1. #1
    MuscleChemistry Newbie Residency Training

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    Default Where to buy sr9009?

    Do either the supplement outlet or musclechem advanced supps carry it?


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    No neither TheSupplementOutlet.com or MCAS carry it. I'm not sure where to get it but i will look

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    Default Where to buy sr9009?

    Thanks. There seems to be 2 sites that sell them, geopeptides and SARMspharm, but there doesn't seem to be much info on them.
    If prefer to get it from someone like you guys, where I know it's legit!


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    RND Solutions: "Stenabolic-SR9" 30ml x 20mg/ml

    Now Only $55

    Minimum Purchase Of 2 Bottles


    https://www.musclechemadvancedsupps....products_id=94

    A decent Stenabolic profile, for oral and injectable versions
    Stenabolic Sr9009
    Where to buy sr9009?

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    Bumping to the top
    Where to buy sr9009?

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    Mimicking Exercise

    Regular physical exercise activates a number of molecular pathways in whole organ systems and reduces the risk of developing numerous chronic diseases (Figure 1A). Although nothing can fully substitute for physical exercise, candidate exercise pills that have emerged in recent years [13
    , 14
    , 15
    , 16
    , 17
    , 18
    , 19
    ] may be an attractive alternative for people who are unable to undertake regular exercise because of medical conditions such as obesity, amputations, spinal injuries, metabolic diseases, and musculoskeletal or cardiovascular conditions. The signaling molecules activated by physical exercise are logically considered to be potent pharmacological targets for such exercise pills.
    Figure 1Proposed Molecular Mechanisms and Beneficial Effects of Physical Exercise and Candidate Exercise Pills. The middle panel (A) indicates some molecular pathways activated by regular (conventional) physical exercise and the resultant beneficial effects, such as mitochondrial biogenesis, oxidative fiber-type transformation, improved fatty acid oxidation, angiogenesis, and increased exercise capacity. (B) None of the candidate exercise pills fully mimics the full palette of the beneficial effects of exercise, but each exercise pill can activate distinct as well as overlapping target transcriptional regulators that partly mimic the beneficial effects induced by exercise. Note that GW501516 (B2) by itself is unable to enhance endurance performance and has synergistic effects when combined with either exercise or AICAR; the combination induces mitochondrial biogenesis and fiber-type transformation and improves exercise capacity. In addition, irisin (B6), as a PGC-1α-dependent myokine, stimulates browning of white fat, consequently enhancing thermogenesis and total body energy expenditure. Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; SIRT1, silent information regulation T1; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; ERRs, estrogen-related receptors; PPARs, peroxisome proliferator-activated receptors; eNOS, endothelial nitric oxide synthase; NO, nitric oxide.





    ‘Exercise pills’ are active compounds that mimic the biochemical and functional effects of regular exercise, such as oxidative fiber-type transformation, mitochondrial biogenesis, improved fatty acid oxidation, angiogenesis, and increased exercise capacity. The concept of ‘exercise pills’ was first introduced by Himms-Hagen in 2004 [20
    ], followed by Narkar and colleagues [14
    ] who suggested that some molecules could mimic the effects of exercise training. Many subsequent studies have explored the development of exercise pills, and currently described potential exercise pills are listed in Table 1. Next, we briefly discuss the supporting evidence and proposed mechanisms for candidate exercise pills.Table 1Current Candidate Exercise Pills
    Compound Category Target Organ Molecular Target Functional Changes Refs
    AICAR AMPK agonist Skeletal muscle AMPK Fiber-type reformation
    Mitochondrial biogenesis
    [14
    , 21
    , 22
    , 23
    , 24
    , 25
    , 26
    , 27
    , 28
    , 29
    , 30
    , 31
    , 32
    , 33
    , 34
    , 35
    , 36
    , 37
    , 38
    , 39
    , 40
    ]
    GW501516 PPARδ agonist Skeletal muscle PPARδ Fiber-type reformation
    Mitochondrial biogenesis
    [14
    , 41
    , 42
    , 43
    , 44
    , 45
    , 46
    , 47
    , 48
    , 49
    ]
    GSK4716 ERR agonist Skeletal muscle ERRγ Mitochondrial biogenesis
    Fiber-type reformation
    angiogenesis
    [15
    , 50
    , 51
    ]
    SR9009 REV-ERB agonist Skeletal muscle REV-ERBα Mitochondrial biogenesis
    Improved energy metabolism
    [18
    , 52
    , 53
    , 54
    , 55
    , 56
    ]
    MOTS-c Mitokine Skeletal muscle AMPK Maintaining metabolic hemostasis
    Restore insulin sensitivity
    [19
    , 57
    ]
    Irisin Myokine Adipose tissue PGC-1α Thermogenesis
    Enhanced energy expenditure
    [17
    , 58
    , 59
    , 60
    , 61
    , 62
    , 63
    , 64
    , 65
    , 66
    , 67
    , 68
    , 69
    , 70
    , 71
    , 72
    , 73
    , 74
    , 75
    ]
    (–)-Epicatechin Phytochemical Skeletal and cardiac muscle NO Mitochondrial biogenesis
    Increased capillaries
    [16
    , 76
    , 77
    , 78
    , 79
    , 80
    , 81
    , 82
    , 83
    , 84
    , 85
    ]
    Resveratrol Phytochemical Cardiovascular PGC-1α/NO Mitochondrial biogenesis
    Angiogenesis
    [13
    , 86
    , 87
    , 88
    , 89
    , 90
    , 91
    , 92
    , 93
    , 94
    , 95
    , 96
    , 97
    , 98
    , 99
    , 100
    , 101
    ]







