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JOURNAL ARTICLE
Anika Shimonty, Fabrizio Pin, Matthew Prideaux, Gang Peng, Joshua Huot, Hyeonwoo Kim, Clifford J Rosen, Bruce M Spiegelman, Lynda F Bonewald
Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (knockout [KO]), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet...
April 25, 2024: ELife
#2
Hans-Georg Sprenger, Melanie J Mittenbühler, Yizhi Sun, Jonathan G Van Vranken, Sebastian Schindler, Abhilash Jayaraj, Sumeet A Khetarpal, Ariana Vargas-Castillo, Anna M Puszynska, Jessica B Spinelli, Andrea Armani, Tenzin Kunchok, Birgitta Ryback, Hyuk-Soo Seo, Kijun Song, Luke Sebastian, Coby O'Young, Chelsea Braithwaite, Sirano Dhe-Paganon, Nils Burger, Evanna L Mills, Steven P Gygi, Haribabu Arthanari, Edward T Chouchani, David M Sabatini, Bruce M Spiegelman
Ergothioneine (EGT) is a diet-derived, atypical amino acid that accumulates to high levels in human tissues. Reduced EGT levels have been linked to age-related disorders, including neurodegenerative and cardiovascular diseases, while EGT supplementation is protective in a broad range of disease and aging models in mice. Despite these promising data, the direct and physiologically relevant molecular target of EGT has remained elusive. Here we use a systematic approach to identify how mitochondria remodel their metabolome in response to exercise training...
April 10, 2024: bioRxiv
#3
JOURNAL ARTICLE
Serge Ducommun, Paulo R Jannig, Igor Cervenka, Marta Murgia, Melanie J Mittenbühler, Ekaterina Chernogubova, José M Dias, Baptiste Jude, Jorge C Correia, Jonathan G Van Vranken, Gabriel Ocana-Santero, Margareta Porsmyr-Palmertz, Sarah McCann Haworth, Vicente Martínez-Redondo, Zhengye Liu, Mattias Carlström, Matthias Mann, Johanna T Lanner, Ana I Teixeira, Lars Maegdefessel, Bruce M Spiegelman, Jorge L Ruas
OBJECTIVE: Skeletal muscle plasticity and remodeling are critical for adapting tissue function to use, disuse, and regeneration. The aim of this study was to identify genes and molecular pathways that regulate the transition from atrophy to compensatory hypertrophy or recovery from injury. Here, we have used a mouse model of hindlimb unloading and reloading, which causes skeletal muscle atrophy, and compensatory regeneration and hypertrophy, respectively. METHODS: We analyzed mouse skeletal muscle at the transition from hindlimb unloading to reloading for changes in transcriptome and extracellular fluid proteome...
March 6, 2024: Molecular Metabolism
#4
JOURNAL ARTICLE
Eben Estell, Tsunagu Ichikawa, Paige Giffault, Lynda Bonewald, Bruce Spiegelman, Clifford Rosen
Irisin is a myokine released from muscle during exercise with distinct signaling effects on tissues throughout the body, including an influence on skeletal remodeling. Our previous work has shown that irisin stimulates resorption, a key first step in bone remodeling, by enhancing osteoclastogenesis. The present study further investigates the action of irisin on the metabolic function of osteoclast progenitors during differentiation. Fluorescent imaging showed increased mitochondrial content and reactive oxygen species production with irisin treatment in osteoclast progenitors after 48 h of osteoclastogenic culture...
December 14, 2023: Biomedicines
#5
Anika Shimonty, Fabrizio Pin, Matt Prideaux, Gang Peng, Joshua R Huot, Hyeonwoo Kim, Clifford J Rosen, Bruce M Spiegelman, Lynda F Bonewald
Irisin, released from exercised muscle, has been shown to have beneficial effects on numerous tissues but its effects on bone are unclear. We found significant sex and genotype differences in bone from wildtype (WT) mice compared to mice lacking Fndc5 (KO), with and without calcium deficiency. Despite their bone being indistinguishable from WT females, KO female mice were partially protected from osteocytic osteolysis and osteoclastic bone resorption when allowed to lactate or when placed on a low-calcium diet...
November 6, 2023: bioRxiv
#6
JOURNAL ARTICLE
P Kent Langston, Yizhi Sun, Birgitta A Ryback, Amber L Mueller, Bruce M Spiegelman, Christophe Benoist, Diane Mathis
Exercise enhances physical performance and reduces the risk of many disorders such as cardiovascular disease, type 2 diabetes, dementia, and cancer. Exercise characteristically incites an inflammatory response, notably in skeletal muscles. Although some effector mechanisms have been identified, regulatory elements activated in response to exercise remain obscure. Here, we have addressed the roles of Foxp3+ CD4+ regulatory T cells (Tregs ) in the healthful activities of exercise via immunologic, transcriptomic, histologic, metabolic, and biochemical analyses of acute and chronic exercise models in mice...
