus muscle. 3. The onset of the responses to clenbuterol were slower and the duration of action longer than those to isoprenaline. 4. High doses of clenbuterol blocked isoprenaline responses on heart rate. 5. Clenbuterol showed selectivity for the trachea and the soleus muscle (β₂-adrenoceptors) as compared with the heart (β₁-adrenoceptors). This could result, at least in part, from its partial agonist activity on the heart.     

Abnormality in fibre type distribution of soleus and plantaris muscles in non-obese diabetic Goto-Kakizaki rats

1. Fibre type distributions of the slow soleus and fast plantaris muscles were investigated in 5-, 9- and 20-week-old male Goto-Kakizaki (GK) rats, as an animal model of non-obese diabetes, and were compared with those of age-matched non-diabetic Wistar rats. 2. Bodyweight and both soleus and plantaris muscle weights were lower in GK rats than in Wistar rats, regardless of age. In addition, both relative soleus and plantaris muscle weights per bodyweight were lower in GK rats than in Wistar rats, regardless of age. 3. In the soleus muscle, a higher percentage of type I fibres and a lower percentage of type IIA fibres were observed in 5- and 9-week-old GK rats. In addition, there were no type IIA fibres in 20-week-old GK rats. 4. In the plantaris muscle, there were no differences in fibre type distribution of 5-week-old GK rats. However, a higher percentage of type IIB fibres and a lower percentage of type I and type IIA fibres were observed in 9- and 20-week-old GK rats. In addition, there were no type I fibres in 20-week-old GK rats. 5. These results indicate that the decreased percentage of high-oxidative fibres (e.g. type IIA fibres in the soleus muscle and type I and type IIA fibres in the plantaris muscle) of the diabetic animals is concerned with an impairment in insulin sensitivity and glucose metabolism and is not related to bodyweight.     

Cerivastatin induces type-I fiber-, not type-II fiber-, predominant muscular toxicity in the young male F344 rats

3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) are associated with adverse skeletal muscle toxicity, but the underlying mechanism remains unclear. To investigate the pathological mechanism of statin-induced myotoxicity, cerivastatin (20 ppm; corresponding to 2 mg/kg/day) was dietarily administered to young male F344 rats for 10 days, and time-course clinical observations, measurement of plasma creatine kinase activity, and light and electron microscopy of type I fiber-predominant skeletal muscle (soleus) or type II fiber-predominant skeletal muscles (extensor digitorum longus and tibialis anterior), were performed. Clinical symptoms including weakness of hind limbs, staggering gait and body weight loss, accompanied by marked plasma creatinine kinase elevation in rats fed cerivastatin at around Day 6 to 8. Interestingly, microscopic examination revealed that cerivastatin-induced muscle damages characterized by hypercontraction (opaque) and necrosis of the fibers were of particular abundance in the soleus muscle at Day 8, whereas these histological lesions in the extensor digitorum longus and tibialis anterior were negligible, even at Day 9. Prior to manifestation of muscle damage, swollen mitochondria and autophagic vacuoles in the soleus were observed as the earliest ultra structural changes at Day 6; then activated lysosomes, disarray of myofibril and dilated sarcoplasmic reticulum vesicles became ubiquitous at Day 8. These results demonstrate that cerivastatin induces type I fiber-predominant muscles injury, which is associated with mitochondrial damage, in young male F344 rats. Since the rat exhibiting type I fiber-targeted injury is a unique animal model for statin-induced myotoxicity, it will be useful for gaining insight into mechanisms of statin-induced myotoxicity.     

Contractile properties of the diaphragm in creatine-fed rats

1. Creatine feeding increases the oxidative capacity of type 1 skeletal muscle fibres and, in soleus muscles, consisting mainly of type 1 fibres, increases fatigue resistance. The diaphragm contains a relatively large content of type 1 fibres and respiratory muscle fatigue is a cause of respiratory failure. The aim of the present study was to determine whether creatine supplements increase fatigue resistance in the diaphragm. 2. Rats were given creatine monohydrate (2.55 g/L) in the drinking water. After 5-6 days, isometric contractile properties were measured in strips of costal diaphragm in Krebs' solution at 30 degrees C. Measurements were also made in soleus muscle strips. Values for strips from creatine-fed rats were compared with those from control rats. 3. Creatine feeding did not increase fatigue resistance and had no effect on twitch or tetanic tension or twitch kinetics in the diaphragm. Creatine increased fatigue resistance in soleus muscles, as reported previously.     

