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| Open AccessTAZ couples Hippo/Wnt signalling and insulin sensitivity through Irs1 expression
Insulin resistance is associated with development of type 2 diabetes. Here the authors show that TAZ interacts with c-Jun and Tead4, inducing expression of the insulin receptor substrate 1 (IRS1) leading to increased glucose uptake in muscle, and that its activity is counteracted by statin administration.
- Jun-Ha Hwang
- , A Rum Kim
- & Jeong-Ho Hong
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Article
| Open AccessProstaglandin E2 mediates sensory nerve regulation of bone homeostasis
Bone is innervated, and its turnover is affected by sympathetic nerve activity. Here, the authors show that prostaglandin E2, secreted by osteoblasts, activates the EP4 receptor on sensory nerves, inhibiting sympathetic nerve activity and modulating bone formation in mice.
- Hao Chen
- , Bo Hu
- & Xu Cao
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Article
| Open AccessRNA-binding protein ZFP36L1 regulates osteoarthritis by modulating members of the heat shock protein 70 family
Osteoarthritis is characterised by degeneration of joint cartilage. Here the authors show that the RNA-binding protein ZFP36L1 is upregulated in chondrocytes of humans and mice with osteoarthritis, and that its knockdown in mouse joints protects chondrocytes against apoptosis by modulating the function of heat shock proteins.
- Young-Ok Son
- , Hyo-Eun Kim
- & Jang-Soo Chun
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Article
| Open AccessClosed-loop functional optogenetic stimulation
Optogenetics is a promising alternative approach for restoration of neuromuscular function. Here the authors establish a closed-loop functional optogenetic stimulation for the control of limb joint angle in murine models, which demonstrates improved control and less fatigue than electrical stimulation systems.
- Shriya S. Srinivasan
- , Benjamin E. Maimon
- & Hugh M. Herr
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Article
| Open AccessThe Trithorax protein Ash1L promotes myoblast fusion by activating Cdon expression
Myoblast fusion in skeletal muscle is a complex process but how this is regulated is unclear. Here, the authors identify Ash1L, a histone methyltransferase, as modulating myoblast fusion via activation of the myogenesis gene Cdon, and observe decreased Ash1L expression in Duchenne muscular dystrophy.
- Ilaria Castiglioni
- , Roberta Caccia
- & Davide Gabellini
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Article
| Open AccessDisease-relevant transcriptional signatures identified in individual smooth muscle cells from healthy mouse vessels
Vascular smooth muscle cell (VSMC) accumulation is associated with cardiovascular disease. Here, the authors combine single-cell RNA sequencing with lineage labelling to profile VSMC heterogeneity in healthy mice. They show that upregulation of Sca1 in a rare VSMC subpopulation marks a cell phenotype that is prevalent in disease.
- Lina Dobnikar
- , Annabel L. Taylor
- & Helle F. Jørgensen
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Article
| Open AccessA missense variant in SLC39A8 is associated with severe idiopathic scoliosis
The majority of scoliosis is considered idiopathic with onset in adolescence (AIS) and has a genetic contribution. Here, the authors perform an exome wide association study of data from 457 severe AIS cases and 987 controls, and find a missense variant in SLC39A8 is associated with AIS.
- Gabe Haller
- , Kevin McCall
- & Christina A. Gurnett
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| Open AccessDynamics of cellular states of fibro-adipogenic progenitors during myogenesis and muscular dystrophy
Fibro-adipogenic progenitors (FAPs) resident in skeletal muscle are involved in both regeneration and maladaptive processes. Here, the authors identify subpopulations of FAPs with biological activities implicated in physiological muscle repair that are altered in pathological conditions such as muscular dystrophies.
- Barbora Malecova
- , Sole Gatto
- & Pier Lorenzo Puri
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Article
| Open AccessNecroptosis mediates myofibre death in dystrophin-deficient mice
Muscular dystrophies are characterised by extensive myofibre cell death. Here Morgan et al. show that RIPK3-mediated necroptosis contributes to myofibre cell death in Duchenne muscular dystrophy, and that RIPK3 deletion protects dystrophic mice against myofibre degeneration.
