MESO-Rx
Anabolic Steroids
Clenbuterol - effective?
- Thread starter JBF
- Start date
yes it works great at burning fat with the preoper diet and training The possible side effects of clenbuterol include those of other CNS stimulants, and include such occurrences as shaky hands, insomnia, sweating, increased blood pressure and nausea. These side effects will generally subside after a week or so of use however, once the user becomes accustomed to the drug. One would typically start a cycle by gradually increasing the dosage each day until a desired range is established. This process will minimize the unwanted side effects seen from the drug which otherwise might be dramatic if a large dose is administered from the onset. Men generally end up in the range of 2-8 20mcg tablets per day for 2weeks on 2 weeks off, although some people do claim to tolerate even higher dosages.Very quickly, the drug will elevate the body temperature. The rise is not usually dramatic, perhaps a half of a Cegree or so, sometimes a little more. This elevation is due to your body burning excess energy (largely from fat) and is usually not uncomfortable. Now that it is working, the number of consecutive days clenbuterol can be used is believed to be dependent on the goal of the individual. To be clear, the athletic benefits of this drug will only last for a limited time and then diminish, largely due to beta-receptor down regulation. People also stack T3 with Clen for even more fat burning.....but when you cycle clen make sure to taper it up start with a pill one day then next do 2 pills and up but if you see the side effects get to bad lower the dose and make sure you use it 2weeks on 2weeks off....everyone is different im so use to clen now i do not taper i start with 200mcg run it 2 weeks then off 2 weeks......the 2weeks you are off you can take a ECA stack for more fat burning and use benadryl to clear and restore beta receptors
I wouldn't take ECA on the off weeks if you're really trying to upregulate your receptors. EC doesn't hit the B2 receptor nearly as hard, but it still does. Ketotifen is a good option for upregulating your receptors either at the same time as clen or during the off weeks.TestFreak said:
swelty said:
Oh yea Bro throw in a ECA stack the 2 weeks you are off Clen
ECA STACK
The ideal ratio for the ECA stack is 10:1 caffeine to ephedrine. Many sources suggest that the ideal dosage is 25mg ephedrine, 250mg caffeine and 80-300mg aspirin. this is an individual thing so I would start at this lower dosage and see how it effects you. The above dosage should be taken 3 times a day with at least 3 hours in between. It is also recommended that your last dose should be before 6:00 pm, or you may have problems getting to sleep. Some people recommend only taking the stack 5 days a week with 2 days off to allow your body a small break from the effects. Others stay on it 7 days a week. Again this is a personal thing so you may want to experiment. Along the same lines, some people will use the stack for weeks without stopping. Other's will cycle the doses i.e. 2 weeks on then a week off etc. it is recommended that 4 weeks would be about the maximum that you should stay on the stack without a break of at least a week. The basic rational is that your body will become used to the ECA stack stimulation and the effects will wear off. By taking a break, it is possible for your body to reap better rewards when you go back on the stack. The wired up feeling is likely to diminish within 1-2 weeks of starting the stack. evidence shows that the fat burning properties of the stack still continue well after that time, so do not assume that an immediate break is needed.
so 2 weeks clen 2 weeks ECA 2 weeks Clen and so on no more than 12 weeks
if you need anymore info please let me know
DocJ
New Member
Here's what I would do:
Week 1-2: Clen
Week 3-4: Upregulate receptors
Week 5-6: ECA
Week 7: Upregulate receptors
Week 8-9: Clen
I never had good results from clen after the first couple times I used it and this method works for me now. Test Freaks method might work well if you've never used clen before.
Week 1-2: Clen
Week 3-4: Upregulate receptors
Week 5-6: ECA
Week 7: Upregulate receptors
Week 8-9: Clen
I never had good results from clen after the first couple times I used it and this method works for me now. Test Freaks method might work well if you've never used clen before.
Clenbuterol is one of those rare gems. It has strong anabolic effects without any HPTA consequences. It does, however, have side effects which are fraught with possible danger. I, personally, like this medication but unfortunately it is unavailable in the USA. The reason is that CB is fed to animals who than store excessive amounts in their livers. When a human consumes this they can readily overdose and die. The mechanism on how CB works has not been elucidated. Following is a brief travel in exploring the mechanism of CB action.
Clenbuterol is a beta-2 adrenergic agonist with some similarities to ephedrine, but its effects are more potent and longer-lasting as a stimulant and thermogenic drug. Clenbuterol is lipophilic and is known to have direct intracellular actions. It is commonly used for smooth muscle relaxant properties. Clenbuterol is commonly prescribed to sufferers of breathing disorders as a decongestant and bronchodilator. People with chronic breathing disorders like asthma use this as a bronchodilator to make breathing easier. It causes an increase in aerobic capacity, CNS stimulation, and an increase in blood pressure and oxygen transportation. It increases the rate at which fat and protein is used up in the body at the same time as slowing down the storage of glycogen.
Traditionally administered locally (by inhalation) at low doses for bronchodilatation in the treatment of asthma, when given at higher doses, systemically, 2-adrenoceptor agonists have potent anabolic effects in healthy muscle. The anabolic effects of clenbuterol administration have previously been shown to be beta-2-AR mediated. Clenbuterols anabolic effects have demonstrated a dose-response relationship between clenbuterol and muscle hypertrophy. The anabolic and lipolytic effects of the beta-2-adrenergic receptor (AR) agonist clenbuterol have been widely investigated in a variety of sedentary laboratory and livestock animals. Clenbuterol administration has been shown to be beneficial in some animal models of Duchenne muscular dystrophy but not in others. Scientific investigations into the effects of clenbuterol in humans are far less numerous than those pertaining to livestock or laboratory animals.
Not surprisingly, the anabolic and lipolytic (i.e., repartitioning) effects of clenbuterol have attracted the attention of many athletes. Bodybuilders in particular take high doses of this beta-2-AR agonist. The protocol for determining an individual's optimal dose is crude and involves ever-increasing daily doses until the side effects can no longer be tolerated. The doses employed vary widely, with men being better able than women to tolerate the side effects, which include tachycardia, hypokalemia, arrhythmia, muscle cramps, and muscle tremors. An average daily dose for males can be eight tablets or ~2 g clenbuterol/kg body wt. In addition, because of its lack of androgenic side effects, clenbuterol is also popular among sedentary as well as athletic women for use as a repartitioning agent. Case reports include body builders who present with tachycardia, myocardial infarction, and end-stage renal disease. Clenbuterol is banned by the World Anti-Doping Agency.
Ageing is associated with a progressive loss of skeletal muscle mass (sarcopenia) and a subsequent decline in muscle strength. Progressive muscle fibre denervation, a loss of motor units, and potential motor unit remodeling have been implicated, but since the slowing of contraction occurs before significant muscle wasting, intrinsic changes to skeletal muscle fibres, including excitationcontraction coupling, cannot be ruled out.