    Candidate Exercise Pills

    AICAR

    AICAR, also known as 5-aminoimidazole-4-carboxamide ribonucleotide, AICA-ribonucleotide, ZMP, and acadesine, is an intermediate metabolite in the de novo synthesis pathway of inosine monophosphate [21
    ]. It was first used in 1992 as a method of protection against cardiac ischemic injury during surgery [22
    ]. Later, AICAR was developed by PeriCor Therapeutics as an adenosine regulating agent and licensed to Schering-Plough in 2007. Recent data by Narkar et al. [14
    ] show that treating mice with AICAR alone for over 4 weeks upregulated gene expression of several proteins involved in oxidative metabolism while also increasing running endurance by 44%. Given this, it seems that AICAR can induce exercise adaptation and increase endurance, even without physical exertion attributable to exercise. Treatment with AICAR for 14 days significantly decreased the proportion of glycolytic fast-twitch (type IIB) myofibers and simultaneously caused even larger increases in the more oxidative and slower-twitch type IIX myofibers in extensor digitorum longus (EDL) muscles [23
    ], indicating that AICAR induces fiber-type transformation in skeletal muscle. This suggests that AICAR could be a promising candidate as an exercise pill.
    AICAR, as a synthetic adenosine monophosphate (AMP) analog, can pharmacologically activate AMP-activated protein kinase (AMPK). It is important to note that AMPK is a heterotrimeric complex that consists of catalytic α subunit and regulatory β and γ subunits: exercise activates all three subunits depending on intensity [24
    ]. AMPK plays a central role in cellular energy metabolism and is often referred to as the ‘metabolic master switch’. It maintains energy balance by promoting cellular uptake of glucose, β-oxidation of fatty acids, and biogenesis of glucose transporter 4 (GLUT4) while concurrently inhibiting ATP-consuming biosynthetic pathways. The energy-sensing capability of AMPK can be attributed to its ability to detect and react to fluctuations in the AMP:ATP ratio, which take place at rest and during exercise [25
    ]. In addition, AMPK is also implicated in the induction of mitochondrial biogenesis [26
    ].
    Furthermore, AICAR affects gene expression and regulation. AICAR increases peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein levels. PGC-1α is a transcriptional coactivator that induces mitochondrial biogenesis and fiber-type transformation in skeletal muscles [27
    ]. AMPK can directly interact with PGC-1α. Several AMPK-induced mitochondrial gene expression pathways occur through PGC-1α activation [28
    , 29
    ] (Figure 1, compound B1).
    Thus, treatment with AICAR activates AMPK, and AMPK then interacts, either directly or indirectly, with PGC-1α, inducing improved oxidative metabolism, mitochondrial biogenesis, and fiber-type transformation in skeletal muscle. Taken together, this suggests that AICAR is capable of mimicking a broad spectrum of exercise-like adaptation in skeletal muscle.
    A new arrival in the exercise mimetic family is compound 14, as reported recently by Asby and colleagues from Southampton University in the UK [30
    ]. Compound 14 is an inhibitor of AICAR transformylase homodimerization and acts differently from treatment with AICAR – this agent increases endogenous levels of AICAR by inhibiting ATIC, leading to a rise in endogenous AICAR and thus activating AMPK and its downstream signaling pathways, including increased fatty acid oxidation and glucose uptake. The detailed study by Asby et al. [30
    ] reported that treatment with compound 14 in obese mice for 7 days lowered blood glucose to near normal levels and improved glucose tolerance by approximately 30% while at the same time causing a significant loss of body weight in animals fed a high-fat diet. It is presently unclear if treatment with compound 14 increased exercise capacity or endurance levels in the treated animals.
    It is important to note that metformin, widely used in the treatment of type 2 diabetes, is also an AMPK-activating agent. Indeed, metformin lowers blood glucose and enhances insulin sensitivity at least in part through activation of AMPK [31
    ]. Of interest, treating healthy individuals with metformin for 7–9 days slightly but significantly reduced key outcomes related to maximal exercise capacity, such as peak oxygen uptake (VO2max), heart rate (HR), peak ventilation (VE), peak respiratory exchange ratio (RER), and exercise duration [32
    ]. Such findings have since been confirmed in patients with heart failure and lower degrees of insulin resistance [33
    , 34
    , 35
    ]. The effects of metformin on exercise capacity are complicated by findings that metformin blunts the full effects of exercise training in prediabetic individuals [36
    ], and other findings retort that it modestly reduces the benefits of exercise on glycemic control (by measuring hemoglobin A1c or HbA1c levels) or fitness (aerobic and/or resistance exercise) in an exercise intervention trial. One possibility is that metformin activates AMPK in hepatocytes and consequently reduces acetyl-CoA carboxylase (ACC) activity. Decreased ACC induces fatty acid oxidation and suppresses expression of lipogenic enzymes [31
    ]. Metformin also inhibits complex 1 of the mitochondrial respiratory chain [37
    , 38
    , 39
    , 40
    ], but unfortunately inhibition of complex 1 reduces the mitochondrial reserve induced by exercise training and decreases exercise performance [35
    ]. Thus, metformin may not be rightly considered a candidate exercise pill.
    GW501516

    GW501516 (also known as GW1516, GSK-516, and endurobol) is a peroxisome proliferator-activated receptor δ (PPARδ) agonist originally developed by GlaxoSmithKline (GSK) in 1992. Initially, GW501516 was used to improve skeletal muscle utilization of fatty acids in preference to carbohydrates, making it a potential treatment for obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome [41
    , 42
    , 43
    , 44
    ]. It has since been shown that GW501516 activates PPARδ, thereby inducing physiological adaptations, such as fiber-type transformation, similar to those seen in response to physical exercise. For example, Narkar et al. [14
    ] reported that treatment with GW501516 when combined with exercise synergistically increased oxidative slow-twitch (type I) fiber and mitochondrial biogenesis, resulting in improved endurance capacity. However, treatment with GW501516 alone did not alter fiber-type composition, indicating that pharmacological activation of PPARδ by itself is insufficient to enhance exercise capacity.
    PPARδ is a member of the nuclear receptor family and plays a crucial role in the transcriptional regulation of skeletal muscle metabolism [45
    , 46
    , 47
    ]. Exercise training induces its expression in type I fibers of skeletal muscle and triggers type I fiber transformation [45
    , 48
    , 49
    ]. Overexpression of PPARδ leads to mitochondrial biogenesis and high levels of oxidative type I fiber composition [46
    ]. Remarkably, GW501516 and AICAR synergistically affect mitochondrial biogenesis and fiber-type transformation and significantly increase exercise endurance more than either compound alone [14
    ] (Figure 1, compound B2). More research is needed to better understand the functional consequences of GW501516 and raise its profile as a possible candidate as an exercise pill.
    GSK4716

    GSK4716 is a synthetic small molecule agonist of estrogen-related receptors (ERRs) and binds to the ERRγ subtype with high selectivity [50
    ]. ERR is a heterotrimeric complex composed of three isoforms: ERRα, ERRβ, and ERRγ. The ERRγ subtype is often described as a key regulator of the oxidative muscle fiber phenotype. It is specifically expressed in slow-twitch muscle types of skeletal muscle and plays an important role in enhancing exercise capacity, activating mitochondrial biogenesis, and controlling angiogenesis and myofibrillar transformation. Recent data show that treatment of mouse myotubules with GSK4716 induced upregulation of ERRγ and its coactivators PGC-1α and PGC-1β by Rangwala et al. [15
    ]. By contrast, other findings indicate that structural remodeling and functional improvements induced by ERRγ are independent of PGC-1α, but are related to ERRγ-directed AMPK activation in the muscle (Figure 1, compound B3) [51
    ]. Clearly, more research is needed to examine this issue in greater detail.
    In summary, GSK4716 activates ERRγ to induce myofibrillar transformation, angiogenesis, mitochondrial biogenesis, and improve exercise performance, and can impart several of the benefits accrued by exercise. Thus, it can be considered a candidate exercise pill.
    SR9009

    SR9009 is a synthetic REV-ERBα agonist developed at The Scripps Research Institute in 2012 [52
    ]. REV-ERBα, also known as NR1D1 (nuclear receptor subfamily 1, group D, member 1), is a member of the REV-ERB family of nuclear receptors [53
    ]. Enhancement of REV-ERBα expression increases mitochondrial content and number, and decreases autophagy flux, thus improving exercise capacity [52
    , 54
    , 55
    , 56
    ]. Recently, an in vivo study found that a single injection of SR9009 induced the expression of genes related to fatty acid catabolism, and enhanced mitochondrial activity; treatment for 12 days enhanced energy consumption without changing the RER, while treatment for 30 days significantly prolonged mouse running times. Additionally, treatment of mouse myocardial cells in vitro with SR9009 increased mitochondrial numbers. In contrast to other nuclear receptors such as PPARα, ERRγ, or coregulators such as PGC-1α, treatment with REV-ERBα triggers skeletal muscle mitochondrial biogenesis through modulation of the liver kinase B1(Lkb1)–AMPK-silent information regulation T1 (SIRT1)–PGC-1α pathway, without inducing a switch of muscle fiber types [18
    ] (Figure 1, compound B4). In addition, REV-ERBα is also a circadian clock component and plays an important role in regulating rhythmic changes in activity and metabolism. It is likely that SR9009 alters circadian regulation of skeletal muscle activity, leading to increased energy expenditure [52
    ].
    Thus, REV-ERBα enhances mitochondrial biogenesis and improves oxidative function. SR9009, a pharmacological agonist of REV-ERBα, may be a promising exercise pill that mimics exercise-like benefits on energy metabolism.
    MOTS-c