Upregulation of fatty acyl-CoA thioesterases in the heart and skeletal muscle of rats fed a high-fat diet

In rodent models of diet-induced obesity, prolonged high-fat feeding increases the cellular uptake of fatty acids and causes lipotoxicity in the heart and skeletal muscle, where substrate overload to beta-oxidation generates mitochondrial stress. We examined the hypothesis that, because of its catalytic properties, acyl-CoA thioesterase (ACOT) would counteract these detrimental situations by modulating intracellular acyl-CoA levels. Rats were fed a low- or high-fat diet for up to 20 weeks, and the expressions of ACOT isoforms and fatty acid beta-oxidation enzymes were analyzed by western blotting. The expressions of ACOT1, ACOT2 and ACOT7 proteins in the heart and soleus muscle were significantly increased, by 2.0-7.6-fold, in rats fed the high-fat diet as compared with the low-fat diet group. These effects were accompanied by increases in carnitine palmitoyltransferase and acyl-CoA oxidase expression. However, ACOT was not induced in the extensor digitorum longus muscle or the liver. Subcellular fractionation of heart and soleus muscle homogenates confirmed expression of both the cytosolic and mitochondrial ACOT isoforms. These results underscore the functional relationship between ACOT and fatty acid oxidation, and suggest adaptive upregulation of ACOT to protect against fatty acid oversupply in the heart and skeletal muscle.     

Endurance training adaptations modulate the redox-force relationship of rat isolated slow-twitch skeletal muscles

1. Studies have shown that, in isolated skeletal muscles, maximum isometric force production (Po) is dependent on muscle redox state. Endurance training increases the anti-oxidant capacity of skeletal muscles, a factor that could impact on the force-producing capacity following exogenous exposure to an oxidant. We tested the hypothesis that 12 weeks treadmill training would increase anti-oxidant capacity in rat skeletal muscles and alter their response to exogenous oxidant exposure. 2. At the conclusion of the 12 week endurance-training programme, soleus (slow-twitch) muscles from trained rats had greater citrate synthase (CS) and catalase (CAT) activity compared with soleus muscles from untrained rats (P < 0.05). In contrast, CAT activity of extensor digitorum longus (EDL; fast-twitch) muscles from trained rats was not different to EDL muscles of untrained rats. The CS activity was lower in EDL muscles from trained compared with untrained rats (P < 0.05). 3. Equilibration with exogenous hydrogen peroxide (H2O2, 5 mmol/L) increased the Po of soleus muscles from untrained rats for the duration of treatment (30 min), whereas the Po of EDL muscles was affected biphasically, with a small increase initially (after 5 min), followed by a more marked decrease in Po (after 30 min). The H2O2-induced increase in Po of soleus muscles from trained rats was less than that in untrained rats (P < 0.05), but no differences were observed in the Po of EDL muscles following training. 4. The results indicate that 12 weeks endurance running training conferred adaptations in soleus but not EDL muscles. These adaptations were associated with an attenuation of the oxidant-induced increase in Po of soleus muscles from trained compared with untrained rats. We conclude that endurance training-adapted soleus muscles have a slightly altered redox-force relationship.     

LONG-TERM CLENBUTEROL ADMINISTRATION ALTERS THE ISOMETRIC CONTRACTILE PROPERTIES OF SKELETAL MUSCLE FROM NORMAL AND DYSTROPHIN-DEFICIENT MDX MICE

1. This study was designed to establish whether long-term treatment with the powerful anabolic agent clenbuterol has beneficial effects on dystrophin-deficient skeletal muscle function. 2. Normal (C57BL/10) and dystrophic (mdx) mice were administered clenbuterol (2 mg/kg per day) for 15 weeks. At 20 weeks of age, the extensor digitorum longus (EDL) and soleus muscles were removed, and their contractile and histochemical properties analysed. 3. Absolute and relative muscle masses were larger (P<0.001) in mdx compared to C57BL/10 mice. These larger muscles produced larger absolute forces (P<0.01) in the soleus of mdx mice compared to normal mice. Relative tetanic force was also larger (P<0.05) in the soleus of mdx mice. In contrast, the absolute tetanic tension of the EDL was reduced (P<0.01) in mdx mice compared to C57BL/10 mice, and both relative twitch and tetanic tensions were also lower (P<0.001) in mdx mice. 4. Clenbuterol increased the lean muscle mass in both normal (10%, P<0.05 and 20%, P<0.01 for the EDL and soleus, respectively) and dystrophic (7%, P<0.05 and 11%, P<0.01) groups. Twitch contraction times were significantly faster in both the EDL (P<0.001) and soleus (P<0.01) muscles following clenbuterol administration, supported by fibre-type transitions towards fast-twitch fibres. Relative force levels of the soleus muscle of both C57BL/10 (40%, P<0.01) and rndx (20%, P<0.01) mice were increased significantly following clenbuterol treatment. No changes in the absolute or relative forces of the EDL muscles were observed in response to clenbuterol administration. 5. Clenbuterol was thus able to increase the force output of a slow-twitch, mixed (hence humanlike) muscle but not fast-twitch muscle from mdx mice. The results lend tentative support to the potential role of clenbuterol as an anabolic agent in the treatment of muscle wasting diseases.     