Developing therapeutic interventions to prevent or reverse the age-related decline in function is of increasing importance. Many elderly people require the use of all their muscle strength to complete simple tasks such as rising from a chair, and any further impairment in muscle function (such as that following extended bed rest after surgery) can result in a loss of functional independence.
Associated with normal ageing is a decrease in the circulating levels of anabolic hormones, including, but not limited to: growth hormone (GH), insulin, insulin-like growth factor I (IGF-I), and testosterone. These hormonal changes are thought to be responsible, at least in part, for the age-related loss of muscle mass and strength. Numerous clinical studies have tried increasing the circulating levels of one or more of these hormones, with the aim of increasing muscle mass and strength. However, to date, hormone replacement therapy has produced mixed success in humans. Studies reporting on the effects of testosterone and testosterone precursor supplementation on muscle mass and strength have produced equivocal results in elderly human subjects. Whereas testosterone has been shown to increase muscle strength in hypogonadal elderly men, testosterone administration to elderly men with normal testosterone levels was associated with an increased risk of polycythemia. Furthermore, testosterone treatment for elderly women may be inappropriate due to the masculinizing effects of androgens.
Several studies have postulated that GH and (or) IGF-I administration may prevent the muscle wasting associated with ageing. To date, GH supplementation has been shown to alter body composition by decreasing body fat mass and increasing lean body mass in elderly men. However, GH did not augment muscle strength or produce muscle hypertrophy. The administration or up-regulation of IGF-I has proven more promising in a number of animal models of pathologies where muscle wasting is indicated, but there is concern that elevated levels of IGF-I may be implicated in tumour formation. Both GH and IGF-I are expensive therapies that must be given daily. These findings suggest that hormone replacement alone has limited therapeutic efficacy for treating sarcopenia in the frail elderly. In the absence of successful hormone replacement therapies, muscle anabolic agents have been used in an attempt to treat sarcopenia.
Clenbuterol is used as an adjunct to ventricular assist devices. Their experimental use in the treatment for muscle wasting conditions has also yielded promising results that are dose dependent. It has been shown to have some therapeutic potential in speeding up the rehabilitation of postoperative muscle wasting in humans and has been proposed for the pharmacological amelioration of cachexia in chronic diseases such as cancer and Duchenne muscular dystrophy.
The diversity of skeletal muscle fiber types, defined by the expression of particular myosin heavy chain (MHC) isoforms, is believed to be due to a combination of distinct myoblast lineage and extrinsic factors. Postnatally, however, exogenous factors such as innervation, neuromuscular activity, and hormone levels (e.g., thyroid hormone) become the main determinants of fiber type, and fiber type transitions can occur due to altered expression of MHC isoforms. Transitions of fiber type in adult skeletal muscle have also been reported in humans during aging, where the decline in both number and size of fast fiber types could contribute to the impaired muscle function reported in the elderly population, and in disease states such as chronic obstructive pulmonary disease and heart failure.
Skeletal muscle has the capacity to change its phenotype, not only in response to altered functional demands, but also under the influence of specific growth factors and hormones. As shown in numerous studies, increased neuromuscular activity and loading both elicit fast-to-slow transitions and decreased neuromuscular activity, and unloading cause transitions in the reverse direction. The intracellular mechanisms that regulate changes in postnatal myosin heavy chain (MHC) expression are not well established.
Understanding of the determination and differentiation of muscle fiber type has been advanced with the discovery of a family of myogenic regulatory factors (MRFs), namely, MyoD, myogenin, myf5, and MRF4. These transcription factors share 80% homology within a basic helix-loop-helix motif that mediates dimerization and DNA binding to the E-box consensus sequence (CANNTG) found in the control regions of muscle-specific genes, including the MHCIIB gene. It has been proposed that these myogenic factors are essential for development and differentiation of skeletal muscle from myoblast cells. Knockout studies in mice have shown that during murine embryogenesis, MyoD, myf5, myogenin, and MRF4 are expressed in overlapping but distinct patterns, with Myf5 and MyoD acting early to establish myoblast lineage and myogenin acting later to control differentiation. After birth, myogenic transcription factor expression decreases, but low levels of expression do persist in adult tissue, indicating a possible role in maintaining MHC phenotype and muscle remodeling in adult tissue. It has been shown that during development in rat skeletal muscle, MyoD and myogenin accumulate differentially in fast and slow muscles, suggesting that MyoD and myogenin may regulate fast and slow myosin expression, respectively. However, it has been shown previously that overexpression of myogenin in transgenic mice resulted in an increase in oxidative enzymes but no change in MHC composition. It would appear that MyoD expression is a more likely determinant of MHC phenotype than myogenin.
One tool that has been used to study the regulation of skeletal muscle fiber type is the administration of beta-2-adrenoceptor agonists such as clenbuterol that, when given chronically, have been reported to induce slow-type I to fast-type II fiber transitions, possibly by signaling through MyoD since changes in muscle fiber type have been associated with altered levels of MyoD expression.
Recently, the effects of mechanical unloading by hindlimb unweighting (HU) on the expression of myosin heavy chain (MHC) isoforms were investigated in rat soleus (SOL) muscle. In agreement with previous studies, pronounced atrophy and slow-to-fast transitions in the MHC isoform pattern were observed. These transitions in MHC protein isoforms were preceded by corresponding changes at the mRNA level. Clenbuterol (CB), a beta-2-adrenergic agonist, is known to induce muscle hypertrophy and has been shown to counteract unloading-induced atrophy. Several studies have established that CB additionally induces slow-to-fast transitions in rat SOL muscle.
An investigation studied the effects of unweighting, CB treatment, and a combination of both on three different rat muscles, SOL, extensor digitorum longus (EDL), and the red portion of the gastrocnemius (GAS) muscle. It was of interest to determine the extent of the adaptive responses of these muscles because of their different fiber type composition and their different functions. The slow SOL as well as the fast GAS are antigravity muscles. The EDL is also fast, but is a nonpostural muscle.
To investigate the plasticity of slow and fast muscles undergoing slow-to-fast transition, rat soleus (SOL), gastrocnemius (GAS), and extensor digitorum longus (EDL) muscles were exposed for 14 days to 1) unweighting by hindlimb suspension (HU), or 2) treatment with the 2-adrenergic agonist clenbuterol (CB), or 3) a combination of both (HU-CB). In general, HU elicited atrophy, CB induced hypertrophy, and HU-CB partially counteracted the HU-induced atrophy. Analyses of myosin heavy (MHC) and light chain (MLC) isoforms revealed HU- and CB-induced slow-to-fast transitions in SOL (increases of MHCIIa with small amounts of MHCIId and MHCIIb) and the upregulation of the slow MHCIa isoform. The HU- and CB-induced changes in GAS consisted of increases in MHCIId and MHCIIb ("fast-to-faster transitions"). Changes in the MLC composition of SOL and GAS consisted of slow-to-fast transitions and mainly encompassed an exchange of MLC1s with MLC1f. In addition, MLC3f was elevated whenever MHCIId and MHCIIb isoforms were increased. Because the EDL is predominantly composed of type IID and IIB fibers, HU, CB, and HU-CB had no significant effect on the MHC and MLC patterns.
