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Topic starter
02/11/2018 6:29 am
2 levels for muscle growth.
J Physiol. 2006 Aug 17;
Akt signalling through GSK-3{beta}, mTOR and Foxo1 is involved in human skeletal muscle hypertrophy and atrophy.
Leger B, Cartoni R, Praz M, Lamon S, Deriaz O, Crettenand A, Gobelet C, Rohmer P, Konzelmann M, Luthi F, Russell AP.
Clinique Romande de Readaptation SUVA Care.
Skeletal muscle size is tightly regulated by the synergy between anabolic and catabolic signaling pathways which, in humans, have not been well characterized. Akt has been suggested to play a pivotal role in the regulation of skeletal muscle hypertrophy and atrophy in rodents and cells. Here we measured the amount of phospho-Akt and several of its downstream anabolic (GSK-3beta, mTOR, p70s6k and 4E-BP1) and catabolic (Foxo1, Foxo3, atrogin-1 and MuRF1) targets. All measurements were performed in human quadriceps muscle biopsies taken after 8 weeks of both hypertrophy stimulating resistance training and atrophy stimulating de-training. Following resistance training a muscle hypertrophy (~10%) and an increase in phospho-Akt, phospho-GSK-3beta and phospho-mTOR protein content was observed. This was paralleled by a decrease in Foxo1 nuclear protein content. Following the de-training period a muscle atrophy (5%), relative to the post-training muscle size, and a decrease in phospho-Akt and GSK-3beta and an increase in Foxo1, was observed. Atrogin-1 and MuRF1 increased after the hypertrophy and decreased after the atrophy phases. We demonstrate, for the first time in human skeletal muscle, that the regulation of Akt and its downstream signaling pathways GSK-3beta, mTOR and Foxo1 are associated with both the skeletal muscle hypertrophy and atrophy processes.
Diabetes. 2006 Jun;55(6):1776-82.
Exercise-Induced Phosphorylation of the Novel Akt Substrates AS160 and Filamin A in Human Skeletal Muscle.
Deshmukh A, Coffey VG, Zhong Z, Chibalin AV, Hawley JA, Zierath JR.
Karolinska Institutet, Department of Molecular MedicineSurgery, Section of Integrative Physiology, von Eulers vag 4, 4th Floor, S-171 77 Stockholm, Sweden.
Skeletal muscle contraction stimulates multiple signaling cascades that govern a variety of metabolic and transcriptional events. Akt/protein kinase B regulates metabolism and growth/muscle hypertrophy
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J Cell Physiol. 2006 Jan;206(1):264-72.
Myostatin auto-regulates its expression by feedback loop through Smad7 dependent mechanism.
Forbes D, Jackman M, Bishop A, Thomas M, Kambadur R, Sharma M.
Animal Genomics, AgResearch, East Street, Hamilton, New Zealand.
Myostatin, a secreted growth factor, is a member of the TGF-beta superfamily and an inhibitor of myogenesis. Previously, we have shown that myostatin gene expression is regulated at the level of transcription and that myostatin is a downstream target gene of MyoD. Here we show that myostatin gene expression is auto-regulated by a negative feedback mechanism. Northern blot analysis indicated that there are relatively higher levels of myostatin mRNA in the biceps femoris muscle of cattle that express a non- functional myostatin allele (Belgian Blue) as compared to normal cattle. In contrast, addition of exogenous myostatin decreases endogenous myostatin mRNA. Consistent with this result, wild type myostatin protein is able to repress myostatin promoter activity via Activin type IIb receptor (ActRIIB) and ALK5 (P < 0.001). However, non-functional myostatin (Piedmontese) failed to repress the myostatin promoter suggesting that myostatin auto-regulates its promoter by negative feedback inhibition. Auto-regulation by myostatin appears to be signaled through Smad7, since the expression of the inhibitory Smad7 is induced by myostatin and the over-expression of Smad7 in turn inhibits the myostatin promoter activity (P < 0.001). In contrast down regulation of Smad7 by siRNA results in increased myostatin mRNA indicating that Smad7 is a negative regulator of myostatin gene expression. Consistent with these results, a decrease in Smad7 mRNA and concomitant increase in myostatin expression is seen in myotubes that express non functional myostatin. In addition, interference with myostatin signaling prevents the induction of Smad7 promoter activity by myostatin. Based on these results, we propose that myostatin auto-regulates its gene expression through a Smad7 dependent mechanism in myogenic cells.
