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| Open AccessLSD1 inhibition circumvents glucocorticoid-induced muscle wasting of male mice
Even though glucocorticoids are potent anti-inflammatory agents, they can cause muscle wasting. Here, the authors show that targeting the glucocorticoid receptor coactivator LSD1 limits muscle loss without reducing the drugs’ efficiency on the immune system.
- Qingshuang Cai
- , Rajesh Sahu
- & Delphine Duteil
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Article
| Open AccessSenescent-like macrophages mediate angiogenesis for endplate sclerosis via IL-10 secretion in male mice
In their previous study, the researchers systematically revealed that endplate sclerosis is a significant aspect of spine degeneration or aging and a primary source of spinal pain. However, the underlying mechanisms of endplate sclerosis remained unclear. In their current report, it is shown that senescent cells accumulate in the sclerotic endplates of lumbar spine instability (LSI) or aging mouse models. The clearance of these senescent cells was found to restrain angiogenesis coupled with endplate sclerosis. Notably, macrophages were identified as undergoing senescence in the sclerotic endplates. The specific knockout of cdkn2a (p16) in macrophages abrogated LSI or aging-induced angiogenesis and sclerosis in the endplates. Moreover, both in vivo and in vitro studies indicated that IL-10 mediates the effects of senescent macrophages on angiogenesis and sclerosis in the endplates. Overall, these findings suggest that senescent macrophages orchestrate angiogenesis coupling with endplate sclerosis via the IL-10/pSTAT3 axis. This study enhances the understanding of the connection between immune senescence and endplate sclerosis and uncovers senescent macrophage-initiated endplate sclerosis as potential therapeutic targets for spinal degeneration.
- Yonggang Fan
- , Weixin Zhang
- & Shuangfei Ni
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Article
| Open AccessMyosin-binding protein C regulates the sarcomere lattice and stabilizes the OFF states of myosin heads
Myosin-binding protein C (MyBP-C) resides and interacts with the myosin filaments in striated muscle and regulates contraction via an unclear mechanism. Here, the authors demonstrate that MyBP-C regulates the performance of myosin heads.
- Anthony L. Hessel
- , Nichlas M. Engels
- & Samantha P. Harris
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Article
| Open AccessDynamic similarity and the peculiar allometry of maximum running speed
How fast can animals run? Here, the authors show that maximum running speed is limited by different musculoskeletal constraints across animal size: kinetic energy capacity in small animals, and work capacity in large animals.
- David Labonte
- , Peter J. Bishop
- & Christofer J. Clemente
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Comment
| Open AccessThe bioethics of skeletal anatomy collections from India
Millions of skeletal remains from South Asia were exported in red markets (the underground economy of human tissues/organs) to educational institutions globally for over a century. It is time to recognize the personhood of the people who were systematically made into anatomical objects and acknowledge the scientific racism in creating and continuing to use them.
- Sabrina C. Agarwal
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Article
| Open AccessArticular surface interactions distinguish dinosaurian locomotor joint poses
Criteria for evaluating joint articulation in vertebrates are lacking. Here, the authors propose an approach for combining measurements of 3D articular overlap, symmetry, and congruence into a single metric, and apply this to examine the walking stride of Deinonychus antirrhopus.
- Armita R. Manafzadeh
- , Stephen M. Gatesy
- & Bhart-Anjan S. Bhullar
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Article
| Open Access5-aminosalicylic acid suppresses osteoarthritis through the OSCAR-PPARγ axis
There is a strong need for the development of effective and safe disease-modifying osteoarthritis drugs. Here, the authors show that 5-ASA, an anti-inflammatory drug used for ulcerative colitis, shows promise in treating osteoarthritis in mice by improving cartilage and reducing inflammation even when administered at late stages of disease.
- Jihee Kim
- , Gina Ryu
- & Soo Young Lee
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Article
| Open AccessFunctional and analytical recapitulation of osteoclast biology on demineralized bone paper
Here, authors report demineralized bone paper-based in vitro osteogenic culture and assay platforms that replicate essential bone tissue complexity, osteoclast processes, and drug responses with high fidelity and predictive power.
- Yongkuk Park
- , Tadatoshi Sato
- & Jungwoo Lee
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Article
| Open AccessMechanical loading and hyperosmolarity as a daily resetting cue for skeletal circadian clocks
The 24-hour circadian clocks in cartilage and intervertebral disc play key roles in regulating tissue physiology, yet how they are reset on a daily basis remains elusive. Here the authors show that daily patterns of mechanical loading and associated changes in osmolarity provide a tissue-type specific entrainment time cue for these skeletal clocks.