Differences exist between the adaptive responses of fast and slow muscles following unweighting and CB treatment. CB induces a greater hypertrophic effect in GAS than in EDL. Although both muscles responded to unweighting with similar losses in mass (~30%), CB treatment counteracts the HU-induced atrophy more efficiently in EDL than in GAS. This difference may be related to the higher content of type I fibers in GAS than in EDL. This is consistent with other literature that CB appears to have a greater hypertrophic effect on type II fibers than on type I fibers.
SOL muscle is capable of changing its phenotype from slow to fast. HU, CB treatment, and the combination of both (HU-CB) all cause the upregulation of the fast MHCIIa and, in addition, the induction of considerable amounts of the faster MHCIId and fastest MHCIIb isoforms. These data lend support to the concept of muscle plasticity spanning from one end to the other along the spectrum of fiber types. Changes in MHC isoforms may occur as progressive slow-to-fast transitions in the order of MHCI MHCIIa MHCIId MHCIIb. Changes in MHC composition are accompanied in both muscles by similar transitions in MLC expression. The slow-to-fast changes occur in the same order established in independent studies on MHC-based fiber types for contractile properties, myosin ATPase activity, tension cost, and ATP phosphorylation potential.
The beta-2-adrenoceptor agonist fenoterol has potent anabolic effects on rat skeletal muscle. Untreated old rats exhibited a loss of skeletal muscle mass and a decrease in force-producing capacity, in both fast and slow muscles, compared with adult rats. There is no age-associated decrease in skeletal muscle beta-adrenoceptor density, nor is the muscle response to chronic beta-agonist stimulation reduced with age. Muscle mass and force-producing capacity of EDL and soleus muscles from old rats treated with fenoterol is equivalent to, or greater than, untreated adult rats. The increase in mass and strength is attributed to a non-selective increase in the cross-sectional area of all muscle fibre types, in both the EDL and soleus. Fenoterol treatment caused a small increase in fatigability due to a decrease in oxidative metabolism in both EDL and soleus muscles, with some cardiac hypertrophy.
Fenoterol is a powerful anabolic agent that can restore muscle mass and strength in old rats. An equimolar dose of clenbuterol, fenoterol has a 1015% greater anabolic effect on rat fast- (EDL) and slow- (soleus) twitch skeletal muscle.
Aging is associated with a slowing of skeletal muscle contractile properties, including a decreased rate of relaxation. In rats, the age-related decrease in the maximal rate of relaxation is reversed after 4-wk administration with the beta-2-adrenoceptor agonist fenoterol. Sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) kinetic properties were assessed in muscle homogenates and enriched SR membranes isolated from the red (RG) and white (WG) portions of the gastrocnemius muscle in adult and aged rats that had been administered fenoterol. Aging was associated with a 29% decrease in the maximal activity (Vmax) of SERCA in the RG but not in the WG muscles. Fenoterol treatment increased the Vmax of SERCA and SERCA1 protein levels in RG and WG. In the RG, fenoterol administration reversed an age-related selective nitration of the SERCA2a isoform. Findings demonstrate that the mechanisms underlying age-related changes in contractile properties are fiber type dependent, whereas the effects of fenoterol administration are independent of age and fiber type.
Beta-2-adrenoceptor agonists such as clenbuterol are known to exert anabolic effects on skeletal muscle. Long-term administration also induces a change of phenotype from slow to fast fiber type. The mechanism of these effects is unclear. One hypothesis to explain the increase in skeletal muscle mass induced by clenbuterol involves the major anabolic hormones such as insulin, growth hormone, and testosterone. However, muscle hypertrophy in response to beta-2-agonists is observed even in severely diabetic insulin-deficient as well as in hypophysectomized or castrated rats. These observations plead against the role of these classical anabolic hormones in the muscle anabolic action of clenbuterol.
The possibility that beta-2-agonists might locally stimulate the production of growth factors by skeletal muscle is suggested by the recent demonstrations showed that clenbuterol could protect cerebral tissue against ischemic damage by inducing local expression of nerve growth factor, basic fibroblast growth factor, and transforming growth factor-1. The induction of local expression of growth factors in skeletal muscle by beta-2-adrenoceptor agonists might thus mediate the anabolic effects of these drugs. In skeletal muscle, it is well established that overloading and stretch result in local production of insulin-like growth factor (IGF) I, which acts in an autocrine and paracrine manner to induce skeletal muscle hypertrophy. It has also been shown that clenbuterol does not increase the serum concentration of IGF-I. It was hypothesized that local changes in IGF-I produced by skeletal muscle could be the signaling mechanisms by which clenbuterol exerts its anabolic effect.
In a previous study, changes in muscle loading induced specific changes not only of IGF-I, but also of IGF-binding protein-4 and -5 (IGFBP-4 and -5) associated with phenotype changes, suggesting a possible role of these binding proteins in the changes of fiber types. On the other hand, thyroid hormones are known to induce a fast muscle phenotype, and triiodothyronine (T3) has been shown to act synergistically with clenbuterol to cause a profound slow-to-fast phenotype change. Clenbuterol induces in skeletal muscle a local overexpression of IGF-I, which could result from a direct effect of the drug on muscle cells. This local overexpression of IGF-I could mediate the anabolic effects of clenbuterol on skeletal muscle.
