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Xuzhu Lin, Erik Hanson, Andrew C Betik, Tara C Brennan-Speranza, Alan Hayes, Itamar Levinger
Undercarboxylated osteocalcin (ucOC) has been implicated in skeletal muscle insulin sensitivity and function. However, whether muscle mass and strength loss in atrophic conditions is related to a reduction in ucOC is not clear. We hypothesized that both immobilization and testosterone depletion would lead to reductions in ucOC, associated with not only the degree of muscle atrophy but also changes to atrophy signaling pathway(s) in male rats. We subjected 8-week-old male Fischer (F344) rats to 7 days of hindlimb immobilization 10 days after castration surgery...
June 13, 2016: Journal of Bone and Mineral Research: the Official Journal of the American Society for Bone and Mineral Research
Sue Goo Rhee, Soo Han Bae
Sestrins 1 to 3 constitute a family of proteins that are induced in mammalian cells in response to environmental stressors. Despite their apparent lack of intrinsic catalytic antioxidant activity, Sestrins protect cells from oxidative stress by lowering intracellular levels of H2O2. Here we review the mechanisms by which various types of cellular stress induce Sestrin gene transcription as well as those underlying the antioxidant function of these proteins. Several transcriptional factors, including p53, HIF-1, FoxO, C/EBP-β, ATF4, Nrf2, and PGC-1α, contribute directly to the transcriptional activation of Sestrin genes in response to various types of stress...
November 2015: Free Radical Biology & Medicine
Prasanna Abeyrathna, Yunchao Su
Akt kinase, a member of AGC kinases, is important in many cellular functions including proliferation, migration, cell growth and metabolism. There are three known Akt isoforms which play critical and diverse roles in the cardiovascular system. Akt activity is regulated by its upstream regulatory pathways at transcriptional and post-translational levels. Beta-catenin/Tcf-4, GLI1 and Stat-3 are some of few known transcriptional regulators of AKT gene. Threonine 308 and serine 473 are the two critical phosphorylation sites of Akt1...
November 2015: Vascular Pharmacology
Masaki Miyazaki, Kazuko Miyazaki, Shuwen Chen, Vivek Chandra, Keisuke Wagatsuma, Yasutoshi Agata, Hans-Reimer Rodewald, Rintaro Saito, Aaron N Chang, Nissi Varki, Hiroshi Kawamoto, Cornelis Murre
It is now well established that the E and Id protein axis regulates multiple steps in lymphocyte development. However, it remains unknown how E and Id proteins mechanistically enforce and maintain the naïve T-cell fate. Here we show that Id2 and Id3 suppressed the development and expansion of innate variant follicular helper T (TFH) cells. Innate variant TFH cells required major histocompatibility complex (MHC) class I-like signaling and were associated with germinal center B cells. We found that Id2 and Id3 induced Foxo1 and Foxp1 expression to antagonize the activation of a TFH transcription signature...
February 15, 2015: Genes & Development
Wan Long Zhu, Honglian Tong, Jing Tsong Teh, Mei Wang
FoxO proteins are important regulators in cellular metabolism and are recognized to be nodes in multiple signaling pathways, most notably those involving PI3K/AKT and mTOR. FoxO proteins primarily function as transcription factors, but recent study suggests that cytosolic FoxO1 participates in the regulation of autophagy. In the current study, we find that cytosolic FoxO1 indeed stimulates cellular autophagy in multiple cancer cell lines, and that it regulates not only basal autophagy but also that induced by rapamycin and that in response to nutrient deprivation...
2014: PloS One
Dongjun Lee, Stephen M Sykes, Demetrios Kalaitzidis, Andrew A Lane, Youmna Kfoury, Marc H G P Raaijmakers, Ying-Hua Wang, Scott A Armstrong, David T Scadden
Central to cellular proliferative, survival, and metabolic responses is the serine/threonine kinase mTOR, which is activated in many human cancers. mTOR is present in distinct complexes that are either modulated by AKT (mTORC1) or are upstream and regulatory of it (mTORC2). Governance of mTORC2 activity is poorly understood. Here, we report a transmembrane molecule in hematopoietic progenitor cells that physically interacts with and inhibits RICTOR, an essential component of mTORC2. Upstream of mTORC2 (UT2) negatively regulates mTORC2 enzymatic activity, reducing AKT(S473), PKCα, and NDRG1 phosphorylation and increasing FOXO transcriptional activity in an mTORC2-dependent manner...
November 11, 2014: Stem Cell Reports
Jose J Limon, Lomon So, Stefan Jellbauer, Honyin Chiu, Juana Corado, Stephen M Sykes, Manuela Raffatellu, David A Fruman
The mammalian target of rapamycin (mTOR) is a kinase that functions in two distinct complexes, mTORC1 and mTORC2. In peripheral B cells, complete deletion of mTOR suppresses germinal center B-cell responses, including class switching and somatic hypermutation. The allosteric mTORC1 inhibitor rapamycin blocks proliferation and differentiation, but lower doses can promote protective IgM responses. To elucidate the complexity of mTOR signaling in B cells further, we used ATP-competitive mTOR kinase inhibitors (TOR-KIs), which inhibit both mTORC1 and mTORC2...