- Michal Dudek
- , Dharshika R. J. Pathiranage
- & Qing-Jun Meng
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Article
| Open AccessReprogramming of cis-regulatory networks during skeletal muscle atrophy in male mice
Skeletal muscle’s metabolic status has an impact on health and the prognosis of chronic diseases. Here the authors unveil an atlas of open chromatin regions in skeletal muscles using single-nucleus techniques on juvenile male mice, highlight regulatory dynamics between normal and denervated states, and pinpoint ELK4 as a pivotal factor in muscle atrophy.
- Hongchun Lin
- , Hui Peng
- & Zhaoyong Hu
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Article
| Open AccessEarly presence of Homo sapiens in Southeast Asia by 86–68 kyr at Tam Pà Ling, Northern Laos
Here the authors report new human fossils from Tam Pà Ling cave, Laos, consisting of a cranial and a tibial fragment, dated to 68–86 thousand years ago. This find confirms that Homo sapiens were present in Southeast Asia by this time and the shape of the fossils indicates they may have descended from non-local populations.
- Sarah E. Freidline
- , Kira E. Westaway
- & Fabrice Demeter
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Article
| Open AccessAugmented temperature fluctuation aggravates muscular atrophy through the gut microbiota
Higher diurnal temperature range in humans correlates with the prevalence of sarcopenia. Here, the authors show that fluctuated temperature exposure accelerates muscle atrophy and dampens exercise performance via altering microbiota composition in aged mice.
- Ya Liu
- , Yifan Guo
- & Yan Huang
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Article
| Open AccessRare genetic variants impact muscle strength
Here, the authors provide an exome study of hand grip strength, a proxy of generalized muscle strength. They identify six exome-wide significant genes, with links to disease, and additivity of rare and common genetic variant effects on muscle strength.
- Yunfeng Huang
- , Dora Bodnar
- & Heiko Runz
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Article
| Open AccessDirectionality of developing skeletal muscles is set by mechanical forces
The mechanisms that drive myocyte orientation and fusion to control muscle directionality are not well understood. Here authors show that the developing skeleton produces mechanical tension that instructs the directional outgrowth of skeletal muscles.
- Kazunori Sunadome
- , Alek G. Erickson
- & Igor Adameyko
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Article
| Open AccessKIAA1199 deficiency enhances skeletal stem cell differentiation to osteoblasts and promotes bone regeneration
The levels of a factor secreted by bone marrow stromal cells, KIAA1199, associate with osteoporotic fracture risk. Here, the authors show that KIAA1199 deficiency can lead to enhanced bone formation, accelerated bone healing, and protects from ovariectomy-induced bone loss.
- Li Chen
- , Kaikai Shi
- & Moustapha Kassem
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Article
| Open AccessDefective BVES-mediated feedback control of cAMP in muscular dystrophy
cAMP is an important second messenger involved in many aspects of biological processes. Here, Li et al. shows that blood vessel epicardial substance (BVES) is a negative regulator of cAMP signaling required for maintaining muscle mass and function.
- Haiwen Li
- , Peipei Wang
- & Renzhi Han
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Article
| Open AccessAge-related matrix stiffening epigenetically regulates α-Klotho expression and compromises chondrocyte integrity
Matrix stiffening is a quintessential feature of aged tissues. Authors show that an aged (stiff) matrix epigenetically represses the gene encoding the longevity factor, α-Klotho, resulting in chondrocyte dysfunction, a leading cause of osteoarthritis.
- Hirotaka Iijima
- , Gabrielle Gilmer
- & Fabrisia Ambrosio
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Article
| Open AccessDisruption of mitochondrial dynamics triggers muscle inflammation through interorganellar contacts and mitochondrial DNA mislocation
Some forms of mitochondrial dysfunction can cause sterile inflammation, but the way in which it might affect muscle fitness is not well understood. Here, the authors show that altered mitochondrial dynamics can cause the production of mitochondrial DNA-driven inflammatory signals mediated by endosome-mitochondria contacts, leading to muscle inflammation, atrophy, reduced physical performance and enhanced exercise-induced inflammatory responses.
- Andrea Irazoki
- , Isabel Gordaliza-Alaguero
- & Antonio Zorzano
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Article
| Open AccessModulating glycosphingolipid metabolism and autophagy improves outcomes in pre-clinical models of myeloma bone disease
Here, the authors show that the glycosylceramide synthesis inhibitor and FDA approved drug Eliglustat inhibits autophagic degradation of TRAF3 which is a key step for osteoclast differentiation and thereby improves myeloma bone lesions.