    MOTS-c (mitochondrial open reading frame of the 12S rRNA-c), a hormone encoded in the DNA of mitochondria, was recently discovered by Lee et al. [19
    ]. It facilitates accumulation of endogenous AICAR, an AMPK activator. As a mitokine, MOTS-c has systemic effects, but appears to chiefly target skeletal muscle [57
    ]. A recent study indicates that MOTS-c treatment restores insulin sensitivity and metabolic homeostasis in mice fed a high-fat diet [19
    ]. In principle, MOTS-c, as a mitochondrial signaling peptide, acts on the folate cycle in muscle and consistently blocks the tethered de novo purine biosynthesis pathway, leading to accumulation of AICAR, AMPK activation, and maintenance of metabolic homeostasis. In addition, MOTS-c also regulates cellular and systemic glucose metabolism and restores insulin sensitivity [19
    ] (Figure 1, compound B5). To summarize, MOTS-c is a recently identified candidate exercise pill, with a limited profile of detailed studies on exercise capacity. Additional studies are needed to better understand its mechanism in the short and long term.
    Irisin

    Irisin is a novel myokine first identified by the Spiegelman group [17
    ]. Irisin is secreted by skeletal muscle in response to exercise and targets white adipose tissue [58
    ]. Exercise induces PGC-1α in muscle, and PGC-1α stimulates the expression of fibronectin type III domain-containing protein 5 (FNDC5) genes. The FNDC5 gene encodes FNDC5, which undergoes post-translational processing to form irisin that is then secreted into circulation. Irisin stimulates browning of white fat and increases the expression of uncoupling protein-1 (UCP-1), thereby enhancing thermogenesis and energy expenditure. For example, injection of irisin for 10 days induces weight loss and maintains glucose homeostasis in obese mice [17
    ]. Thus, irisin mimics some important beneficial effects of physical exercise (Figure 1, compound B6).
    Despite a number of recent studies demonstrating that irisin has exercise-like effects, some controversy remains about the claim that irisin is a candidate exercise pill [59
    , 60
    , 61
    ]. For example, a study by Raschke et al. [62
    ] indicated that FNDC5 mRNA expression was not altered in muscle biopsies from human endurance and strength training studies, and questioned whether the beneficial effects of irisin in mice can be translated to humans. Another consideration is that although there are many studies regarding the effects of exercise on human serum irisin levels [63
    , 64
    , 65
    , 66
    ], these studies make conflicting claims about the relationship between circulating irisin levels and exercise [67
    , 68
    , 69
    , 70
    , 71
    , 72
    , 73
    , 74
    ]. Many studies used commercially available ELISA kits to examine serum irisin levels that caused Albrecht et al. [59
    ] to call into question the accuracy of these data, because when they used western blot analysis with four different antibodies and a sensitive detection system to examine circulating irisin in humans or several animal species, they found unchanged serum irisin levels before and after exercise. In addition, Timmons et al. [61
    ] detected no significant increases in FNDC5 mRNA in human muscle biopsies when examined by gene expression arrays after exercise.
    A recent follow-up study by the Spiegelman group used state-of-the-art quantitative mass spectrometry (an antibody-independent method) to detect levels of the irisin peptide in human plasma. Circulating irisin levels (∼3.6ng/ml in sedentary individuals) were significantly increased (to ∼4.3ng/ml) by aerobic interval training [75
    ]. Importantly, this study provides fresh evidence that substantiates the earlier report by this group [17
    ]. More research is clearly necessary to examine this issue in greater detail, with an emphasis on detection methods and levels in acute and chronic exercise of varying levels of intensity.
    (–)-Epicatechin

    The flavonoid (–)-epicatechin, the most common isomer of epicatechin, is present in plants such as cocoa, tea, and grapes and has been shown to enhance angiogenesis and mitochondrial function both in sedentary conditions and after endurance exercise. One study reported that (–)-epicatechin alone or together with exercise induced structural and metabolic adaptation in skeletal and cardiac muscle and improved endurance capacity [16
    ]. Another study indicated that (–)-epicatechin treatment alone significantly increased mitochondrial signaling, and cumulatively enhanced exercise performance when combined with 8 weeks of exercise training [76
    ]. In addition, (–)-epicatechin may also improve myocardial capillary formation in response to exercise [77
    ].
    The beneficial effects of (–)-epicatechin may be attributable to activation of the vascular endothelial growth factor (VEGF)–endothelial nitric oxide synthase (eNOS)–nitric oxide (NO) pathway. Some animal studies demonstrate that (–)-epicatechin increases NO production in endothelial cells [78
    ] and attenuates myocardial injury [79
    , 80
    ]. There are several studies showing that the NO pathway may play a role in mitochondrial biogenesis [81
    , 82
    , 83
    ] and angiogenesis [84
    ] in skeletal muscle. Remarkably, only (–)-epicatechin, and not the stereoisomers (+)-epicatechin, (–)-catechin, or (+)-catechin, is able to induce in vivo capillary formation [85
    ] (Figure 1, compound B7).
    In summary, (–)-epicatechin, as a natural extract, mimics many exercise-like benefits such as improved mitochondrial function and increased capillary formation in skeletal and cardiac muscle, and provides a promising theoretical basis for its potential application as an exercise pill.
    Resveratrol

    Resveratrol (3,5,4′-trihydroxystilbene) is a naturally occurring polyphenol present in many foods, including red wine, grapes, and blueberries. Resveratrol enhances mitochondrial biogenesis, stimulates angiogenesis, improves exercise capacity, and increases insulin sensitivity in the same manner as exercise training. In animal studies, resveratrol-treated mice had improved mitochondrial function and endurance capacity [13
    ], and resveratrol treatment for 12 weeks induced AMPK expression and ameliorated the whole-body insulin tolerance in KKAy mice, a model of obese type 2 diabetes [86
    ]. Furthermore, studies in humans show similar adaptations triggered by resveratrol through improvement of mitochondrial efficiency [87
    , 88
    ].
    As with exercise training, resveratrol activates the energy-sensing enzyme AMPK [89
    ]. On the one hand, AMPK activation stimulates the NAD+-dependent type III deacetylase SIRT1 by increasing cellular NAD+ levels [90
    , 91
    ]. SIRT1 deacetylates PGC-1α and modulates its activity [92
    , 93
    ]. On the other hand, AMPK activation also directly regulates the activity of PGC-1α [94
    ]. Increased PGC-1α triggers gene transcription of nuclear-encoded mitochondrial proteins (NEMPs) and enhances mitochondrial biogenesis [95
    , 96
    ]. In addition, Fukuda et al. [97
    ] reported that resveratrol can also stimulate the VEGF–eNOS–NO pathway, which enhances angiogenesis (Figure 1, compound B8).
    However, discrepant results were described by Higashida et al. [89
    ] who reported that resveratrol failed to affect mitochondrial biogenesis, despite AMPK activation in skeletal muscle cells. It appears that the inconsistent results of different studies may be related to the differences in the dosage of resveratrol used, as confirmed by several studies showing that dosage plays a crucial role in beneficial effects with resveratrol treatment [13
    , 98
    , 99
    ], and that common resveratrol supplements have levels of resveratrol that are too low to induce changes in mitochondrial properties [100
    , 101
    ]. Thus, further research is necessary to understand the optimal dosage of resveratrol required to induce its exercise-like effects in humans.
    Exercise Pills and Vasculature, Epigenetics