November 25, 2014: Proceedings of the National Academy of Sciences of the United States of America
Anthony M J Sanchez, Henri Bernardi, Guillaume Py, Robin B Candau
Physical exercise is a stress that can substantially modulate cellular signaling mechanisms to promote morphological and metabolic adaptations. Skeletal muscle protein and organelle turnover is dependent on two major cellular pathways: Forkhead box class O proteins (FOXO) transcription factors that regulate two main proteolytic systems, the ubiquitin-proteasome, and the autophagy-lysosome systems, including mitochondrial autophagy, and the MTORC1 signaling associated with protein translation and autophagy inhibition...
October 15, 2014: American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
Harita Dharaneeswaran, Md Ruhul Abid, Lei Yuan, Dylan Dupuis, David Beeler, Katherine C Spokes, Lauren Janes, Tracey Sciuto, Peter M Kang, Shou-Ching S Jaminet, Ann Dvorak, Marianne A Grant, Erzsébet Ravasz Regan, William C Aird
RATIONALE: Forkhead box-O transcription factors (FoxOs) transduce a wide range of extracellular signals, resulting in changes in cell survival, cell cycle progression, and several cell type-specific responses. FoxO1 is expressed in many cell types, including endothelial cells (ECs). Previous studies have shown that Foxo1 knockout in mice results in embryonic lethality at E11 because of impaired vascular development. In contrast, somatic deletion of Foxo1 is associated with hyperproliferation of ECs...
July 7, 2014: Circulation Research
Bodo C Melnik
In this issue, Hellmann-Regen et al. suggested that anti-acne effects of erythromycin and tetracyclines may be related to their inhibitory effect of cytochrome P450-mediated degradation of all-trans-retinoic acid (ATRA). We have recently proposed that all anti-acne agents function by attenuation of increased mTORC1 signalling. This commentary links the P450 system to mTORC1 regulation in acne. Drug-mediated induction of P450 activity or P450 mutants with increased catabolic activity may reduce cellular ATRA levels and FoxO1 expression, thus reducing FoxO-mediated mTORC1 inhibition...
May 2014: Experimental Dermatology
Huibin Tang, Ken Inoki, Myung Lee, Erika Wright, Andy Khuong, Amanda Khuong, Sista Sugiarto, Matthew Garner, Jihye Paik, Ronald A DePinho, Daniel Goldman, Kun-Liang Guan, Joseph B Shrager
Skeletal muscle mass and function are regulated by motor innervation, and denervation results in muscle atrophy. The activity of mammalian target of rapamycin complex 1 (mTORC1) is substantially increased in denervated muscle, but its regulatory role in denervation-induced atrophy remains unclear. At early stages after denervation of skeletal muscle, a pathway involving class II histone deacetylases and the transcription factor myogenin mediates denervation-induced muscle atrophy. We found that at later stages after denervation of fast-twitch muscle, activation of mTORC1 contributed to atrophy and that denervation-induced atrophy was mitigated by inhibition of mTORC1 with rapamycin...
February 25, 2014: Science Signaling
Arthur J Chu
Through pattern recognition receptors, infections and tissue injuries drive innate immune cells to trigger inflammation with elevated cytokines, chemokines, growth factors, and other mediators. Inflammation resolves upon removal of pathogenic signals and the presence of pro-resolving conditions including combating adaptive immunity. Failure of resolution progresses into chronic inflammation, manifesting as detrimental disease development known as inflammatory diseases including cardiovascular diseases, diabetes, obesity, cancers, etc...
February 2014: Inflammation & Allergy Drug Targets
Yeting Guo, Harry R Gosker, Annemie M W J Schols, Sophia Kapchinsky, Jean Bourbeau, Marco Sandri, R Thomas Jagoe, Richard Debigaré, François Maltais, Tanja Taivassalo, Sabah N A Hussain
RATIONALE: Locomotor muscle atrophy develops in patients with chronic obstructive pulmonary disease (COPD) partly because of increased protein degradation by the ubiquitin-proteasome system. It is not known if autophagy also contributes to protein degradation. OBJECTIVES: To investigate whether autophagy is enhanced in locomotor muscles of stable patients with COPD, to quantify autophagy-related gene expression in these muscles, and to identify mechanisms of autophagy induction...
December 1, 2013: American Journal of Respiratory and Critical Care Medicine
Stefania Saoncella, Beatrice Tassone, Erika Deklic, Fabio Avolio, Cristina Jon, Giusy Tornillo, Elisa De Luca, Enzo Di Iorio, Roberto Piva, Sara Cabodi, Emilia Turco, Pier Paolo Pandolfi, Enzo Calautti
Signals downstream of Akt can either favor or oppose stem cell (SC) maintenance, but how this dual role can be achieved is still undefined. Using human limbal keratinocyte stem cells (LKSCs), a SC type used in transplantation therapies for corneal regeneration, we show that Akt signaling is prominent in SC populations both in vivo and in vitro, and that Akt1 promotes while Akt2 opposes SC self-renewal. Noteworthy, loss of Akt2 signaling enhances LKSC maintenance ex vivo, whereas Akt1 depletion anticipates SC exhaustion...