November 3, 2023: Science Immunology
#7
JOURNAL ARTICLE
Eunhee Kim, Hyeonwoo Kim, Mark P Jedrychowski, Grisilda Bakiasi, Joseph Park, Jane Kruskop, Younjung Choi, Sang Su Kwak, Luisa Quinti, Doo Yeon Kim, Christiane D Wrann, Bruce M Spiegelman, Rudolph E Tanzi, Se Hoon Choi
A pathological hallmark of Alzheimer's disease (AD) is the deposition of amyloid-β (Aβ) protein in the brain. Physical exercise has been shown to reduce Aβ burden in various AD mouse models, but the underlying mechanisms have not been elucidated. Irisin, an exercise-induced hormone, is the secreted form of fibronectin type-III-domain-containing 5 (FNDC5). Here, using a three-dimensional (3D) cell culture model of AD, we show that irisin significantly reduces Aβ pathology by increasing astrocytic release of the Aβ-degrading enzyme neprilysin (NEP)...
August 30, 2023: Neuron
#8
JOURNAL ARTICLE
Pedro Saavedra, Phillip A Dumesic, Yanhui Hu, Elizabeth Filine, Patrick Jouandin, Richard Binari, Sarah E Wilensky, Jonathan Rodiger, Haiyun Wang, Weihang Chen, Ying Liu, Bruce M Spiegelman, Norbert Perrimon
Metabolic flexibility of muscle tissue describes the adaptive capacity to use different energy substrates according to their availability. The disruption of this ability associates with metabolic disease. Here, using a Drosophila model of systemic metabolic dysfunction triggered by yorkie-induced gut tumors, we show that the transcription factor REPTOR is an important regulator of energy metabolism in muscles. We present evidence that REPTOR is activated in muscles of adult flies with gut yorkie-tumors, where it modulates glucose metabolism...
August 15, 2023: Nature Communications
#9
JOURNAL ARTICLE
Mu A, Thomas E Wales, Haixia Zhou, Sorin-Valeriu Draga-Coletă, Christoph Gorgulla, Katherine A Blackmore, Melanie J Mittenbühler, Caroline R Kim, Dina Bogoslavski, Qiuyang Zhang, Zi-Fu Wang, Mark P Jedrychowski, Hyuk-Soo Seo, Kijun Song, Andrew Z Xu, Luke Sebastian, Steven P Gygi, Haribabu Arthanari, Sirano Dhe-Paganon, Patrick R Griffin, John R Engen, Bruce M Spiegelman
Exercise benefits the human body in many ways. Irisin is secreted by muscle, increased with exercise, and conveys physiological benefits, including improved cognition and resistance to neurodegeneration. Irisin acts via αV integrins; however, a mechanistic understanding of how small polypeptides like irisin can signal through integrins is poorly understood. Using mass spectrometry and cryo-EM, we demonstrate that the extracellular heat shock protein 90α (eHsp90α) is secreted by muscle with exercise and activates integrin αVβ5...
June 1, 2023: Molecular Cell
#10
JOURNAL ARTICLE
Wejdan M Alenezi, Caitlin T Fierheller, Corinne Serruya, Timothée Revil, Kathleen K Oros, Deepak N Subramanian, Jeffrey Bruce, Dan Spiegelman, Trevor Pugh, Ian G Campbell, Anne-Marie Mes-Masson, Diane Provencher, William D Foulkes, Zaki El Haffaf, Guy Rouleau, Luigi Bouchard, Celia M T Greenwood, Jiannis Ragoussis, Patricia N Tonin
Not all familial ovarian cancer (OC) cases are explained by pathogenic germline variants in known risk genes. A candidate gene approach involving DNA repair pathway genes was applied to identify rare recurring pathogenic variants in familial OC cases not associated with known OC risk genes from a population exhibiting genetic drift. Whole exome sequencing (WES) data of 15 OC cases from 13 families tested negative for pathogenic variants in known OC risk genes were investigated for candidate variants in 468 DNA repair pathway genes...
2023: Frontiers in Oncology
#11
Phillip A Dumesic, Sarah E Wilensky, Symanthika Bose, Jonathan G Van Vranken, Steven P Gygi, Bruce M Spiegelman
Adipose thermogenesis involves specialized mitochondrial function that counteracts metabolic disease through dissipation of chemical energy as heat. However, inflammation present in obese adipose tissue can impair oxidative metabolism. Here, we show that PGC1α, a key governor of mitochondrial biogenesis and thermogenesis, is negatively regulated at the level of mRNA translation by the little-known RNA-binding protein RBM43. Rbm43 is expressed selectively in white adipose depots that have low thermogenic potential, and is induced by inflammatory cytokines...