- Houfu Leng
- , Hanlin Zhang
- & Nicole J. Horwood
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Article
| Open AccessExceptional preservation and foot structure reveal ecological transitions and lifestyles of early theropod flyers
The shape of bird toe pads and foot scales can be used to infer their behaviour. Here, the authors examine fossil evidence of toe pads and scales, in addition to claws and bones, from birds and close relatives, illustrating diverse lifestyles and ecological roles among early theropod flyers.
- Michael Pittman
- , Phil R. Bell
- & Thomas G. Kaye
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Article
| Open AccessMuscle 4EBP1 activation modifies the structure and function of the neuromuscular junction in mice
The group of Shih-Yin Tsai observed age-associated neuromuscular junction structural instability in male but not female mice which is driven by dysregulation of mTOR complex 1 activity. Genetic activation of the downstream phosphorylation target 4EBP1 in the muscle remodeled the neuromuscular junction and enhanced synaptic transmission.
- Seok-Ting J. Ang
- , Elisa M. Crombie
- & Shih-Yin Tsai
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Article
| Open AccessSirt6 attenuates chondrocyte senescence and osteoarthritis progression
Ji and colleagues identify Sirt6 as a regulator of chondrocyte senescence. Mechanistically, Sirt6 physically interacts with STAT5 and deacetylates it at K163, which reduces the IL-15/JAK3-induced STAT5 translocation from cytoplasm to nucleus.
- Ming-liang Ji
- , Hua Jiang
- & Jun Lu
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Article
| Open AccessBiasing the conformation of ELMO2 reveals that myoblast fusion can be exploited to improve muscle regeneration
Myoblast fusion is essential for development of multinucleated myofibers. Here, the authors show that ablation of Elmo 1 and Elmo2 impairs myoblast fusion in mice, and that expression of an open conformation of Elmo2 promotes muscle regeneration and improves the phenotype of Dysferlin-null dystrophic mice.
- Viviane Tran
- , Sarah Nahlé
- & Jean-François Côté
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Article
| Open AccessDifferential impact of ubiquitous and muscle dynamin 2 isoforms in muscle physiology and centronuclear myopathy
Dynamin 2 is a large GTPase linked to several human diseases. Here, Gómez-Oca et al. investigate the functions of muscle dynamin 2 isoforms and provide insights into their differential implication in centronuclear myopathy pathogenesis and treatment.
- Raquel Gómez-Oca
- , Evelina Edelweiss
- & Jocelyn Laporte
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Article
| Open AccessCryogenic contrast-enhanced microCT enables nondestructive 3D quantitative histopathology of soft biological tissues
The authors present cryogenic contrast-enhanced MicroCT (cryo-CECT), which by freezing stained samples at optimal freezing rates improves the visualization of the tissue microstructure. They demonstrate quantitative 3D analysis of individual tissue constituents, such as muscle and collagen fibers.
- Arne Maes
- , Camille Pestiaux
- & Greet Kerckhofs
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Article
| Open AccessRunx2 and Runx3 differentially regulate articular chondrocytes during surgically induced osteoarthritis development
Possible distinct contributions of Runx 2 and Runx3 in osteoarthritis have not been clarified. Nagata et al. show that Runx3 protects adult articular cartilage by extracellular matrix protein production in normal conditions, while Runx2 exerts both catabolic and anabolic effects during inflammation.
- Kosei Nagata
- , Hironori Hojo
- & Taku Saito
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Article
| Open AccessMitochondrial network configuration influences sarcomere and myosin filament structure in striated muscles
How different physical configurations between sarcomeres and mitochondria alter energetic support for contractile function of skeletal muscle is not clear. Here the authors use advanced 3D imaging and analysis techniques to show how space is made for mitochondria within the tightly packed sarcomere networks of striated muscle cells.
- Prasanna Katti
- , Alexander S. Hall
- & Brian Glancy
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Article
| Open AccessOsteocyte CIITA aggravates osteolytic bone lesions in myeloma
Osteocytes play an important role in the development and progression of tumour-associated bone disease. Here the authors report an interaction between malignant plasma cells and osteocytes in multiple myeloma and show that the osteocyte-expressed major histocompatibility complex class II transactivator (CIITA) contributes to myeloma-induced bone lesions.
- Huan Liu
- , Jin He
- & Jing Yang
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Article
| Open AccessDepletion of skeletal muscle satellite cells attenuates pathology in muscular dystrophy
Boyer et al. created genetic mouse models of muscular dystrophy in which satellite cells were selectively depleted. The depletion of satellite cells at select times was protective. Myofibers no longer had plasma membrane instability leading to tissue wasting in the muscular dystrophies.