Mol Cell Biol. 2006 Aug;26(16):6248-60.
Smad7 promotes and enhances skeletal muscle differentiation.
Kollias HD, Perry RL, Miyake T, Aziz A, McDermott JC.
Department of Biology, 327 Farquharson, LSB, York University, 4700 Keele St., Toronto M3J 1P3 Ontario, Canada.
Transforming growth factor beta1 (TGF-beta1) and myostatin signaling, mediated by the same Smad downstream effectors, potently repress skeletal muscle cell differentiation. Smad7 inhibits these cytokine signaling pathways. The role of Smad7 during skeletal muscle cell differentiation was assessed. In these studies, we document that increased expression of Smad7 abrogates myostatin- but not TGF-beta1-mediated repression of myogenesis. Further, constitutive expression of exogenous Smad7 potently enhanced skeletal muscle differentiation and cellular hypertrophy. Conversely, targeting of endogenous Smad7 by small interfering RNA inhibited C2C12 muscle cell differentiation, indicating an essential role for Smad7 during myogenesis. Congruent with a role for Smad7 in myogenesis, we observed that the muscle regulatory factor (MyoD) binds to and transactivates the Smad7 proximal promoter region. Finally, we document that Smad7 directly interacts with MyoD and enhances MyoD transcriptional activity. Thus, Smad7 cooperates with MyoD, creating a positive loop to induce Smad7 expression and to promote MyoD driven myogenesis. Taken together, these data implicate Smad7 as a fundamental regulator of differentiation in skeletal muscle cells.
interwined:
J Cell Physiol. 2006 Nov;209(2):501-14.
Myostatin induces cachexia by activating the ubiquitin proteolytic system through an NF-kappaB-independent, FoxO1-dependent mechanism.
McFarlane C, Plummer E, Thomas M, Hennebry A, Ashby M, Ling N, Smith H, Sharma M, Kambadur R.
AgResearch, Functional Muscle Genomics, East Street, Hamilton, New Zealand.
Myostatin, a transforming growth factor-beta (TGF-beta) super-family member, has been well characterized as a negative regulator of muscle growth and development. Myostatin has been implicated in several forms of muscle wasting including the severe cachexia observed as a result of conditions such as AIDS and liver cirrhosis. Here we show that Myostatin induces cachexia by a mechanism independent of NF-kappaB. Myostatin treatment resulted in a reduction in both myotube number and size in vitro, as well as a loss in body mass in vivo. Furthermore, the expression of the myogenic genes myoD and pax3 was reduced, while NF-kappaB (the p65 subunit) localization and expression remained unchanged. In addition, promoter analysis has confirmed Myostatin inhibition of myoD and pax3. An increase in the expression of genes involved in ubiquitin-mediated proteolysis is observed during many forms of muscle wasting. Hence we analyzed the effect of Myostatin treatment on proteolytic gene expression. The ubiquitin associated genes atrogin-1, MuRF-1, and E214k were upregulated following Myostatin treatment. We analyzed how Myostatin may be signaling to induce cachexia.Myostatin signaling reversed the IGF-1/PI3K/AKT hypertrophy pathway by inhibiting AKT phosphorylation thereby increasing the levels of active FoxO1, allowing for increased expression of atrophy-related genes. Therefore, our results suggest that Myostatin induces cachexia through an NF-kappaB-independent mechanism. Furthermore, increased Myostatin levels appear to antagonize hypertrophy signaling through regulation of the AKT-FoxO1 pathway.
dr frankenstein
Topic starter
02/11/2018 7:26 am
Am J Physiol Endocrinol Metab. 2006 Oct 31
AS160 phosphorylation is associated with activation of {alpha}2{beta}2{gamma}1 but not {alpha}2{beta}2{gamma}3 AMPK trimeric complex in skeletal muscle during exercise in humans.