January 7, 2023: bioRxiv
#12
JOURNAL ARTICLE
Melanie J Mittenbühler, Mark P Jedrychowski, Jonathan G Van Vranken, Hans-Georg Sprenger, Sarah Wilensky, Phillip A Dumesic, Yizhi Sun, Andrea Tartaglia, Dina Bogoslavski, Mu A, Haopeng Xiao, Katherine A Blackmore, Anita Reddy, Steven P Gygi, Edward T Chouchani, Bruce M Spiegelman
Proteins are secreted from cells to send information to neighboring cells or distant tissues. Because of the highly integrated nature of energy balance systems, there has been particular interest in myokines and adipokines. These are challenging to study through proteomics because serum or plasma contains highly abundant proteins that limit the detection of proteins with lower abundance. We show here that extracellular fluid (EF) from muscle and fat tissues of mice shows a different protein composition than either serum or tissues...
March 7, 2023: Cell Metabolism
#13
JOURNAL ARTICLE
Haopeng Xiao, Luiz H M Bozi, Yizhi Sun, Christopher L Riley, Vivek M Philip, Mandy Chen, Jiaming Li, Tian Zhang, Evanna L Mills, Margo P Emont, Wenfei Sun, Anita Reddy, Ryan Garrity, Jiani Long, Tobias Becher, Laura Potano Vitas, Dina Laznik-Bogoslavski, Martha Ordonez, Xinyue Liu, Xiong Chen, Yun Wang, Weihai Liu, Nhien Tran, Yitong Liu, Yang Zhang, Aaron M Cypess, Andrew P White, Yuchen He, Rebecca Deng, Heiko Schöder, Joao A Paulo, Mark P Jedrychowski, Alexander S Banks, Yu-Hua Tseng, Paul Cohen, Linus T Tsai, Evan D Rosen, Samuel Klein, Maria Chondronikola, Fiona E McAllister, Nick Van Bruggen, Edward L Huttlin, Bruce M Spiegelman, Gary A Churchill, Steven P Gygi, Edward T Chouchani
Brown adipose tissue (BAT) regulates metabolic physiology. However, nearly all mechanistic studies of BAT protein function occur in a single inbred mouse strain, which has limited the understanding of generalizable mechanisms of BAT regulation over physiology. Here, we perform deep quantitative proteomics of BAT across a cohort of 163 genetically defined diversity outbred mice, a model that parallels the genetic and phenotypic variation found in humans. We leverage this diversity to define the functional architecture of the outbred BAT proteome, comprising 10,479 proteins...
November 2, 2022: Cell
#14
JOURNAL ARTICLE
Tae-In Kam, Hyejin Park, Shih-Ching Chou, Jonathan G Van Vranken, Melanie J Mittenbühler, Hyeonwoo Kim, Mu A, Yu Ree Choi, Devanik Biswas, Justin Wang, Yu Shin, Alexis Loder, Senthilkumar S Karuppagounder, Christiane D Wrann, Valina L Dawson, Bruce M Spiegelman, Ted M Dawson
Physical activity provides clinical benefit in Parkinson's disease (PD). Irisin is an exercise-induced polypeptide secreted by skeletal muscle that crosses the blood-brain barrier and mediates certain effects of exercise. Here, we show that irisin prevents pathologic α-synuclein (α-syn)-induced neurodegeneration in the α-syn preformed fibril (PFF) mouse model of sporadic PD. Intravenous delivery of irisin via viral vectors following the stereotaxic intrastriatal injection of α-syn PFF cause a reduction in the formation of pathologic α-syn and prevented the loss of dopamine neurons and lowering of striatal dopamine...
September 6, 2022: Proceedings of the National Academy of Sciences of the United States of America
#15
JOURNAL ARTICLE
Yizhi Sun, Bruce M Spiegelman
Adaptive thermogenesis has attracted much attention because of its ability to increase systemic energy expenditure and to counter obesity and diabetes. Thermogenic fat cells use creatine to stimulate futile substrate cycling, dissipating chemical energy as heat; but the molecular basis is unclear. Latest data show that thermogenic fat cells localize tissue-nonspecific alkaline phosphatase (TNAP) to mitochondria to hydrolyze phosphocreatine, which initiates a futile cycle of creatine dephosphorylation and phosphorylation...