    While exercise pills arguably can mimic the benefits of exercise in skeletal muscle, their effects in the vasculature are confounded by some important challenges. Exercise increases laminar shear stress in the vasculature to affect multiple signaling pathways (Figure 2), including the phosphoinositide 3-kinase (PI3K), small GTPases such as Ras, extracellular signal-regulated kinase (also known as mitogen-activated protein kinase, MAPK), and NO pathways [102
    ]. Our current understanding is that exercise increases luminal endothelial shear stress, and then mainly activates PI3K to phosphorylate protein kinase B (Akt) and induce Akt-mediated eNOS phosphorylation, leading to higher NO production and its resultant beneficial cardiovascular protective effects. However, of the current list of candidate exercise pills, only (–)-epicatechin and resveratrol activate eNOS expression and increases NO synthesis.
    Figure 2The Possible Molecular Mechanisms of Exercise and Exercise Pills in the Vasculature. Exercise increases laminar shear stress in the vasculature to affect multiple signaling pathways. However of the current list of candidate exercise pills, only (–)-epicatechin and resveratrol activate eNOS expression and increases NO synthesis, mimicking exercise-like beneficial effects. Abbreviations: PI3K, phosphoinositide 3-kinase; Akt, phosphorylate protein kinase B; MAPK, mitogen-activated protein kinase; PGI2, prostaglandin I2; eNOS, endothelial nitric oxide synthase; NO, nitric oxide.





    An emerging area of interest is the epigenetic effect of exercise. A recent study in Sweden examined DNA methylation and associated transcriptomic changes in 23 healthy young males and females (average age, 27 years; body mass index, 24kg/m2) who were asked to exercise (four times a week for 3 months) on stationary bikes but using only one leg (using an ingenious but simple design whereby the second unexercised leg served as a control) [103
    ]. In addition to the expected physical changes in the exercised leg, there were also almost 5000 sites across the genome with new methylation – with increases in sites related to structural remodeling and glucose metabolism and decreases in those associated with inflammatory/immune responses. Promising preclinical data in rats selectively bred to be high performance runners show that resveratrol can further enhance their performance [104
    ], an effect that may be related to the effects of resveratrol on gene regulation of SIRT1 that increases AMPK phosphorylation [105
    ]. It is unclear if exercise pills can enhance exercise performance in humans and how this may be related to epigenetic regulation of specific genes.
    Concluding Remarks

    Current candidate exercise pills can be divided into three categories: pharmacological agonists (AICAR, GW501516, GSK4716, and SR9009), hormones (MOST-c and irisin), and phytochemicals [resveratrol and (–)-epicatechin]. Except for the two phytochemicals that are not used to mimic exercise, the other exercise pills are still in experimental stages. For a better understanding of some of these exercise pills, we compared the signaling pathways and physiological adaptation among candidate exercise pills described to date (Figure 3). None of the candidate exercise pills fully mimics the full palette of the beneficial effects of exercise, but each exercise pill can activate distinct as well as overlapping target transcriptional regulators that partly mimic profound beneficial effects in some target organs induced by exercise and enhance exercise capacity (Table 2). Further development of exercise pills that act in combination may be more effective than single compounds.
    Figure 3Comparison of Signaling Pathways and Physiological Adaptation among Exercise Pills. Current candidate exercise pills can be divided into three categories: pharmacological agonists (AICAR, GW501516, GSK4716, and SR9009), hormones (MOST-c and irisin), and phytochemicals [resveratrol and (–)-epicatechin]. Each exercise pill can activate specific target transcriptional regulators that partly mimic profound beneficial effects in some target organs induced by exercise. Abbreviations: (–)-epi, (–)-epicatechin; Resv, Resveratrol.



    Where to buy sr9009?

  7. #7
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    Mimicking Exercise

    Regular physical exercise activates a number of molecular pathways in whole organ systems and reduces the risk of developing numerous chronic diseases (Figure 1A). Although nothing can fully substitute for physical exercise, candidate exercise pills that have emerged in recent years [13
    , 14
    , 15
    , 16
    , 17
    , 18
    , 19
    ] may be an attractive alternative for people who are unable to undertake regular exercise because of medical conditions such as obesity, amputations, spinal injuries, metabolic diseases, and musculoskeletal or cardiovascular conditions. The signaling molecules activated by physical exercise are logically considered to be potent pharmacological targets for such exercise pills.
    Figure 1Proposed Molecular Mechanisms and Beneficial Effects of Physical Exercise and Candidate Exercise Pills. The middle panel (A) indicates some molecular pathways activated by regular (conventional) physical exercise and the resultant beneficial effects, such as mitochondrial biogenesis, oxidative fiber-type transformation, improved fatty acid oxidation, angiogenesis, and increased exercise capacity. (B) None of the candidate exercise pills fully mimics the full palette of the beneficial effects of exercise, but each exercise pill can activate distinct as well as overlapping target transcriptional regulators that partly mimic the beneficial effects induced by exercise. Note that GW501516 (B2) by itself is unable to enhance endurance performance and has synergistic effects when combined with either exercise or AICAR; the combination induces mitochondrial biogenesis and fiber-type transformation and improves exercise capacity. In addition, irisin (B6), as a PGC-1α-dependent myokine, stimulates browning of white fat, consequently enhancing thermogenesis and total body energy expenditure. Abbreviations: AMPK, adenosine monophosphate-activated protein kinase; SIRT1, silent information regulation T1; PGC-1α, peroxisome proliferator-activated receptor-γ coactivator-1α; ERRs, estrogen-related receptors; PPARs, peroxisome proliferator-activated receptors; eNOS, endothelial nitric oxide synthase; NO, nitric oxide.





    ‘Exercise pills’ are active compounds that mimic the biochemical and functional effects of regular exercise, such as oxidative fiber-type transformation, mitochondrial biogenesis, improved fatty acid oxidation, angiogenesis, and increased exercise capacity. The concept of ‘exercise pills’ was first introduced by Himms-Hagen in 2004 [20
    ], followed by Narkar and colleagues [14
    ] who suggested that some molecules could mimic the effects of exercise training. Many subsequent studies have explored the development of exercise pills, and currently described potential exercise pills are listed in Table 1. Next, we briefly discuss the supporting evidence and proposed mechanisms for candidate exercise pills.Table 1Current Candidate Exercise Pills
    Compound Category Target Organ Molecular Target Functional Changes Refs
    AICAR AMPK agonist Skeletal muscle AMPK Fiber-type reformation
    Mitochondrial biogenesis
    [14
    , 21
    , 22
    , 23
    , 24
    , 25
    , 26
    , 27
    , 28
    , 29
    , 30
    , 31
    , 32
    , 33
    , 34
    , 35
    , 36
    , 37
    , 38
    , 39
    , 40
    ]
    GW501516 PPARδ agonist Skeletal muscle PPARδ Fiber-type reformation
    Mitochondrial biogenesis
    [14
    , 41
    , 42
    , 43
    , 44
    , 45
    , 46
    , 47
    , 48
    , 49
    ]
    GSK4716 ERR agonist Skeletal muscle ERRγ Mitochondrial biogenesis
    Fiber-type reformation
    angiogenesis
    [15
    , 50
    , 51
    ]
    SR9009 REV-ERB agonist Skeletal muscle REV-ERBα Mitochondrial biogenesis
    Improved energy metabolism
    [18
    , 52
    , 53
    , 54
    , 55
    , 56
    ]
    MOTS-c Mitokine Skeletal muscle AMPK Maintaining metabolic hemostasis
    Restore insulin sensitivity
    [19
    , 57
    ]
    Irisin Myokine Adipose tissue PGC-1α Thermogenesis
    Enhanced energy expenditure
    [17
    , 58
    , 59
    , 60
    , 61
    , 62
    , 63
    , 64
    , 65
    , 66
    , 67
    , 68
    , 69
    , 70
    , 71
    , 72
    , 73
    , 74
    , 75
    ]
    (–)-Epicatechin Phytochemical Skeletal and cardiac muscle NO Mitochondrial biogenesis
    Increased capillaries
    [16
    , 76
    , 77
    , 78
    , 79
    , 80
    , 81
    , 82
    , 83
    , 84
    , 85
    ]
    Resveratrol Phytochemical Cardiovascular PGC-1α/NO Mitochondrial biogenesis
    Angiogenesis
    [13
    , 86
    , 87
    , 88
    , 89
    , 90
    , 91
    , 92
    , 93
    , 94
    , 95
    , 96
    , 97
    , 98
    , 99
    , 100
    , 101
    ]