- Justin G. Boyer
- , Jiuzhou Huo
- & Jeffery D. Molkentin
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Article
| Open AccessRegulation of the evolutionarily conserved muscle myofibrillar matrix by cell type dependent and independent mechanisms
Recent work has shown that mammalian muscle cells are comprised of multiple branching sarcomeres, though how this connectivity is regulated has remained unknown. Here the authors show three different mechanisms which regulate connectivity of the muscle contractile apparatus.
- Peter T. Ajayi
- , Prasanna Katti
- & Brian Glancy
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Article
| Open AccessSmall extracellular vesicle-mediated miR-320e transmission promotes osteogenesis in OPLL by targeting TAK1
The pathological mechanisms that lead to Ossification of the posterior longitudinal ligament (OPLL) are unclear. Here, the authors show that OPLL ligament cells produce small extracellular vesicles that induce ossification via miR-320e/TAK1 signaling in mice and human posterior longitudinal ligament cells.
- Chen Xu
- , Zicheng Zhang
- & Wen Yuan
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Article
| Open AccessThe myokine Fibcd1 is an endogenous determinant of myofiber size and mitigates cancer-induced myofiber atrophy
Myofiber atrophy occurs in many diseases but the mechanisms responsible for myofiber size determination are incompletely understood. Here, the authors show that the muscle-secreted factor Fibcd1 is necessary to maintain myofiber size and mitigates myofiber atrophy induced by cancer cachexia
- Flavia A. Graca
- , Mamta Rai
- & Fabio Demontis
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Article
| Open AccessEnhancement of anaerobic glycolysis – a role of PGC-1α4 in resistance exercise
Resistance exercise training (RET) is an effective countermeasure to sarcopenia, related frailty and metabolic disorders. Here, the authors show that an RET-induced increase in PGC-1α4 expression not only promotes muscle hypertrophy but also enhances glycolysis, providing a rapid supply of ATP for muscle contractions.
- Jin-Ho Koh
- , Mark W. Pataky
- & K. Sreekumaran Nair
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Article
| Open AccessDistinct and additive effects of calorie restriction and rapamycin in aging skeletal muscle
The anti-aging intervention calorie restriction (CR) is thought to act via the nutrient-sensing multiprotein complex mTORC1. Here the authors show that the mTORC1-inhibitor rapamycin and CR use largely distinct mechanisms to slow mouse muscle aging.
- Daniel J. Ham
- , Anastasiya Börsch
- & Markus A. Rüegg
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Article
| Open AccessSirt6 reprograms myofibers to oxidative type through CREB-dependent Sox6 suppression
Exercise is helpful to counteract obesity and the related complications, and positive effects are associated to a switch of muscle fibres to an oxidative type. Here, the authors show that sirtuin 6 overexpression in mice induces such a switch by modulating Sox6 and CREB signalling, suggesting that sirtuin 6 may be a target for exercise mimetics.
- Mi-Young Song
- , Chang Yeob Han
- & Byung-Hyun Park
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Article
| Open AccessLong-chain ceramides are cell non-autonomous signals linking lipotoxicity to endoplasmic reticulum stress in skeletal muscle
Endoplasmic Reticulum stress induces cell non-autonomous Unfolded Protein Response (UPR) activation. Here the authors show that long-chain ceramides are secreted from muscle cells in extracellular vesicles and induce cell non-autonomous UPR activation in muscle cells in response to lipotoxcity.
- Ben D. McNally
- , Dean F. Ashley
- & Lee D. Roberts
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Article
| Open AccessMechanism of action and therapeutic route for a muscular dystrophy caused by a genetic defect in lipid metabolism
Mutations in the CHKB gene cause muscular dystrophy. Here, the authors show that in mouse models of the disease changes in lipid metabolism are associated with decreased PPAR signaling, and show PPAR agonists can rescue expression of injury markers in myocytes in vitro.
- Mahtab Tavasoli
- , Sarah Lahire
- & Christopher R. McMaster
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Article
| Open AccessAged bone matrix-derived extracellular vesicles as a messenger for calcification paradox
This study uncovers the role of extracellular vesicles from bone matrix as a messenger in the development of osteoporosis and vascular calcification (calcification paradox) during skeletal aging and menopause by transferring miR-483-5p and miR-2861.
- Zhen-Xing Wang
- , Zhong-Wei Luo
- & Hui Xie
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Article
| Open AccessOsteoblast-derived vesicles induce a switch from bone-formation to bone-resorption in vivo
Bone remodeling involves a switch between bone formation and resorption, but the mechanisms is unclear. Here, the authors show that intercellular communication via extracellular vesicles secreted by mature osteoblasts is a key factor for the switching, via a microRNA-mediated mechanism.