- Jennifer E. Morgan
- , Alexandre Prola
- & Maximilien Bencze
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Article
| Open AccessJNK regulates muscle remodeling via myostatin/SMAD inhibition
Endurance and resistance exercise have different effects on skeletal muscle phenotype. Using mouse models and human subjects, the authors show that JNK/Smad2 signaling acts as molecular switch that when activated by resistance exercise leads to hypertrophy, and when inhibited promotes endurance adaptations in muscle.
- Sarah J. Lessard
- , Tara L. MacDonald
- & Laurie J. Goodyear
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Article
| Open AccessOsteocytic oxygen sensing controls bone mass through epigenetic regulation of sclerostin
Osteocytes reside in a low oxygen environment, but it is not clear if oxygen sensing regulates their function. Here, the authors show that deletion of the oxygen sensor prolyl hydroxylase 2 in osteocytes leads to increased bone mass via regulation of sclerostin, and reduces bone loss in mouse models of osteoporosis.
- Steve Stegen
- , Ingrid Stockmans
- & Geert Carmeliet
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Article
| Open AccessDkk3 dependent transcriptional regulation controls age related skeletal muscle atrophy
Ageing is associated with muscle atrophy. Here, the authors show that the secreted glycoprotein Dickkopf 3 promotes muscle atrophy by inducing nuclear import of beta-catenin, its association with FoxO3 and the consequent activation of the atrophy-related genes Atrogin1 and MuRF1.
- Jie Yin
- , Lele Yang
- & Ping Hu
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Article
| Open AccessGauging force by tapping tendons
Mechanical forces exerted on tendons during locomotion cannot be readily measured without invasive methods. Here, the authors develop a non-invasive wearable device to track tendon loads by measuring shear wave propagation speed, and demonstrate its use during dynamic human movements.
- Jack A. Martin
- , Scott C. E. Brandon
- & Darryl G. Thelen
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Article
| Open AccessInhibition of overactive TGF-β attenuates progression of heterotopic ossification in mice
Heterotopic ossification (HO) is a painful disease of unknown etiology characterized by extraskeletal bone formation after injury. Here the authors show that TGF-β is increased in HO lesions, where it promotes the early stages of HO pathology, and demonstrate that TGF-β inhibition ameliorates HO in mice.
- Xiao Wang
- , Fengfeng Li
- & Xu Cao
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Article
| Open AccessActivin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva
Fibrodysplasia ossificans progressiva is a severe disorder characterized by heterotopic ossification, and is caused by mutations in ACVR1. Here, the authors show that expression of mutant ACVR1 in fibro/adipogenic progenitors recapitulates disease progression, and that this can be halted by systemic inhibition of activin A in mice.
- John B. Lees-Shepard
- , Masakazu Yamamoto
- & David J. Goldhamer
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Article
| Open AccessLsd1 regulates skeletal muscle regeneration and directs the fate of satellite cells
Satellite cells can differentiate both into myocytes and brown adipocytes. Here, the authors show that the histone demethylase Lsd1 prevents adipogenic differentiation of satellite cells by repressing expression of Glis1, and that its ablation changes satellite cell fate towards brown adipocytes and delays muscle regeneration in mice.
- Milica Tosic
- , Anita Allen
- & Roland Schüle
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Article
| Open AccessEngineering human pluripotent stem cells into a functional skeletal muscle tissue
The generation of functional skeletal muscle tissue from human pluripotent stem cells has not been reported. Here, the authors describe engineering of contractile skeletal muscle bundles in culture, which become vascularized and maintain functionality when transplanted into mice.
- Lingjun Rao
- , Ying Qian
- & Nenad Bursac
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Article
| Open AccessShort-chain fatty acids regulate systemic bone mass and protect from pathological bone loss
Short-chain fatty acids (SCFA) are a main class of metabolites derived from fermentation of dietary fibre in the intestine. Here, the authors show that dietary administration of SCFA is associated with inhibition of osteoclast differentiation, increased bone mass, and reduced pathological bone loss in mice.