    Candidate Exercise Pills

    AICAR

    AICAR, also known as 5-aminoimidazole-4-carboxamide ribonucleotide, AICA-ribonucleotide, ZMP, and acadesine, is an intermediate metabolite in the de novo synthesis pathway of inosine monophosphate [21
    ]. It was first used in 1992 as a method of protection against cardiac ischemic injury during surgery [22
    ]. Later, AICAR was developed by PeriCor Therapeutics as an adenosine regulating agent and licensed to Schering-Plough in 2007. Recent data by Narkar et al. [14
    ] show that treating mice with AICAR alone for over 4 weeks upregulated gene expression of several proteins involved in oxidative metabolism while also increasing running endurance by 44%. Given this, it seems that AICAR can induce exercise adaptation and increase endurance, even without physical exertion attributable to exercise. Treatment with AICAR for 14 days significantly decreased the proportion of glycolytic fast-twitch (type IIB) myofibers and simultaneously caused even larger increases in the more oxidative and slower-twitch type IIX myofibers in extensor digitorum longus (EDL) muscles [23
    ], indicating that AICAR induces fiber-type transformation in skeletal muscle. This suggests that AICAR could be a promising candidate as an exercise pill.
    AICAR, as a synthetic adenosine monophosphate (AMP) analog, can pharmacologically activate AMP-activated protein kinase (AMPK). It is important to note that AMPK is a heterotrimeric complex that consists of catalytic α subunit and regulatory β and γ subunits: exercise activates all three subunits depending on intensity [24
    ]. AMPK plays a central role in cellular energy metabolism and is often referred to as the ‘metabolic master switch’. It maintains energy balance by promoting cellular uptake of glucose, β-oxidation of fatty acids, and biogenesis of glucose transporter 4 (GLUT4) while concurrently inhibiting ATP-consuming biosynthetic pathways. The energy-sensing capability of AMPK can be attributed to its ability to detect and react to fluctuations in the AMP:ATP ratio, which take place at rest and during exercise [25
    ]. In addition, AMPK is also implicated in the induction of mitochondrial biogenesis [26
    ].
    Furthermore, AICAR affects gene expression and regulation. AICAR increases peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) protein levels. PGC-1α is a transcriptional coactivator that induces mitochondrial biogenesis and fiber-type transformation in skeletal muscles [27
    ]. AMPK can directly interact with PGC-1α. Several AMPK-induced mitochondrial gene expression pathways occur through PGC-1α activation [28
    , 29
    ] (Figure 1, compound B1).
    Thus, treatment with AICAR activates AMPK, and AMPK then interacts, either directly or indirectly, with PGC-1α, inducing improved oxidative metabolism, mitochondrial biogenesis, and fiber-type transformation in skeletal muscle. Taken together, this suggests that AICAR is capable of mimicking a broad spectrum of exercise-like adaptation in skeletal muscle.
    A new arrival in the exercise mimetic family is compound 14, as reported recently by Asby and colleagues from Southampton University in the UK [30
    ]. Compound 14 is an inhibitor of AICAR transformylase homodimerization and acts differently from treatment with AICAR – this agent increases endogenous levels of AICAR by inhibiting ATIC, leading to a rise in endogenous AICAR and thus activating AMPK and its downstream signaling pathways, including increased fatty acid oxidation and glucose uptake. The detailed study by Asby et al. [30
    ] reported that treatment with compound 14 in obese mice for 7 days lowered blood glucose to near normal levels and improved glucose tolerance by approximately 30% while at the same time causing a significant loss of body weight in animals fed a high-fat diet. It is presently unclear if treatment with compound 14 increased exercise capacity or endurance levels in the treated animals.
    It is important to note that metformin, widely used in the treatment of type 2 diabetes, is also an AMPK-activating agent. Indeed, metformin lowers blood glucose and enhances insulin sensitivity at least in part through activation of AMPK [31
    ]. Of interest, treating healthy individuals with metformin for 7–9 days slightly but significantly reduced key outcomes related to maximal exercise capacity, such as peak oxygen uptake (VO2max), heart rate (HR), peak ventilation (VE), peak respiratory exchange ratio (RER), and exercise duration [32
    ]. Such findings have since been confirmed in patients with heart failure and lower degrees of insulin resistance [33
    , 34
    , 35
    ]. The effects of metformin on exercise capacity are complicated by findings that metformin blunts the full effects of exercise training in prediabetic individuals [36
    ], and other findings retort that it modestly reduces the benefits of exercise on glycemic control (by measuring hemoglobin A1c or HbA1c levels) or fitness (aerobic and/or resistance exercise) in an exercise intervention trial. One possibility is that metformin activates AMPK in hepatocytes and consequently reduces acetyl-CoA carboxylase (ACC) activity. Decreased ACC induces fatty acid oxidation and suppresses expression of lipogenic enzymes [31
    ]. Metformin also inhibits complex 1 of the mitochondrial respiratory chain [37
    , 38
    , 39
    , 40
    ], but unfortunately inhibition of complex 1 reduces the mitochondrial reserve induced by exercise training and decreases exercise performance [35
    ]. Thus, metformin may not be rightly considered a candidate exercise pill.
    GW501516

    GW501516 (also known as GW1516, GSK-516, and endurobol) is a peroxisome proliferator-activated receptor δ (PPARδ) agonist originally developed by GlaxoSmithKline (GSK) in 1992. Initially, GW501516 was used to improve skeletal muscle utilization of fatty acids in preference to carbohydrates, making it a potential treatment for obesity, type 2 diabetes, dyslipidemia, and metabolic syndrome [41
    , 42
    , 43
    , 44
    ]. It has since been shown that GW501516 activates PPARδ, thereby inducing physiological adaptations, such as fiber-type transformation, similar to those seen in response to physical exercise. For example, Narkar et al. [14
    ] reported that treatment with GW501516 when combined with exercise synergistically increased oxidative slow-twitch (type I) fiber and mitochondrial biogenesis, resulting in improved endurance capacity. However, treatment with GW501516 alone did not alter fiber-type composition, indicating that pharmacological activation of PPARδ by itself is insufficient to enhance exercise capacity.
    PPARδ is a member of the nuclear receptor family and plays a crucial role in the transcriptional regulation of skeletal muscle metabolism [45
    , 46
    , 47
    ]. Exercise training induces its expression in type I fibers of skeletal muscle and triggers type I fiber transformation [45
    , 48
    , 49
    ]. Overexpression of PPARδ leads to mitochondrial biogenesis and high levels of oxidative type I fiber composition [46
    ]. Remarkably, GW501516 and AICAR synergistically affect mitochondrial biogenesis and fiber-type transformation and significantly increase exercise endurance more than either compound alone [14
    ] (Figure 1, compound B2). More research is needed to better understand the functional consequences of GW501516 and raise its profile as a possible candidate as an exercise pill.
    GSK4716