Since MyoD expression has been reported to be higher in fast muscles than in slow muscles, it is not known whether these changes in expression of MyoD following fiber type transitions are a consequence or cause of change in MHC phenotype. Furthermore, although administration of clenbuterol is known to bring about slow to fast fiber type transitions, it also causes substantial hemodynamic changes, which might preclude its use in a clinical setting. Theoretically, one way of reducing these undesirable effects would be to administer a prodrug that is metabolized to a beta-2-agonist in vivo, but it is not known if such a strategy would also reduce the phenotypic effects. BRL-47672 has a chemical structure similar to the beta-2-agonist clenbuterol but has little direct action on beta-2-adrenoceptors. In vitro BRL-47672 had a low affinity for rat beta-2-adrenoceptors compared with clenbuterol and was a poor activator of rat adenylyl cyclase activity in rat skeletal muscle. Conversely, acute administration in vivo resulted in increased adenylyl cyclase activation and, over 6 days of administration, an increase in skeletal muscle mass. Furthermore, these anabolic effects of BRL-47672 were not blocked by daily injection of the beta-2-adrenoceptor-selective antagonist ICI-118551 but were blocked when ICI-118551 was administered in the diet. The addition of the 1-adrenoceptor-selective antagonist CGP-20712A to the diet failed to dampen the anabolic effects of BRL-47672. This led us to conclude that BRL-47672 has little direct action on beta-2-adrenoceptors per se but is metabolized rapidly in vivo to a potent beta-2-agonist. BRL-47672 was a less potent stimulator of heart rate than clenbuterol, which seems logical given its reported lack of direct effect on beta-2-adrenoceptors. On the basis of these observations it is not unreasonable to infer that chronic administration of BRL-47672 would influence cell signaling pathways associated with skeletal muscle mass and fiber type in the rat in a manner similar to clenbuterol while having a comparatively attenuated hemodynamic effect.
To assess to what extent the use of BRL-47672 minimized cardiovascular effects, its hemodynamic actions were compared with those of clenbuterol. The effect of BRL-47672 on heart rate, mean arterial blood pressure, and hindquarters vascular conductance was significantly less than that of clenbuterol. The acute and chronic effects of administration of BRL-47672, the prodrug of the beta-2-adrenoceptor agonist clenbuterol, was examined on MHC and MyoD transcription factor expression to determine whether or not changes in MHC composition are preceded by changes in MyoD protein expression. These data suggest that increased expression of fast-type MHCIIA expression in rat SOL induced by BRL-47672 administration is preceded by up-regulation of the transcription factor, MyoD. BRL-47672 induced MHC remodeling to the same extent as clenbuterol, but with lesser cardiovascular effects.
Skeletal muscle contains three major pathways of protein degradation: a lysosomal pathway, a calcium-dependent pathway, and an ATP-dependent ubiquitin-proteasome pathway. Of the three, the ubiquitin-proteasome pathway is responsible for the bulk of muscle proteolysis, including the major contractile proteins actin and myosin. It is important that this system also degrades damaged proteins after oxidative stress since HU has been shown to increase oxidative stress and to decrease antioxidant capacity in skeletal muscle.
Ubiquitin-Proteasome Pathway - Intracellular proteolytic systems recognize and destroy misfolded or damaged proteins, unassembled polypeptide chains, and short-lived regulatory proteins. There are several mechanisms for protein degradation within cells. Two systems that play important roles in proteolysis resulting from cell stress are the calpain proteases and the ubiquitin-proteasome pathway. The ubiquitin-proteasome pathway functions widely in intracellular protein turnover. It plays a central role in degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen processing and presentation. The pathway employs an enzymatic cascade by which multiple ubiquitin molecules are covalently attached to the protein substrate. The polyubiquitin modification marks the protein for destruction and directs it to the 26S proteasome complex for degradation.
Adrenergic agonists such as clenbuterol (CB) induce muscle hypertrophy and attenuate muscle atrophy due to disuse or inactivity. These results suggest that CB induces hypertrophy and alleviates HU-induced atrophy, particularly in the fast muscles, at least in part through a muscle-specific inhibition of the ubiquitin-proteasome pathway and that these effects are not mediated by the local production of IGF-I in skeletal muscle.
Hindlimb unweighting (HU) is often used to model the effects of disuse and microgravity on skeletal muscle. HU causes severe muscle atrophy, especially in muscles composed primarily of slow fibers, and the precise mechanism causing the atrophy remains unclear. HU causes muscle atrophy mainly by increasing the rate of protein degradation, although a decrease in protein synthesis also occurs. CB is a beta-2-adrenergic agonist with growth-promoting properties that cause increases in muscle mass and reduction in muscle atrophy attributable to muscular dystrophy, denervation, and hindlimb suspension.
A mediator of the action of CB may be IGF-I. Although IGF-I is known to play a pivotal role in myogenesis and postnatal skeletal muscle growth through its stimulation of protein synthesis, it is not known whether IGF-I is a mediator of CB-induced muscle hypertrophy. Recently, it has been shown that CB administration to rats caused a transient increase in muscle IGF-I protein content and that IGF-I inhibits protein degradation both in vivo and in vitro, possibly by suppressing the upregulation of several components of the ubiquitin-proteasome pathway.
It remains that the molecular mechanism by which CB exerts effects remains poorly understood. HU-induced muscle atrophy is associated with increased activity of the ubiquitin-proteasome system in both slow- and fast-twitch muscle, although to a different degree. Upregulation of the ubiquitin proteasome occurred in all HU-induced muscles tested but was more pronounced in muscles composed primarily of slow-twitch fibers (soleus) than in fast-twitch muscles (plantaris - PA and tibialis anterior - TA). CB treatment attenuated these effects by reducing the activation of ubiquitin-proteasome proteolysis in the predominantly fast-twitch PA and TA but not in the slow-twitch Sol. CB did not elevate IGF-I protein content in either of the muscles examined. These results suggest that CB induces hypertrophy and alleviates HU-induced atrophy, particularly in the fast muscles, at least in part through a muscle-specific inhibition of the ubiquitin-proteasome pathway and that these effects are not mediated by the local production of IGF-I in skeletal muscle.
Mike
Clenbuterol is a beta-2 adrenergic agonist with some similarities to ephedrine, but its effects are more potent and longer-lasting as a stimulant and thermogenic drug. Clenbuterol is lipophilic and is known to have direct intracellular actions. It is commonly used for smooth muscle relaxant properties. Clenbuterol is commonly prescribed to sufferers of breathing disorders as a decongestant and bronchodilator. People with chronic breathing disorders like asthma use this as a bronchodilator to make breathing easier. It causes an increase in aerobic capacity, CNS stimulation, and an increase in blood pressure and oxygen transportation. It increases the rate at which fat and protein is used up in the body at the same time as slowing down the storage of glycogen.
Traditionally administered locally (by inhalation) at low doses for bronchodilatation in the treatment of asthma, when given at higher doses, systemically, 2-adrenoceptor agonists have potent anabolic effects in healthy muscle. The anabolic effects of clenbuterol administration have previously been shown to be beta-2-AR mediated. Clenbuterols anabolic effects have demonstrated a dose-response relationship between clenbuterol and muscle hypertrophy. The anabolic and lipolytic effects of the beta-2-adrenergic receptor (AR) agonist clenbuterol have been widely investigated in a variety of sedentary laboratory and livestock animals. Clenbuterol administration has been shown to be beneficial in some animal models of Duchenne muscular dystrophy but not in others. Scientific investigations into the effects of clenbuterol in humans are far less numerous than those pertaining to livestock or laboratory animals.