May 2022: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
#16
JOURNAL ARTICLE
Paulo R Jannig, Phillip A Dumesic, Bruce M Spiegelman, Jorge L Ruas
The peroxisome proliferator-activated receptor γ coactivator-1α (Ppargc1a) gene encodes several PGC-1α isoforms that regulate mitochondrial bioenergetics and cellular adaptive processes. Expressing specific PGC-1α isoforms in mice can confer protection in different disease models. This SnapShot summarizes how regulation of Ppargc1a transcription, splicing, translation, protein stability, and activity underlies its multifaceted functions. To view this SnapShot, open or download the PDF.
April 14, 2022: Cell
#17
JOURNAL ARTICLE
Evanna L Mills, Cathal Harmon, Mark P Jedrychowski, Haopeng Xiao, Anja V Gruszczyk, Gary A Bradshaw, Nhien Tran, Ryan Garrity, Dina Laznik-Bogoslavski, John Szpyt, Hannah Prendeville, Lydia Lynch, Michael P Murphy, Steven P Gygi, Bruce M Spiegelman, Edward T Chouchani
Uncoupling protein 1 (UCP1) is a major regulator of brown and beige adipocyte energy expenditure and metabolic homeostasis. However, the widely employed UCP1 loss-of-function model has recently been shown to have a severe deficiency in the entire electron transport chain of thermogenic fat. As such, the role of UCP1 in metabolic regulation in vivo remains unclear. We recently identified cysteine-253 as a regulatory site on UCP1 that elevates protein activity upon covalent modification. Here, we examine the physiological importance of this site through the generation of a UCP1 cysteine-253-null (UCP1 C253A) mouse, a precise genetic model for selective disruption of UCP1 in vivo...
January 4, 2022: Cell Metabolism
#18
Mohammad R Islam, Sophia Valaris, Michael F Young, Erin B Haley, Renhao Luo, Sabrina F Bond, Sofia Mazuera, Robert R Kitchen, Barbara J Caldarone, Luis E B Bettio, Brian R Christie, Angela B Schmider, Roy J Soberman, Antoine Besnard, Mark P Jedrychowski, Hyeonwoo Kim, Hua Tu, Eunhee Kim, Se Hoon Choi, Rudolph E Tanzi, Bruce M Spiegelman, Christiane D Wrann
No abstract text is available yet for this article.
October 2021: Nature metabolism
#19
JOURNAL ARTICLE
Mohammad R Islam, Sophia Valaris, Michael F Young, Erin B Haley, Renhao Luo, Sabrina F Bond, Sofia Mazuera, Robert R Kitchen, Barbara J Caldarone, Luis E B Bettio, Brian R Christie, Angela B Schmider, Roy J Soberman, Antoine Besnard, Mark P Jedrychowski, Hyeonwoo Kim, Hua Tu, Eunhee Kim, Se Hoon Choi, Rudolph E Tanzi, Bruce M Spiegelman, Christiane D Wrann
Identifying secreted mediators that drive the cognitive benefits of exercise holds great promise for the treatment of cognitive decline in ageing or Alzheimer's disease (AD). Here, we show that irisin, the cleaved and circulating form of the exercise-induced membrane protein FNDC5, is sufficient to confer the benefits of exercise on cognitive function. Genetic deletion of Fndc5/irisin (global Fndc5 knock-out (KO) mice; F5KO) impairs cognitive function in exercise, ageing and AD. Diminished pattern separation in F5KO mice can be rescued by delivering irisin directly into the dentate gyrus, suggesting that irisin is the active moiety...
August 2021: Nature metabolism
#20
JOURNAL ARTICLE
Zewen Jiang, Meng Zhao, Laetitia Voilquin, Yunshin Jung, Mari A Aikio, Tanushi Sahai, Florence Y Dou, Alexander M Roche, Ivan Carcamo-Orive, Joshua W Knowles, Martin Wabitsch, Eric A Appel, Caitlin L Maikawa, Joao Paulo Camporez, Gerald I Shulman, Linus Tsai, Evan D Rosen, Christopher D Gardner, Bruce M Spiegelman, Katrin J Svensson
With the increasing prevalence of type 2 diabetes and fatty liver disease, there is still an unmet need to better treat hyperglycemia and hyperlipidemia. Here, we identify isthmin-1 (Ism1) as an adipokine and one that has a dual role in increasing adipose glucose uptake while suppressing hepatic lipid synthesis. Ism1 ablation results in impaired glucose tolerance, reduced adipose glucose uptake, and reduced insulin sensitivity, demonstrating an endogenous function for Ism1 in glucose regulation. Mechanistically, Ism1 activates a PI3K-AKT signaling pathway independently of the insulin and insulin-like growth factor receptors...
September 7, 2021: Cell Metabolism
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