Treebak JT, Birk JB, Rose AJ, Kiens B, Richter EA, Wojtaszewski JF.
Institute of Exercise and Sport Sciences; Department of Human Physiology, University of Copenhagen, Copenhagen, Denmark.
We investigated time- and intensity-dependent effects of exercise on AS160 phosphorylation in human skeletal muscle. Subjects performed cycle exercise for 1) 90 min (67% VO2peak, n=8), 2) 20 min (80% VO2peak, n=11), 3) two min (110% of peak work rate, n=9), or 4) 30 sec (maximal sprint, n=10). Muscle biopsies were obtained before, during and after exercise. In trial 1, AS160 phosphorylation increased at 60 min (60%, p=0.06) and further at 90 min of exercise (120%, p<0.05). alpha2beta2gamma3 AMPK activity increased significantly to a steady state level after 30 min, whereas alpha2beta2gamma1 AMPK activity increased after 60 min of exercise with a further significant increase after 90 min. alpha2beta2gamma1 AMPK activity and AS160 phosphorylation correlated positively (r(2)=0.55). In exercise trials 2, 3, and 4, alpha2beta2gamma3 AMPK activity but neither AS160 phosphorylation nor alpha2beta2gamma1 AMPK activity increased. Akt Ser-473 phosphorylation was unchanged in all trials whereas Akt Thr-308 phosphorylation increased significantly in trial 3 and 4 only. These results show that AS160 is phosphorylated in a time but not intensity dependent manner, and suggest that alpha2beta2gamma1 AMPK may act in a pathway responsible for exercise-induced AS160 phosphorylation. Furthermore, we show that AMPK complexes in skeletal muscle are activated differently depending on exercise intensity and duration. Key words: Akt, Akt substrate of 160 kDa, 5'AMP activated protein kinase.
J Appl Physiol. 2006 Jan;100(1):129-35.
Inhibition of stretch-activated channels during eccentric muscle contraction attenuates p70S6K activation.
Spangenburg EE, McBride TA.
Exercise Biology Program, Division of Biological Sciences, School of Medicine, University of California-Davis, USA.
Eccentric contractions (EC) are known to result in muscle hypertrophy, potentially through activation of the Akt-mammalian target of rapamycin-p70 S6 kinase (p70S6K) signaling pathway. Previous work has also demonstrated that EC result in the opening of stretch-activated channels (SAC), and inhibition of these channels resulted in an attenuation of EC-induced muscle hypertrophy. The purpose of this study was to test the hypothesis that a known intracellular pathway directly associated with muscle hypertrophy is coupled to the opening of SAC. Specifically, we measured the activation of the Akt, GSK-3beta, p70S6K, and ribosomal protein S6 following a single bout of EC in the rat tibialis anterior (TA) muscle. The TA muscles performed four sets of six repetitions of EC. In vivo blockade of SAC was performed by a continuous oral treatment with streptomycin in the drinking water (4 g/l) or by intravenous infusion of 80 micromol/kg gadolinium (Gd3+). EC increased the degree of Akt and p70S6K phosphorylation in the TA muscle, whereas in animals in which SAC had been inhibited, there was a reduced capacity for EC to induce Akt or p70S6K phosphorylation. Accompanying this reduced activation of Akt and p70S6K was a failure to phosphorylate GSK-3beta or S6 when SAC were inhibited. The results from these data indicate the necessity of functional SAC for the complete activation of Akt and p70S6K pathway in response to EC
dr frankenstein
02/11/2018 8:26 am
Man oh man, that's complex.