    GSK4716 is a synthetic small molecule agonist of estrogen-related receptors (ERRs) and binds to the ERRγ subtype with high selectivity [50
    ]. ERR is a heterotrimeric complex composed of three isoforms: ERRα, ERRβ, and ERRγ. The ERRγ subtype is often described as a key regulator of the oxidative muscle fiber phenotype. It is specifically expressed in slow-twitch muscle types of skeletal muscle and plays an important role in enhancing exercise capacity, activating mitochondrial biogenesis, and controlling angiogenesis and myofibrillar transformation. Recent data show that treatment of mouse myotubules with GSK4716 induced upregulation of ERRγ and its coactivators PGC-1α and PGC-1β by Rangwala et al. [15
    ]. By contrast, other findings indicate that structural remodeling and functional improvements induced by ERRγ are independent of PGC-1α, but are related to ERRγ-directed AMPK activation in the muscle (Figure 1, compound B3) [51
    ]. Clearly, more research is needed to examine this issue in greater detail.
    In summary, GSK4716 activates ERRγ to induce myofibrillar transformation, angiogenesis, mitochondrial biogenesis, and improve exercise performance, and can impart several of the benefits accrued by exercise. Thus, it can be considered a candidate exercise pill.
    SR9009

    SR9009 is a synthetic REV-ERBα agonist developed at The Scripps Research Institute in 2012 [52
    ]. REV-ERBα, also known as NR1D1 (nuclear receptor subfamily 1, group D, member 1), is a member of the REV-ERB family of nuclear receptors [53
    ]. Enhancement of REV-ERBα expression increases mitochondrial content and number, and decreases autophagy flux, thus improving exercise capacity [52
    , 54
    , 55
    , 56
    ]. Recently, an in vivo study found that a single injection of SR9009 induced the expression of genes related to fatty acid catabolism, and enhanced mitochondrial activity; treatment for 12 days enhanced energy consumption without changing the RER, while treatment for 30 days significantly prolonged mouse running times. Additionally, treatment of mouse myocardial cells in vitro with SR9009 increased mitochondrial numbers. In contrast to other nuclear receptors such as PPARα, ERRγ, or coregulators such as PGC-1α, treatment with REV-ERBα triggers skeletal muscle mitochondrial biogenesis through modulation of the liver kinase B1(Lkb1)–AMPK-silent information regulation T1 (SIRT1)–PGC-1α pathway, without inducing a switch of muscle fiber types [18
    ] (Figure 1, compound B4). In addition, REV-ERBα is also a circadian clock component and plays an important role in regulating rhythmic changes in activity and metabolism. It is likely that SR9009 alters circadian regulation of skeletal muscle activity, leading to increased energy expenditure [52
    ].
    Thus, REV-ERBα enhances mitochondrial biogenesis and improves oxidative function. SR9009, a pharmacological agonist of REV-ERBα, may be a promising exercise pill that mimics exercise-like benefits on energy metabolism.
    MOTS-c

    MOTS-c (mitochondrial open reading frame of the 12S rRNA-c), a hormone encoded in the DNA of mitochondria, was recently discovered by Lee et al. [19
    ]. It facilitates accumulation of endogenous AICAR, an AMPK activator. As a mitokine, MOTS-c has systemic effects, but appears to chiefly target skeletal muscle [57
    ]. A recent study indicates that MOTS-c treatment restores insulin sensitivity and metabolic homeostasis in mice fed a high-fat diet [19
    ]. In principle, MOTS-c, as a mitochondrial signaling peptide, acts on the folate cycle in muscle and consistently blocks the tethered de novo purine biosynthesis pathway, leading to accumulation of AICAR, AMPK activation, and maintenance of metabolic homeostasis. In addition, MOTS-c also regulates cellular and systemic glucose metabolism and restores insulin sensitivity [19
    ] (Figure 1, compound B5). To summarize, MOTS-c is a recently identified candidate exercise pill, with a limited profile of detailed studies on exercise capacity. Additional studies are needed to better understand its mechanism in the short and long term.
    Irisin

    Irisin is a novel myokine first identified by the Spiegelman group [17
    ]. Irisin is secreted by skeletal muscle in response to exercise and targets white adipose tissue [58
    ]. Exercise induces PGC-1α in muscle, and PGC-1α stimulates the expression of fibronectin type III domain-containing protein 5 (FNDC5) genes. The FNDC5 gene encodes FNDC5, which undergoes post-translational processing to form irisin that is then secreted into circulation. Irisin stimulates browning of white fat and increases the expression of uncoupling protein-1 (UCP-1), thereby enhancing thermogenesis and energy expenditure. For example, injection of irisin for 10 days induces weight loss and maintains glucose homeostasis in obese mice [17
    ]. Thus, irisin mimics some important beneficial effects of physical exercise (Figure 1, compound B6).
    Despite a number of recent studies demonstrating that irisin has exercise-like effects, some controversy remains about the claim that irisin is a candidate exercise pill [59
    , 60
    , 61
    ]. For example, a study by Raschke et al. [62
    ] indicated that FNDC5 mRNA expression was not altered in muscle biopsies from human endurance and strength training studies, and questioned whether the beneficial effects of irisin in mice can be translated to humans. Another consideration is that although there are many studies regarding the effects of exercise on human serum irisin levels [63
    , 64
    , 65
    , 66
    ], these studies make conflicting claims about the relationship between circulating irisin levels and exercise [67
    , 68
    , 69
    , 70
    , 71
    , 72
    , 73
    , 74
    ]. Many studies used commercially available ELISA kits to examine serum irisin levels that caused Albrecht et al. [59
    ] to call into question the accuracy of these data, because when they used western blot analysis with four different antibodies and a sensitive detection system to examine circulating irisin in humans or several animal species, they found unchanged serum irisin levels before and after exercise. In addition, Timmons et al. [61
    ] detected no significant increases in FNDC5 mRNA in human muscle biopsies when examined by gene expression arrays after exercise.
    A recent follow-up study by the Spiegelman group used state-of-the-art quantitative mass spectrometry (an antibody-independent method) to detect levels of the irisin peptide in human plasma. Circulating irisin levels (∼3.6ng/ml in sedentary individuals) were significantly increased (to ∼4.3ng/ml) by aerobic interval training [75
    ]. Importantly, this study provides fresh evidence that substantiates the earlier report by this group [17
    ]. More research is clearly necessary to examine this issue in greater detail, with an emphasis on detection methods and levels in acute and chronic exercise of varying levels of intensity.
    (–)-Epicatechin

    The flavonoid (–)-epicatechin, the most common isomer of epicatechin, is present in plants such as cocoa, tea, and grapes and has been shown to enhance angiogenesis and mitochondrial function both in sedentary conditions and after endurance exercise. One study reported that (–)-epicatechin alone or together with exercise induced structural and metabolic adaptation in skeletal and cardiac muscle and improved endurance capacity [16
    ]. Another study indicated that (–)-epicatechin treatment alone significantly increased mitochondrial signaling, and cumulatively enhanced exercise performance when combined with 8 weeks of exercise training [76
    ]. In addition, (–)-epicatechin may also improve myocardial capillary formation in response to exercise [77
    ].
    The beneficial effects of (–)-epicatechin may be attributable to activation of the vascular endothelial growth factor (VEGF)–endothelial nitric oxide synthase (eNOS)–nitric oxide (NO) pathway. Some animal studies demonstrate that (–)-epicatechin increases NO production in endothelial cells [78
    ] and attenuates myocardial injury [79
    , 80
    ]. There are several studies showing that the NO pathway may play a role in mitochondrial biogenesis [81
    , 82
    , 83
    ] and angiogenesis [84
    ] in skeletal muscle. Remarkably, only (–)-epicatechin, and not the stereoisomers (+)-epicatechin, (–)-catechin, or (+)-catechin, is able to induce in vivo capillary formation [85
    ] (Figure 1, compound B7).
    In summary, (–)-epicatechin, as a natural extract, mimics many exercise-like benefits such as improved mitochondrial function and increased capillary formation in skeletal and cardiac muscle, and provides a promising theoretical basis for its potential application as an exercise pill.
    Resveratrol