Not surprisingly, the anabolic and lipolytic (i.e., repartitioning) effects of clenbuterol have attracted the attention of many athletes. Bodybuilders in particular take high doses of this beta-2-AR agonist. The protocol for determining an individual's optimal dose is crude and involves ever-increasing daily doses until the side effects can no longer be tolerated. The doses employed vary widely, with men being better able than women to tolerate the side effects, which include tachycardia, hypokalemia, arrhythmia, muscle cramps, and muscle tremors. An average daily dose for males can be eight tablets or ~2 g clenbuterol/kg body wt. In addition, because of its lack of androgenic side effects, clenbuterol is also popular among sedentary as well as athletic women for use as a repartitioning agent. Case reports include body builders who present with tachycardia, myocardial infarction, and end-stage renal disease. Clenbuterol is banned by the World Anti-Doping Agency.
Ageing is associated with a progressive loss of skeletal muscle mass (sarcopenia) and a subsequent decline in muscle strength. Progressive muscle fibre denervation, a loss of motor units, and potential motor unit remodeling have been implicated, but since the slowing of contraction occurs before significant muscle wasting, intrinsic changes to skeletal muscle fibres, including excitationcontraction coupling, cannot be ruled out.
Developing therapeutic interventions to prevent or reverse the age-related decline in function is of increasing importance. Many elderly people require the use of all their muscle strength to complete simple tasks such as rising from a chair, and any further impairment in muscle function (such as that following extended bed rest after surgery) can result in a loss of functional independence.
Associated with normal ageing is a decrease in the circulating levels of anabolic hormones, including, but not limited to: growth hormone (GH), insulin, insulin-like growth factor I (IGF-I), and testosterone. These hormonal changes are thought to be responsible, at least in part, for the age-related loss of muscle mass and strength. Numerous clinical studies have tried increasing the circulating levels of one or more of these hormones, with the aim of increasing muscle mass and strength. However, to date, hormone replacement therapy has produced mixed success in humans. Studies reporting on the effects of testosterone and testosterone precursor supplementation on muscle mass and strength have produced equivocal results in elderly human subjects. Whereas testosterone has been shown to increase muscle strength in hypogonadal elderly men, testosterone administration to elderly men with normal testosterone levels was associated with an increased risk of polycythemia. Furthermore, testosterone treatment for elderly women may be inappropriate due to the masculinizing effects of androgens.
Several studies have postulated that GH and (or) IGF-I administration may prevent the muscle wasting associated with ageing. To date, GH supplementation has been shown to alter body composition by decreasing body fat mass and increasing lean body mass in elderly men. However, GH did not augment muscle strength or produce muscle hypertrophy. The administration or up-regulation of IGF-I has proven more promising in a number of animal models of pathologies where muscle wasting is indicated, but there is concern that elevated levels of IGF-I may be implicated in tumour formation. Both GH and IGF-I are expensive therapies that must be given daily. These findings suggest that hormone replacement alone has limited therapeutic efficacy for treating sarcopenia in the frail elderly. In the absence of successful hormone replacement therapies, muscle anabolic agents have been used in an attempt to treat sarcopenia.
Clenbuterol is used as an adjunct to ventricular assist devices. Their experimental use in the treatment for muscle wasting conditions has also yielded promising results that are dose dependent. It has been shown to have some therapeutic potential in speeding up the rehabilitation of postoperative muscle wasting in humans and has been proposed for the pharmacological amelioration of cachexia in chronic diseases such as cancer and Duchenne muscular dystrophy.
The diversity of skeletal muscle fiber types, defined by the expression of particular myosin heavy chain (MHC) isoforms, is believed to be due to a combination of distinct myoblast lineage and extrinsic factors. Postnatally, however, exogenous factors such as innervation, neuromuscular activity, and hormone levels (e.g., thyroid hormone) become the main determinants of fiber type, and fiber type transitions can occur due to altered expression of MHC isoforms. Transitions of fiber type in adult skeletal muscle have also been reported in humans during aging, where the decline in both number and size of fast fiber types could contribute to the impaired muscle function reported in the elderly population, and in disease states such as chronic obstructive pulmonary disease and heart failure.
Skeletal muscle has the capacity to change its phenotype, not only in response to altered functional demands, but also under the influence of specific growth factors and hormones. As shown in numerous studies, increased neuromuscular activity and loading both elicit fast-to-slow transitions and decreased neuromuscular activity, and unloading cause transitions in the reverse direction. The intracellular mechanisms that regulate changes in postnatal myosin heavy chain (MHC) expression are not well established.
Understanding of the determination and differentiation of muscle fiber type has been advanced with the discovery of a family of myogenic regulatory factors (MRFs), namely, MyoD, myogenin, myf5, and MRF4. These transcription factors share 80% homology within a basic helix-loop-helix motif that mediates dimerization and DNA binding to the E-box consensus sequence (CANNTG) found in the control regions of muscle-specific genes, including the MHCIIB gene. It has been proposed that these myogenic factors are essential for development and differentiation of skeletal muscle from myoblast cells. Knockout studies in mice have shown that during murine embryogenesis, MyoD, myf5, myogenin, and MRF4 are expressed in overlapping but distinct patterns, with Myf5 and MyoD acting early to establish myoblast lineage and myogenin acting later to control differentiation. After birth, myogenic transcription factor expression decreases, but low levels of expression do persist in adult tissue, indicating a possible role in maintaining MHC phenotype and muscle remodeling in adult tissue. It has been shown that during development in rat skeletal muscle, MyoD and myogenin accumulate differentially in fast and slow muscles, suggesting that MyoD and myogenin may regulate fast and slow myosin expression, respectively. However, it has been shown previously that overexpression of myogenin in transgenic mice resulted in an increase in oxidative enzymes but no change in MHC composition. It would appear that MyoD expression is a more likely determinant of MHC phenotype than myogenin.
One tool that has been used to study the regulation of skeletal muscle fiber type is the administration of beta-2-adrenoceptor agonists such as clenbuterol that, when given chronically, have been reported to induce slow-type I to fast-type II fiber transitions, possibly by signaling through MyoD since changes in muscle fiber type have been associated with altered levels of MyoD expression.
Recently, the effects of mechanical unloading by hindlimb unweighting (HU) on the expression of myosin heavy chain (MHC) isoforms were investigated in rat soleus (SOL) muscle. In agreement with previous studies, pronounced atrophy and slow-to-fast transitions in the MHC isoform pattern were observed. These transitions in MHC protein isoforms were preceded by corresponding changes at the mRNA level. Clenbuterol (CB), a beta-2-adrenergic agonist, is known to induce muscle hypertrophy and has been shown to counteract unloading-induced atrophy. Several studies have established that CB additionally induces slow-to-fast transitions in rat SOL muscle.