"The medals don't mean anything and the glory doesn't last. It's all about your happiness. The rewards are going to come, but my happiness is just loving the sport and having fun performing" ~ Jackie Joyner Kersee.
02/11/2018 9:15 am
What did he say !
"If we knew what it was we were doing, it would not be called research, would it?"
- Albert Einstein
Topic starter
02/11/2018 10:06 am
Man oh man, that's complex.
i like complex things gui,
Ontology is my preferred area #1.
Neuroendocrinology #2.
dr frankenstein
Topic starter
02/11/2018 10:51 am
Med Sci Sports Exerc. 2006 Nov;38(11):1950-7.
mTOR Signaling and the Molecular Adaptation to Resistance Exercise.
Bodine SC.
Section of Neurobiology, Physiology & Behavior, University of California, Davis, Davis, CA.
Skeletal muscle size is dynamic and responsive to extracellular signals such as mechanical load, neural activity, hormones, growth factors, and cytokines. The signaling pathways responsible for regulating cell size in adult skeletal muscle under growth and atrophy conditions are poorly understood. However, recent evidence suggests a role for the PI3K/Akt/mTOR pathway. Protein translation is regulated through the phosphorylation of initiation factors that are controlled by signaling pathways downstream of PI3K/Akt. Recent work in mammals has suggested that activation of Akt/PKB, a Ser-Thr phosphatidylinositol-regulated kinase, and its downstream targets, glycogen synthase kinase-3 (GSK3) and the mammalian target of rapamycin (mTOR), may be critical regulators of postnatal cell size in multiple organ systems, including skeletal muscle. This paper will review some of the recent data that demonstrate the critical role of Akt/mTOR signaling in the regulation of postnatal muscle size, especially under conditions of increased external loading.
dr frankenstein
Topic starter
02/11/2018 11:34 am
Essays Biochem. 2006;42:61-74.
Resistance exercise, muscle loading/unloading and the control of muscle mass.
Baar K, Nader G, Bodine S.
Division of Molecular Physiology, University of Dundee, Dundee U.K.
Muscle mass is determined by the difference between the rate of protein synthesis and degradation. If synthesis is greater than degradation, muscle mass will increase (hypertrophy) and when the reverse is true muscle mass will decrease (atrophy). Following resistance exercise/increased loading there is a transient increase in protein synthesis within muscle. This change in protein synthesis correlates with an increase in the activity of protein kinase B/Akt and mTOR (mammalian target of rapamycin). mTOR increases protein synthesis by increasing translation initiation and by inducing ribosomal biogenesis. By contrast, unloading or inactivity results in a decrease in protein synthesis and a significant increase in muscle protein breakdown. The decrease in synthesis is due in part to the inactivation of mTOR and therefore a decrease in translation initiation, but also to a decrease in the rate of translation elongation. The increase in degradation is the result of a co-ordinated response of the calpains, lysosomal proteases and the ATP-dependent ubiquitin-proteosome. Caspase 3 and the calpains act upstream of the ubiquitin-proteosome system to assist in the complete breakdown of the myofibrillar proteins. Two muscle specific E3 ubiquitin ligases, MuRF1 and MAFbx/atrogen-1, have been identified as key regulators of muscle atrophy. In this chapter, these pathways and how the balance between anabolism and catabolism is affected by loading and unloading will be discussed.
dr frankenstein
02/11/2018 12:17 pm
The role of mTor signaling in muscle growth has been well established for many years. Its the primary reason we still adhere to many of our nutritional standards, since the pathways that target mTor are heavily regulated by amino acid and glucose concentrations in the muscle.
I have one or two great papers on mTor and downstream targets, if that sort of thing interests you.
Good things come to those who weight.
The Big Cat is a researcher and theoreticist. His advice must never be taken in the stead of proper advice from a medical professional, it is entirely intended for research purposes.