March 2014: Stem Cells
Jinwei Du, Qiang Li, Fangqiang Tang, Michelle A Puchowitz, Hisashi Fujioka, Sally L Dunwoodie, David Danielpour, Yu-Chung Yang
Mammalian adult hematopoietic stem cells (HSCs) reside in the hypoxic bone marrow microenvironment and display a distinct metabolic phenotype compared with their progenitors. It has been proposed that HSCs generate energy mainly through anaerobic glycolysis in a pyruvate dehydrogenase kinase (Pdk)-dependent manner. Cited2 is an essential regulator for HSC quiescence, apoptosis, and function. Herein, we show that conditional deletion of Cited2 in murine HSCs results in elevated levels of reactive oxygen species, decreased cellular glutathione content, increased mitochondrial activity, and decreased glycolysis...
January 15, 2014: Stem Cells and Development
Perrine Castets, Markus A Rüegg
Autophagy impairment has been implicated in several muscle disorders and in age-related dysfunction. Although previous reports pointed to FOXO as a positive regulator of autophagy in skeletal muscle, it remained unclear what is triggering autophagy. We found that TSC muscle knockout (TSCmKO) mice, characterized by specific depletion of TSC1 in skeletal muscle, and thus constant activation of MTORC1, develop a late-onset myopathy marked by the accumulation of autophagic substrates. In those mice, autophagy induction is blocked despite FOXO activation because of constant MTORC1-dependent inhibition of ULK1...
September 2013: Autophagy
Zhe Zhang, Mai Tsukikawa, Min Peng, Erzsebet Polyak, Eiko Nakamaru-Ogiso, Julian Ostrovsky, Shana McCormack, Emily Place, Colleen Clarke, Gail Reiner, Elizabeth McCormick, Eric Rappaport, Richard Haas, Joseph A Baur, Marni J Falk
Primary mitochondrial respiratory chain (RC) diseases are heterogeneous in etiology and manifestations but collectively impair cellular energy metabolism. Mechanism(s) by which RC dysfunction causes global cellular sequelae are poorly understood. To identify a common cellular response to RC disease, integrated gene, pathway, and systems biology analyses were performed in human primary RC disease skeletal muscle and fibroblast transcriptomes. Significant changes were evident in muscle across diverse RC complex and genetic etiologies that were consistent with prior reports in other primary RC disease models and involved dysregulation of genes involved in RNA processing, protein translation, transport, and degradation, and muscle structure...
2013: PloS One
A Lin, J Yao, L Zhuang, D Wang, J Han, E W-F Lam, B Gan
Normal cells possess adaptive mechanisms to couple energy availability with cell growth (cell size increase) and survival, and imbalances are associated with major diseases such as cancer. Inactivation of critical regulators involved in energy stress response, including adenosine monophosphate-activated protein kinase (AMPK), liver kinase B1 (LKB1), tuberous sclerosis complex 1 (TSC1) and tuberous sclerosis complex 2 (TSC2), leads to uncontrolled cell growth yet increased apoptosis under energy stress. These energy stress regulators are also important in tumor suppression and metabolism...
June 12, 2014: Oncogene
Lakshmipathi Vadlakonda, Abhinandita Dash, Mukesh Pasupuleti, Kotha Anil Kumar, Pallu Reddanna
The serine threonine protein kinase, Akt, is at the central hub of signaling pathways that regulates cell growth, differentiation, and survival. The reciprocal relation that exists between the two activating phosphorylation sites of Akt, T308 and S473, and the two mTOR complexes, C1 and C2, forms the central controlling hub that regulates these cellular functions. In our previous review "PI3Kinase (PI3K)-AKT-mTOR and Wnt signaling pathways in cell cycle" we discussed the reciprocal relation between mTORC1 and C2 complexes in regulating cell metabolism and cell cycle progression in cancer cells...
2013: Frontiers in Oncology
M Sandri, L Barberi, A Y Bijlsma, B Blaauw, K A Dyar, G Milan, C Mammucari, C G M Meskers, G Pallafacchina, A Paoli, D Pion, M Roceri, V Romanello, A L Serrano, L Toniolo, L Larsson, A B Maier, P Muñoz-Cánoves, A Musarò, M Pende, C Reggiani, R Rizzuto, S Schiaffino
During ageing skeletal muscles undergo a process of structural and functional remodelling that leads to sarcopenia, a syndrome characterized by loss of muscle mass and force and a major cause of physical frailty. To determine the causes of sarcopenia and identify potential targets for interventions aimed at mitigating ageing-dependent muscle wasting, we focussed on the main signalling pathway known to control protein turnover in skeletal muscle, consisting of the insulin-like growth factor 1 (IGF1), the kinase Akt and its downstream effectors, the mammalian target of rapamycin (mTOR) and the transcription factor FoxO...
June 2013: Biogerontology
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