An investigation studied the effects of unweighting, CB treatment, and a combination of both on three different rat muscles, SOL, extensor digitorum longus (EDL), and the red portion of the gastrocnemius (GAS) muscle. It was of interest to determine the extent of the adaptive responses of these muscles because of their different fiber type composition and their different functions. The slow SOL as well as the fast GAS are antigravity muscles. The EDL is also fast, but is a nonpostural muscle.
To investigate the plasticity of slow and fast muscles undergoing slow-to-fast transition, rat soleus (SOL), gastrocnemius (GAS), and extensor digitorum longus (EDL) muscles were exposed for 14 days to 1) unweighting by hindlimb suspension (HU), or 2) treatment with the 2-adrenergic agonist clenbuterol (CB), or 3) a combination of both (HU-CB). In general, HU elicited atrophy, CB induced hypertrophy, and HU-CB partially counteracted the HU-induced atrophy. Analyses of myosin heavy (MHC) and light chain (MLC) isoforms revealed HU- and CB-induced slow-to-fast transitions in SOL (increases of MHCIIa with small amounts of MHCIId and MHCIIb) and the upregulation of the slow MHCIa isoform. The HU- and CB-induced changes in GAS consisted of increases in MHCIId and MHCIIb ("fast-to-faster transitions"). Changes in the MLC composition of SOL and GAS consisted of slow-to-fast transitions and mainly encompassed an exchange of MLC1s with MLC1f. In addition, MLC3f was elevated whenever MHCIId and MHCIIb isoforms were increased. Because the EDL is predominantly composed of type IID and IIB fibers, HU, CB, and HU-CB had no significant effect on the MHC and MLC patterns.
Differences exist between the adaptive responses of fast and slow muscles following unweighting and CB treatment. CB induces a greater hypertrophic effect in GAS than in EDL. Although both muscles responded to unweighting with similar losses in mass (~30%), CB treatment counteracts the HU-induced atrophy more efficiently in EDL than in GAS. This difference may be related to the higher content of type I fibers in GAS than in EDL. This is consistent with other literature that CB appears to have a greater hypertrophic effect on type II fibers than on type I fibers.
SOL muscle is capable of changing its phenotype from slow to fast. HU, CB treatment, and the combination of both (HU-CB) all cause the upregulation of the fast MHCIIa and, in addition, the induction of considerable amounts of the faster MHCIId and fastest MHCIIb isoforms. These data lend support to the concept of muscle plasticity spanning from one end to the other along the spectrum of fiber types. Changes in MHC isoforms may occur as progressive slow-to-fast transitions in the order of MHCI MHCIIa MHCIId MHCIIb. Changes in MHC composition are accompanied in both muscles by similar transitions in MLC expression. The slow-to-fast changes occur in the same order established in independent studies on MHC-based fiber types for contractile properties, myosin ATPase activity, tension cost, and ATP phosphorylation potential.
The beta-2-adrenoceptor agonist fenoterol has potent anabolic effects on rat skeletal muscle. Untreated old rats exhibited a loss of skeletal muscle mass and a decrease in force-producing capacity, in both fast and slow muscles, compared with adult rats. There is no age-associated decrease in skeletal muscle beta-adrenoceptor density, nor is the muscle response to chronic beta-agonist stimulation reduced with age. Muscle mass and force-producing capacity of EDL and soleus muscles from old rats treated with fenoterol is equivalent to, or greater than, untreated adult rats. The increase in mass and strength is attributed to a non-selective increase in the cross-sectional area of all muscle fibre types, in both the EDL and soleus. Fenoterol treatment caused a small increase in fatigability due to a decrease in oxidative metabolism in both EDL and soleus muscles, with some cardiac hypertrophy.
Fenoterol is a powerful anabolic agent that can restore muscle mass and strength in old rats. An equimolar dose of clenbuterol, fenoterol has a 1015% greater anabolic effect on rat fast- (EDL) and slow- (soleus) twitch skeletal muscle.
Aging is associated with a slowing of skeletal muscle contractile properties, including a decreased rate of relaxation. In rats, the age-related decrease in the maximal rate of relaxation is reversed after 4-wk administration with the beta-2-adrenoceptor agonist fenoterol. Sarcoendoplasmic reticulum Ca2+-ATPase (SERCA) kinetic properties were assessed in muscle homogenates and enriched SR membranes isolated from the red (RG) and white (WG) portions of the gastrocnemius muscle in adult and aged rats that had been administered fenoterol. Aging was associated with a 29% decrease in the maximal activity (Vmax) of SERCA in the RG but not in the WG muscles. Fenoterol treatment increased the Vmax of SERCA and SERCA1 protein levels in RG and WG. In the RG, fenoterol administration reversed an age-related selective nitration of the SERCA2a isoform. Findings demonstrate that the mechanisms underlying age-related changes in contractile properties are fiber type dependent, whereas the effects of fenoterol administration are independent of age and fiber type.
Beta-2-adrenoceptor agonists such as clenbuterol are known to exert anabolic effects on skeletal muscle. Long-term administration also induces a change of phenotype from slow to fast fiber type. The mechanism of these effects is unclear. One hypothesis to explain the increase in skeletal muscle mass induced by clenbuterol involves the major anabolic hormones such as insulin, growth hormone, and testosterone. However, muscle hypertrophy in response to beta-2-agonists is observed even in severely diabetic insulin-deficient as well as in hypophysectomized or castrated rats. These observations plead against the role of these classical anabolic hormones in the muscle anabolic action of clenbuterol.
The possibility that beta-2-agonists might locally stimulate the production of growth factors by skeletal muscle is suggested by the recent demonstrations showed that clenbuterol could protect cerebral tissue against ischemic damage by inducing local expression of nerve growth factor, basic fibroblast growth factor, and transforming growth factor-1. The induction of local expression of growth factors in skeletal muscle by beta-2-adrenoceptor agonists might thus mediate the anabolic effects of these drugs. In skeletal muscle, it is well established that overloading and stretch result in local production of insulin-like growth factor (IGF) I, which acts in an autocrine and paracrine manner to induce skeletal muscle hypertrophy. It has also been shown that clenbuterol does not increase the serum concentration of IGF-I. It was hypothesized that local changes in IGF-I produced by skeletal muscle could be the signaling mechanisms by which clenbuterol exerts its anabolic effect.
In a previous study, changes in muscle loading induced specific changes not only of IGF-I, but also of IGF-binding protein-4 and -5 (IGFBP-4 and -5) associated with phenotype changes, suggesting a possible role of these binding proteins in the changes of fiber types. On the other hand, thyroid hormones are known to induce a fast muscle phenotype, and triiodothyronine (T3) has been shown to act synergistically with clenbuterol to cause a profound slow-to-fast phenotype change. Clenbuterol induces in skeletal muscle a local overexpression of IGF-I, which could result from a direct effect of the drug on muscle cells. This local overexpression of IGF-I could mediate the anabolic effects of clenbuterol on skeletal muscle.