    Resveratrol (3,5,4′-trihydroxystilbene) is a naturally occurring polyphenol present in many foods, including red wine, grapes, and blueberries. Resveratrol enhances mitochondrial biogenesis, stimulates angiogenesis, improves exercise capacity, and increases insulin sensitivity in the same manner as exercise training. In animal studies, resveratrol-treated mice had improved mitochondrial function and endurance capacity [13
    ], and resveratrol treatment for 12 weeks induced AMPK expression and ameliorated the whole-body insulin tolerance in KKAy mice, a model of obese type 2 diabetes [86
    ]. Furthermore, studies in humans show similar adaptations triggered by resveratrol through improvement of mitochondrial efficiency [87
    , 88
    ].
    As with exercise training, resveratrol activates the energy-sensing enzyme AMPK [89
    ]. On the one hand, AMPK activation stimulates the NAD+-dependent type III deacetylase SIRT1 by increasing cellular NAD+ levels [90
    , 91
    ]. SIRT1 deacetylates PGC-1α and modulates its activity [92
    , 93
    ]. On the other hand, AMPK activation also directly regulates the activity of PGC-1α [94
    ]. Increased PGC-1α triggers gene transcription of nuclear-encoded mitochondrial proteins (NEMPs) and enhances mitochondrial biogenesis [95
    , 96
    ]. In addition, Fukuda et al. [97
    ] reported that resveratrol can also stimulate the VEGF–eNOS–NO pathway, which enhances angiogenesis (Figure 1, compound B8).
    However, discrepant results were described by Higashida et al. [89
    ] who reported that resveratrol failed to affect mitochondrial biogenesis, despite AMPK activation in skeletal muscle cells. It appears that the inconsistent results of different studies may be related to the differences in the dosage of resveratrol used, as confirmed by several studies showing that dosage plays a crucial role in beneficial effects with resveratrol treatment [13
    , 98
    , 99
    ], and that common resveratrol supplements have levels of resveratrol that are too low to induce changes in mitochondrial properties [100
    , 101
    ]. Thus, further research is necessary to understand the optimal dosage of resveratrol required to induce its exercise-like effects in humans.
    Exercise Pills and Vasculature, Epigenetics

    While exercise pills arguably can mimic the benefits of exercise in skeletal muscle, their effects in the vasculature are confounded by some important challenges. Exercise increases laminar shear stress in the vasculature to affect multiple signaling pathways (Figure 2), including the phosphoinositide 3-kinase (PI3K), small GTPases such as Ras, extracellular signal-regulated kinase (also known as mitogen-activated protein kinase, MAPK), and NO pathways [102
    ]. Our current understanding is that exercise increases luminal endothelial shear stress, and then mainly activates PI3K to phosphorylate protein kinase B (Akt) and induce Akt-mediated eNOS phosphorylation, leading to higher NO production and its resultant beneficial cardiovascular protective effects. However, of the current list of candidate exercise pills, only (–)-epicatechin and resveratrol activate eNOS expression and increases NO synthesis.
    Figure 2The Possible Molecular Mechanisms of Exercise and Exercise Pills in the Vasculature. Exercise increases laminar shear stress in the vasculature to affect multiple signaling pathways. However of the current list of candidate exercise pills, only (–)-epicatechin and resveratrol activate eNOS expression and increases NO synthesis, mimicking exercise-like beneficial effects. Abbreviations: PI3K, phosphoinositide 3-kinase; Akt, phosphorylate protein kinase B; MAPK, mitogen-activated protein kinase; PGI2, prostaglandin I2; eNOS, endothelial nitric oxide synthase; NO, nitric oxide.





    An emerging area of interest is the epigenetic effect of exercise. A recent study in Sweden examined DNA methylation and associated transcriptomic changes in 23 healthy young males and females (average age, 27 years; body mass index, 24kg/m2) who were asked to exercise (four times a week for 3 months) on stationary bikes but using only one leg (using an ingenious but simple design whereby the second unexercised leg served as a control) [103
    ]. In addition to the expected physical changes in the exercised leg, there were also almost 5000 sites across the genome with new methylation – with increases in sites related to structural remodeling and glucose metabolism and decreases in those associated with inflammatory/immune responses. Promising preclinical data in rats selectively bred to be high performance runners show that resveratrol can further enhance their performance [104
    ], an effect that may be related to the effects of resveratrol on gene regulation of SIRT1 that increases AMPK phosphorylation [105
    ]. It is unclear if exercise pills can enhance exercise performance in humans and how this may be related to epigenetic regulation of specific genes.
    Concluding Remarks

    Current candidate exercise pills can be divided into three categories: pharmacological agonists (AICAR, GW501516, GSK4716, and SR9009), hormones (MOST-c and irisin), and phytochemicals [resveratrol and (–)-epicatechin]. Except for the two phytochemicals that are not used to mimic exercise, the other exercise pills are still in experimental stages. For a better understanding of some of these exercise pills, we compared the signaling pathways and physiological adaptation among candidate exercise pills described to date (Figure 3). None of the candidate exercise pills fully mimics the full palette of the beneficial effects of exercise, but each exercise pill can activate distinct as well as overlapping target transcriptional regulators that partly mimic profound beneficial effects in some target organs induced by exercise and enhance exercise capacity (Table 2). Further development of exercise pills that act in combination may be more effective than single compounds.
    Figure 3Comparison of Signaling Pathways and Physiological Adaptation among Exercise Pills. Current candidate exercise pills can be divided into three categories: pharmacological agonists (AICAR, GW501516, GSK4716, and SR9009), hormones (MOST-c and irisin), and phytochemicals [resveratrol and (–)-epicatechin]. Each exercise pill can activate specific target transcriptional regulators that partly mimic profound beneficial effects in some target organs induced by exercise. Abbreviations: (–)-epi, (–)-epicatechin; Resv, Resveratrol.



    Where to buy sr9009?

  8. #8
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    Drug Candidate Leads to Improved Endurance