- Maki Uenaka
- , Erika Yamashita
- & Masaru Ishii
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Article
| Open AccessTAZ links exercise to mitochondrial biogenesis via mitochondrial transcription factor A
Mitochondrial biogenesis is stimulated to meet energy requirements in response to extracellular signals including exercise. TAZ is revealed as a novel stimulator for mitochondrial biogenesis and facilitates exercise-induced muscle adaptation.
- Jun-Ha Hwang
- , Kyung Min Kim
- & Jeong-Ho Hong
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Article
| Open AccessRare SLC13A1 variants associate with intervertebral disc disorder highlighting role of sulfate in disc pathology
Little is known about the biology of back pain, a leading cause of disability. Here the authors report 30 new back pain loci, implicating genes involved in cartilage/bone biology, as well as neurological and inflammatory processes.
- Gyda Bjornsdottir
- , Lilja Stefansdottir
- & Kari Stefansson
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Article
| Open AccessMacrophages in epididymal adipose tissue secrete osteopontin to regulate bone homeostasis
Visceral adipose tissue secretes cytokines to regulate the homeostasis of organs. Here, the authors show that epididymal white adipose tissue-secreted osteopontin induces lipophagocytic mobilization of macrophages and promotes bone matrix degradation via activating osteoclasts.
- Bingyang Dai
- , Jiankun Xu
- & Ling Qin
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Article
| Open AccessClenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells
In this study, the authors demonstrated that agents targeting skeletal muscle metabolism by modulating β2-adrenergic receptor-dependent signaling may prove beneficial as novel antidiabetic drugs.
- Jaroslawna Meister
- , Derek B. J. Bone
- & Jürgen Wess
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Article
| Open AccessTargeting necroptosis in muscle fibers ameliorates inflammatory myopathies
Polymyositis (PM) is a chronic inflammatory myopathy characterized by progressive muscle weakness. Here the authors showed that muscle fibers in PM undergo necroptosis and aggravate inflammation via releasing pro-inflammatory molecules such as HMGB1.
- Mari Kamiya
- , Fumitaka Mizoguchi
- & Shinsuke Yasuda
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Article
| Open AccessMechanical force promotes dimethylarginine dimethylaminohydrolase 1-mediated hydrolysis of the metabolite asymmetric dimethylarginine to enhance bone formation
Mechanical force is critical for the development and remodeling of bones. Here the authors report that mechanical force regulates the production of the metabolite asymmetric dimethylarginine via regulating the expression of the hydrolytic enzyme dimethylarginine dimethylaminohydrolase 1 in osteoblasts.
- Ziang Xie
- , Lei Hou
- & Shunwu Fan
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Article
| Open AccessThe m6A methyltransferase METTL3 regulates muscle maintenance and growth in mice
Muscle undergoes hypertrophy and atrophy in response to physiological stimuli or in pathological conditions, which is partially controlled through altered gene expression. Here the authors report that m6A methyltransferase METTL3 and mRNA m6A post-transcriptional modifications as a mechanism that regulates muscle hypertrophy and atrophy via myostatin signalling in mice.
- Jennifer M. Petrosino
- , Scott A. Hinger
- & Federica Accornero
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Article
| Open AccessTargeting chondrocytes for arresting bony fusion in ankylosing spondylitis
Current treatments cannot significantly alleviate the radiographic progression in ankylosing spondylitis (AS), which results in joints stiffness and bony fusion of AS. Smo inhibitor sonidegib retards the pathological new bone formation in AS through targeting dysfunctional chondrogenesis.
- Fenli Shao
- , Qianqian Liu
- & Yang Sun
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Article
| Open AccessAutomated bone mineral density prediction and fracture risk assessment using plain radiographs via deep learning
Dual-energy X-ray absorptiometry and the Fracture Risk Assessment Tool are recommended tools for osteoporotic fracture risk evaluation, but are underutilized. Here, the authors present an opportunistic tool to identify fractures, predict bone mineral density and evaluate fracture risk using plain pelvis and lumbar spine radiographs.
- Chen-I Hsieh
- , Kang Zheng
- & Chang-Fu Kuo
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Article
| Open AccessTNF-α-mediated m6A modification of ELMO1 triggers directional migration of mesenchymal stem cell in ankylosing spondylitis
Abnormal functions of mesenchymal stem cells (MSC) contribute into the pathogenensis of ankylosing spondylitis (AS). Here, the authors show that TNF-α at high concentration induces enhances migration of AS-MSC through METTL14 mediated m6A modification of the ELMO1 3′ UTR.
- Zhongyu Xie
- , Wenhui Yu
- & Huiyong Shen