Since MyoD expression has been reported to be higher in fast muscles than in slow muscles, it is not known whether these changes in expression of MyoD following fiber type transitions are a consequence or cause of change in MHC phenotype. Furthermore, although administration of clenbuterol is known to bring about slow to fast fiber type transitions, it also causes substantial hemodynamic changes, which might preclude its use in a clinical setting. Theoretically, one way of reducing these undesirable effects would be to administer a prodrug that is metabolized to a beta-2-agonist in vivo, but it is not known if such a strategy would also reduce the phenotypic effects. BRL-47672 has a chemical structure similar to the beta-2-agonist clenbuterol but has little direct action on beta-2-adrenoceptors. In vitro BRL-47672 had a low affinity for rat beta-2-adrenoceptors compared with clenbuterol and was a poor activator of rat adenylyl cyclase activity in rat skeletal muscle. Conversely, acute administration in vivo resulted in increased adenylyl cyclase activation and, over 6 days of administration, an increase in skeletal muscle mass. Furthermore, these anabolic effects of BRL-47672 were not blocked by daily injection of the beta-2-adrenoceptor-selective antagonist ICI-118551 but were blocked when ICI-118551 was administered in the diet. The addition of the 1-adrenoceptor-selective antagonist CGP-20712A to the diet failed to dampen the anabolic effects of BRL-47672. This led us to conclude that BRL-47672 has little direct action on beta-2-adrenoceptors per se but is metabolized rapidly in vivo to a potent beta-2-agonist. BRL-47672 was a less potent stimulator of heart rate than clenbuterol, which seems logical given its reported lack of direct effect on beta-2-adrenoceptors. On the basis of these observations it is not unreasonable to infer that chronic administration of BRL-47672 would influence cell signaling pathways associated with skeletal muscle mass and fiber type in the rat in a manner similar to clenbuterol while having a comparatively attenuated hemodynamic effect.
To assess to what extent the use of BRL-47672 minimized cardiovascular effects, its hemodynamic actions were compared with those of clenbuterol. The effect of BRL-47672 on heart rate, mean arterial blood pressure, and hindquarters vascular conductance was significantly less than that of clenbuterol. The acute and chronic effects of administration of BRL-47672, the prodrug of the beta-2-adrenoceptor agonist clenbuterol, was examined on MHC and MyoD transcription factor expression to determine whether or not changes in MHC composition are preceded by changes in MyoD protein expression. These data suggest that increased expression of fast-type MHCIIA expression in rat SOL induced by BRL-47672 administration is preceded by up-regulation of the transcription factor, MyoD. BRL-47672 induced MHC remodeling to the same extent as clenbuterol, but with lesser cardiovascular effects.
Skeletal muscle contains three major pathways of protein degradation: a lysosomal pathway, a calcium-dependent pathway, and an ATP-dependent ubiquitin-proteasome pathway. Of the three, the ubiquitin-proteasome pathway is responsible for the bulk of muscle proteolysis, including the major contractile proteins actin and myosin. It is important that this system also degrades damaged proteins after oxidative stress since HU has been shown to increase oxidative stress and to decrease antioxidant capacity in skeletal muscle.
Ubiquitin-Proteasome Pathway - Intracellular proteolytic systems recognize and destroy misfolded or damaged proteins, unassembled polypeptide chains, and short-lived regulatory proteins. There are several mechanisms for protein degradation within cells. Two systems that play important roles in proteolysis resulting from cell stress are the calpain proteases and the ubiquitin-proteasome pathway. The ubiquitin-proteasome pathway functions widely in intracellular protein turnover. It plays a central role in degradation of short-lived and regulatory proteins important in a variety of basic cellular processes, including regulation of the cell cycle, modulation of cell surface receptors and ion channels, and antigen processing and presentation. The pathway employs an enzymatic cascade by which multiple ubiquitin molecules are covalently attached to the protein substrate. The polyubiquitin modification marks the protein for destruction and directs it to the 26S proteasome complex for degradation.
Adrenergic agonists such as clenbuterol (CB) induce muscle hypertrophy and attenuate muscle atrophy due to disuse or inactivity. These results suggest that CB induces hypertrophy and alleviates HU-induced atrophy, particularly in the fast muscles, at least in part through a muscle-specific inhibition of the ubiquitin-proteasome pathway and that these effects are not mediated by the local production of IGF-I in skeletal muscle.
Hindlimb unweighting (HU) is often used to model the effects of disuse and microgravity on skeletal muscle. HU causes severe muscle atrophy, especially in muscles composed primarily of slow fibers, and the precise mechanism causing the atrophy remains unclear. HU causes muscle atrophy mainly by increasing the rate of protein degradation, although a decrease in protein synthesis also occurs. CB is a beta-2-adrenergic agonist with growth-promoting properties that cause increases in muscle mass and reduction in muscle atrophy attributable to muscular dystrophy, denervation, and hindlimb suspension.
A mediator of the action of CB may be IGF-I. Although IGF-I is known to play a pivotal role in myogenesis and postnatal skeletal muscle growth through its stimulation of protein synthesis, it is not known whether IGF-I is a mediator of CB-induced muscle hypertrophy. Recently, it has been shown that CB administration to rats caused a transient increase in muscle IGF-I protein content and that IGF-I inhibits protein degradation both in vivo and in vitro, possibly by suppressing the upregulation of several components of the ubiquitin-proteasome pathway.
It remains that the molecular mechanism by which CB exerts effects remains poorly understood. HU-induced muscle atrophy is associated with increased activity of the ubiquitin-proteasome system in both slow- and fast-twitch muscle, although to a different degree. Upregulation of the ubiquitin proteasome occurred in all HU-induced muscles tested but was more pronounced in muscles composed primarily of slow-twitch fibers (soleus) than in fast-twitch muscles (plantaris - PA and tibialis anterior - TA). CB treatment attenuated these effects by reducing the activation of ubiquitin-proteasome proteolysis in the predominantly fast-twitch PA and TA but not in the slow-twitch Sol. CB did not elevate IGF-I protein content in either of the muscles examined. These results suggest that CB induces hypertrophy and alleviates HU-induced atrophy, particularly in the fast muscles, at least in part through a muscle-specific inhibition of the ubiquitin-proteasome pathway and that these effects are not mediated by the local production of IGF-I in skeletal muscle.
Mike
Mike,
Despite the enormous body of evidence that clenbutertol is anabolic in animals the data in humans are scanty.
My clen days are over!
J Appl Physiol. 2004 Dec 10; [Epub ahead of print] Related Articles, Links
{beta}2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle.