Characterization of beta 1- and beta 2-adrenoceptors in rat skeletal muscles.

Binding studies with (-)-[125I]cyanopindolol (ICYP) were conducted to characterize beta-adrenoceptors in plantaris and soleus muscles of rats (male, 250-300 g). The distribution of beta 1- and beta 2-adrenoceptors in different muscle fiber types, identified in serial sections by succinic dehydrogenase (SDH) staining, was studied by autoradiography. The densities of binding sites (Bmax, fmol/mg protein) were 5.4 +/- 0.9 (mean +/- SEM) in plantaris and 11.5 +/- 2.0 in soleus muscle. In plantaris muscle, monophasic competition curves were observed when binding experiments were performed using CGP20712A (50 pM to 0.5 mM), a beta 1-adrenoceptor selective antagonist, or ICI 118,551 (50 pM to 20 microM), a beta 2-adrenoceptor selective antagonist, to compete for ICYP binding. Analysis with LIGAND revealed a single binding site with a KD value of 2.41 +/- 0.56 nM (mean +/- SEM) for ICI 118,551 and 8.93 +/- 3.00 microM for CGP 20712A, indicating the presence of a homogeneous population of beta 2-adrenoceptors. In soleus muscle, competition curves were biphasic with 16-21% beta 1-adrenoceptors. Autoradiographic studies supported the findings from binding studies with membrane homogenates. The ICYP binding pattern was associated closely with the muscle fiber types identified by SDH staining. Propranolol-resistant binding sites were observed, and these sites were associated with muscle fibers positive to SDH staining.     

Effect of chronic K+ deficiency on contractile properties of soleus muscle in rats: evidence of sex differences

1. Alterations in skeletal muscle function of chronically K(+)-depleted male and female rats were investigated in isolated soleus muscles. 2. By 16 weeks K+ deficiency, plasma K+ concentrations in both male and female rats were reduced to approximately 2 mEq/L, which was accompanied by an approximate 50% reduction in muscle K+ content and a marked increase in muscle Na+ content. These changes were similar in both males and females. 3. Plasma creatine phosphokinase activity progressively increased with time in K(+)-depleted male rats, whereas only a slight increase was observed in female rats. 4. Maximum isometric twitch tension (Pt) and tetanic tension (Po) of K(+)-depleted soleus muscles from male rats was markedly suppressed; this was not seen for soleus muscles obtained from female rats. 5. After exposure to insulin in low-K+ solution, the contractile tension of soleus from the K(+)-depleted male rats was suppressed to a greater extent. 6. All alterations in muscle function during chronic K+ depletion were restored to normal after 2 weeks K+ repletion. 7. The results suggest that there is a preponderance for male over female rats in developing alterations in skeletal muscle function during chronic K+ deficiency. The changes may be associated with abnormalities of muscle membrane permeability and cellular function.     

Effect of hindlimb suspension and clenbuterol treatment on polyamine levels in skeletal muscle

Polyamines are unbiquitous, naturally occurring small aliphatic, polycationic, endogenous compounds. They are involved in many cellular processes and may serve as secondary or tertiary messengers to hormonal regulation. The relationship of polyamines and skeletal muscle mass of adductor longus, extensor digitorum longus, and gastrocnemius under unloading (hindlimb suspension) conditions was investigated. Unloading significantly affected skeletal muscle polyamine levels in a fiber-type-specific fashion. Under loading conditions, clenbuterol treatment increased all polyamine levels, whereas under unloading conditions, only the spermidine levels were consistently increased. Unloading attenuated the anabolic effects of clenbuterol in predominately slow-twitch muscles (adductor longus), but had little impact on clenbuterol's action as a countermeasure in fast- twitch muscles such as the extensor digitorum longus. Spermidine appeared to be the primary polyamine involved in skeletal muscle atrophy/hypertrophy.     

Calpastatin overexpression in the skeletal muscle of mice prevents clenbuterol-induced muscle hypertrophy and phenotypic shift

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