    By Eric Sauter

    An international group of scientists has shown that a drug candidate designed by scientists from the Florida campus of The Scripps Research Institute (TSRI) significantly increases exercise endurance in animal models.
    These findings could lead to new approaches to helping people with conditions that acutely limit exercise tolerance, such as obesity, chronic obstructive pulmonary disease (COPD) and congestive heart failure, as well as the decline of muscle capacity associated with aging.
    The study was published July 14, 2013, by the journal Nature Medicine.
    The drug candidate, SR9009, is one of a pair of compounds developed in the laboratory of TSRI Professor Thomas Burris and described in a March 2012 issue of the journal Nature as reducing obesity in animal models. The compounds affect the core biological clock, which synchronizes the rhythm of the body’s activity with the 24-hour cycle of day and night.
    The compounds work by binding to one of the body’s natural molecules called Rev-erbα, which influences lipid and glucose metabolism in the liver, the production of fat-storing cells and the response of macrophages (cells that remove dying or dead cells) during inflammation.
    In the new study, a team led by scientists at the Institut Pasteur de Lille in France demonstrated that mice lacking Rev-erbα had decreased skeletal muscle metabolic activity and running capacity. Burris’ group showed that activation of Rev-erbα with SR9009 led to increased metabolic activity in skeletal muscle in both culture and in mice. The treated mice had a 50 percent increase in running capacity, measured by both time and distance.
    “The animals actually get muscles like an athlete who has been training,” said Burris. “The pattern of gene expression after treatment with SR9009 is that of an oxidative-type muscle— again, just like an athlete.”
    The authors of the new study suggest that Rev-erbα affects muscle cells by promoting both the creation of new mitochondria (often referred to as the “power plants” of the cell) and the clearance of those mitochondria that are defective.
    The study, “Rev-Erbα Modulates Skeletal Muscle Oxidative Capacity by Regulating Mitochondrial Biogenesis and Autophagy” was led by Estelle Woldt and Yasmine Sebti (first authors) and Bart Staels and Hélène Duez (senior authors) of Institut Pasteur de Lille, France. Other contributors include Christian Duhem, Jérôme Eeckhoute, Charlotte Paquet, Stéphane Delhaye and Philippe Lefebvre of Institut Pasteur de Lille, France; Laura Solt, Youseung Shin, Thomas Burris and Theodore M. Kamenecka of TSRI; Steve Lancel and Rémi Nevière of Université Lille Nord de France; and Matthijs K.C. Hesselink, Gert Schaart and Patrick Schrauwen of Maastricht University Medical Center, Maastricht, the Netherlands. For further information, see https://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3213.html
    The study was supported by a Marie Curie International Reintegration Grant (FP7), the European Commission (FP7) consortium Eurhythdia, Région Nord Pas-de-Calais/FEDER, a CPER “starting grant,” the European Genomic Institute for Diabetes (ANR-10-LABX-46), an unrestricted ITMO/Astra Zeneca grant, a joint Société Francophone du Diabète MSD research fellowship, Research Grant from the European Foundation for the Study of Diabetes, National Institutes of Health grant (MH093429 and DK080201) and a VICI Research grant for innovative research from the Netherlands Organization for Scientific Research (918.96.618).
    Where to buy sr9009?

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    Drug Candidate Leads to Improved Endurance

    By Eric Sauter

    An international group of scientists has shown that a drug candidate designed by scientists from the Florida campus of The Scripps Research Institute (TSRI) significantly increases exercise endurance in animal models.
    These findings could lead to new approaches to helping people with conditions that acutely limit exercise tolerance, such as obesity, chronic obstructive pulmonary disease (COPD) and congestive heart failure, as well as the decline of muscle capacity associated with aging.
    The study was published July 14, 2013, by the journal Nature Medicine.
    The drug candidate, SR9009, is one of a pair of compounds developed in the laboratory of TSRI Professor Thomas Burris and described in a March 2012 issue of the journal Nature as reducing obesity in animal models. The compounds affect the core biological clock, which synchronizes the rhythm of the body’s activity with the 24-hour cycle of day and night.
    The compounds work by binding to one of the body’s natural molecules called Rev-erbα, which influences lipid and glucose metabolism in the liver, the production of fat-storing cells and the response of macrophages (cells that remove dying or dead cells) during inflammation.
    In the new study, a team led by scientists at the Institut Pasteur de Lille in France demonstrated that mice lacking Rev-erbα had decreased skeletal muscle metabolic activity and running capacity. Burris’ group showed that activation of Rev-erbα with SR9009 led to increased metabolic activity in skeletal muscle in both culture and in mice. The treated mice had a 50 percent increase in running capacity, measured by both time and distance.
    “The animals actually get muscles like an athlete who has been training,” said Burris. “The pattern of gene expression after treatment with SR9009 is that of an oxidative-type muscle— again, just like an athlete.”
    The authors of the new study suggest that Rev-erbα affects muscle cells by promoting both the creation of new mitochondria (often referred to as the “power plants” of the cell) and the clearance of those mitochondria that are defective.
    The study, “Rev-Erbα Modulates Skeletal Muscle Oxidative Capacity by Regulating Mitochondrial Biogenesis and Autophagy” was led by Estelle Woldt and Yasmine Sebti (first authors) and Bart Staels and Hélène Duez (senior authors) of Institut Pasteur de Lille, France. Other contributors include Christian Duhem, Jérôme Eeckhoute, Charlotte Paquet, Stéphane Delhaye and Philippe Lefebvre of Institut Pasteur de Lille, France; Laura Solt, Youseung Shin, Thomas Burris and Theodore M. Kamenecka of TSRI; Steve Lancel and Rémi Nevière of Université Lille Nord de France; and Matthijs K.C. Hesselink, Gert Schaart and Patrick Schrauwen of Maastricht University Medical Center, Maastricht, the Netherlands. For further information, see https://www.nature.com/nm/journal/vaop/ncurrent/full/nm.3213.html
    The study was supported by a Marie Curie International Reintegration Grant (FP7), the European Commission (FP7) consortium Eurhythdia, Région Nord Pas-de-Calais/FEDER, a CPER “starting grant,” the European Genomic Institute for Diabetes (ANR-10-LABX-46), an unrestricted ITMO/Astra Zeneca grant, a joint Société Francophone du Diabète MSD research fellowship, Research Grant from the European Foundation for the Study of Diabetes, National Institutes of Health grant (MH093429 and DK080201) and a VICI Research grant for innovative research from the Netherlands Organization for Scientific Research (918.96.618).
    Where to buy sr9009?

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    Michael AB Naafs*Department of Endocrinology, International Health Consultancy, NetherlandsReceived: January 18, 2018; Published: January 23, 2018


    SR 9009 (Stenabolic) is a REV-ERB (revised-viral nuclearerythroblastosis receptors) agonist, that can modulate theexpressions of circadian core clock proteins and therefore help tomodulate the circadian rythm. Modulation of the REV-ERB activityby synthetic agonists e.g., SR 9009 SR 9011 alters the expression ofgenes involved in lipid and glucose metabolism and, therefore playsan important role in maintaining the energy homeotasis.

    Effects ofSR9009 and SR9011 in animal studies are increased basal oxygenconsumption, decreased lipogenesis, cholesterol and bileacidsynthesis in the liver, increased mitochondrial content, glucose andfatty oxidation in the skeletal muscle and decreased lipid storagein the white adipose tissue.


    The observed increase in energyexpenditure and decrease in fat mass make the REV-ERB agonistspromising drug candidates for the treatment of several metabolicdisorders.They are also attractive for performance enhancement byathletes. Such use can be classified as doping [48].SR9009 (Stenabolic) has been developed by Scripps Researchby the team of Prof. Thomas Burris.


    Stenabolic is taken orally asa metabolism enhancer believed tohave results similar to Cardarine, but with considerable more extrabenefits. It is recommended as a very good addition to any steroid(Anavar or Trembolone) or SARMs cycle, especially when usedtogether with Cardarine. The half-life is short, 30-60 minutes,so thedose should be spaced through the day e.g.,10 mg 4-6 times daily.Again no adverse effects are reported.
    Where to buy sr9009?

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    If, studies were conducted , and they were, showing oral administration or sr9009 to be effective at 20mg, 10mg, or any other number that may have been used in studies we dont know about, and those studies conclusively showed this dosaged to be effective. Why then would anyone give a shit whether just 2% was bioavailable after ingestion?

    Oral steroids, some of which as much as 60% - 70% are rendered useless after ingesting, but they work like a fucking charm! I never seen anyone say man, fuck anadrol, you only get 30% out of it orally. i want to inject it. lol.
    Where to buy sr9009?

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    I guess you told me ha ha! I didn't even realize you guys were selling it .
    Gimme Fuel, Gimme fire, Gimme that which I desire....

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