Burniston JG, Tan LB, Goldspink DF.
Research Institute for Sports and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom.
High doses of the beta2-adrenergic receptor (AR) agonist, clenbuterol, can induce necrotic myocyte death in the heart and slow-twitch skeletal muscle of the rat. However, it is not known if this agent can also induce myocyte apoptosis and whether this would occur at a lower dose than previously reported for myocyte necrosis. Male Wistar rats were given single subcutaneous injections of clenbuterol. Immunohistochemistry was used to detect myocyte specific apoptosis (detected on cryosections using a caspase 3 antibody and confirmed using annexin V, single-strand DNA labelling and TUNEL). Myocyte apoptosis was first detected at 2 h, and peaked 4 h after clenbuterol administration. The lowest dose of clenbuterol to induce cardiomyocyte apoptosis was 1 microg kg(-1), with peak apoptosis (0.35 +/- 0.005 %; P<0.05) occurring in response to 5 mg kg(-1) . In the soleus, peak apoptosis (5.8 +/- 2 %; P<0.05) was induced by the lower dose of 10 microg kg(-1). Cardiomyocyte apoptosis occurred throughout the ventricles, atria and papillary muscles. However, this damage was most abundant in the left ventricular subendocardium at a point 1.6 mm, that is, approximately one-quarter of the way from the apex towards the base. beta-AR antagonism (involving propranolol, bisoprolol or ICI 118,551) or reserpine was used to show that clenbuterol-induced myocardial apoptosis was mediated through neuromodulation of the sympathetic system and the cardiomyocyte beta1-AR, whereas in the soleus direct stimulation of the myocyte beta2-AR was involved. These data show that when administered in vivo, beta2-AR stimulation by clenbuterol is detrimental to cardiac and skeletal muscles even at low doses, by inducing apoptosis through beta1- and beta2-AR, respectively
Dustin
Despite the enormous body of evidence that clenbutertol is anabolic in animals the data in humans are scanty.
My clen days are over!
J Appl Physiol. 2004 Dec 10; [Epub ahead of print] Related Articles, Links
{beta}2-Adrenergic receptor stimulation in vivo induces apoptosis in the rat heart and soleus muscle.
Burniston JG, Tan LB, Goldspink DF.
Research Institute for Sports and Exercise Sciences, Liverpool John Moores University, Liverpool, United Kingdom.
High doses of the beta2-adrenergic receptor (AR) agonist, clenbuterol, can induce necrotic myocyte death in the heart and slow-twitch skeletal muscle of the rat. However, it is not known if this agent can also induce myocyte apoptosis and whether this would occur at a lower dose than previously reported for myocyte necrosis. Male Wistar rats were given single subcutaneous injections of clenbuterol. Immunohistochemistry was used to detect myocyte specific apoptosis (detected on cryosections using a caspase 3 antibody and confirmed using annexin V, single-strand DNA labelling and TUNEL). Myocyte apoptosis was first detected at 2 h, and peaked 4 h after clenbuterol administration. The lowest dose of clenbuterol to induce cardiomyocyte apoptosis was 1 microg kg(-1), with peak apoptosis (0.35 +/- 0.005 %; P<0.05) occurring in response to 5 mg kg(-1) . In the soleus, peak apoptosis (5.8 +/- 2 %; P<0.05) was induced by the lower dose of 10 microg kg(-1). Cardiomyocyte apoptosis occurred throughout the ventricles, atria and papillary muscles. However, this damage was most abundant in the left ventricular subendocardium at a point 1.6 mm, that is, approximately one-quarter of the way from the apex towards the base. beta-AR antagonism (involving propranolol, bisoprolol or ICI 118,551) or reserpine was used to show that clenbuterol-induced myocardial apoptosis was mediated through neuromodulation of the sympathetic system and the cardiomyocyte beta1-AR, whereas in the soleus direct stimulation of the myocyte beta2-AR was involved. These data show that when administered in vivo, beta2-AR stimulation by clenbuterol is detrimental to cardiac and skeletal muscles even at low doses, by inducing apoptosis through beta1- and beta2-AR, respectively
Dustin
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srch4info
New Member
I never even would have though about Clen except that in my search for some fat loss products/info Clen keeps popping up... now I am more than intrigued but I am also more than a little scared by this product.
I do have a few questions to start:
Is the study that Dustin has referenced an absolute, indesputable, definitive study? I mean after all we all read conflicting studies about everything from caffeine to aspirin.
I am 47y/o, 5'8", 162#'s, 21% BF I recently started TRT and have been on Androgel 5G/day for the last 65 days. I am in good health but do not work out(I used to work out HARD but got lazy and way too busy) although I just started to walk and will be doing some cardio soon. Can I do Clen while on TRT without screwing things up?
How much fat can a person (me) expect to lose? Over what period of time?
This thread references ECA stacks but where can you get an ECA stack now?
I do have a few questions to start:
Is the study that Dustin has referenced an absolute, indesputable, definitive study? I mean after all we all read conflicting studies about everything from caffeine to aspirin.
I am 47y/o, 5'8", 162#'s, 21% BF I recently started TRT and have been on Androgel 5G/day for the last 65 days. I am in good health but do not work out(I used to work out HARD but got lazy and way too busy) although I just started to walk and will be doing some cardio soon. Can I do Clen while on TRT without screwing things up?
How much fat can a person (me) expect to lose? Over what period of time?
This thread references ECA stacks but where can you get an ECA stack now?
try working out! why take a chance with clen, that is the issue. is it worth getting permanent heart damage because you are too lazy to work out and diet? it is all about informed choices, having been made aware of the risks have yo researched it more and weighed the possible downsides with the possible benefits? If the risk is worth it to you then go for it.
jb
jb
srch4info said:
Connections between myocardial -adrenergic signaling and apoptosis are well established.
Muller FU, Neumann J, Schmitz W. Transcriptional regulation by cAMP in the heart. Mol Cell Biochem. 2000; 212: 1117
Adams JW, Brown JH. G-proteins in growth and apoptosis: lessons from the heart. Oncogene. 2001; 20: 16261634
Dustin
MANWHORE
Subscriber
I am getting it for many around my way but i'm also getting Winny for many which is not used by those i know .. or have been in the game very long which Mast and Tren being out there .. I believe Clen is anabolic in Animals but not so much in humans just like it effects the heart receptors in humans and not animals because they have less Beta .. All in All,i say YES it is effective for fat loss when keeping off AAS just not sure how much more or less compaired to Ephedrine .. I wish i could cap that stuff up because i'd make a fortune .. Just to small a weight and i'm not into geting it in a solution right nowJBF said:
I'd just like to iterate that taking ECA during your off-weeks is a stupid idea if you're trying to give your beta receptors a chance to upregulate after the clen.TestFreak said:
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