- Sébastien Lucas
- , Yasunori Omata
- & Mario M. Zaiss
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| Open AccessPAX7 target genes are globally repressed in facioscapulohumeral muscular dystrophy skeletal muscle
Facioscapulohumeral muscular dystrophy is a myopathy linked to ectopic expression of the DUX4 transcription factor. The authors show that the suppression of targets genes of the myogenesis regulator PAX7 is a signature of FSHD, and might explain oxidative stress sensitivity and epigenetic changes.
- Christopher R. S. Banerji
- , Maryna Panamarova
- & Peter S. Zammit
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| Open AccessComplement C3a signaling facilitates skeletal muscle regeneration by regulating monocyte function and trafficking
Regeneration of skeletal muscle is accompanied by a transitory inflammatory phase. Here the authors show that the complement C3 component is activated following muscle injury, and signals through the alternative complement pathway to regulate immune cell infiltration and muscle regeneration.
- Congcong Zhang
- , Chunxiao Wang
- & Jie Du
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Article
| Open AccessDownregulation of myostatin pathway in neuromuscular diseases may explain challenges of anti-myostatin therapeutic approaches
Drugs targeting myostatin reverse muscle wasting in animal models, but have limited efficacy in patients. The authors show that the myostatin pathway is downregulated in patients, possibly explaining the poor outcome of anti-myostatin approaches, and that it can be reactivated by correcting disease-causing mutations in mice.
- Virginie Mariot
- , Romain Joubert
- & Julie Dumonceaux
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Article
| Open AccessMyD88 promotes myoblast fusion in a cell-autonomous manner
Myoblast fusion is essential for skeletal muscle development and regeneration. Here the authors show that MyD88 is upregulated during myogenesis and during muscle growth, signals via the NF-κB and Wnt pathways, and that its expression modulates myoblast fusion and myofiber size in mice.
- Sajedah M. Hindi
- , Jonghyun Shin
- & Ashok Kumar
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Article
| Open AccessDJ-1 controls bone homeostasis through the regulation of osteoclast differentiation
Osteoclasts are involved in arthritis, and their differentiation depends on RANKL signaling. The author show that the ROS-scavenging protein DJ-1 negatively regulates RANKL signaling and that its ablation increases osteoclast numbers and exacerbates bone damage in mouse models of arthritis.
- Hyuk Soon Kim
- , Seung Taek Nam
- & Wahn Soo Choi
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Article
| Open AccessProgrammed cell senescence in skeleton during late puberty
Mesenchymal stem cells are essential for bone development, but it is unclear if their activity is maintained after late puberty, when bone growth decelerates. The authors show that during late puberty in mice, these cells undergo senescence under the epigenetic control of Ezh2.
- Changjun Li
- , Yu Chai
- & Mei Wan
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Article
| Open Accessαv integrins on mesenchymal cells regulate skeletal and cardiac muscle fibrosis
The mechanisms underlying tissue fibrosis are unclear. The authors show that mesenchymal cells expressing PDGFRβ mediate fibrosis in skeletal muscle and heart via a mechanism involving αv integrin, and that inhibitors of αv integrins attenuate fibrotic responses in mice.
- I. R. Murray
- , Z. N. Gonzalez
- & N. C. Henderson
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Article
| Open AccessIrisin is a pro-myogenic factor that induces skeletal muscle hypertrophy and rescues denervation-induced atrophy
Exercise induces expression of the myokine Irisin. Here the authors show that Irisin promotes muscle hypertrophy and regeneration following injury or denervation in mice, by activating satellite cells and modulating protein synthesis and degradation.
- Musarrat Maisha Reza
- , Nathiya Subramaniyam
- & Ravi Kambadur
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| Open AccessReducing sarcolipin expression mitigates Duchenne muscular dystrophy and associated cardiomyopathy in mice
Sarcolipin is an inhibitor of the ATP dependent calcium pump SERCA, and is abnormally elevated in Duchenne muscular dystrophy. The authors show that reducing sarcolipin expression ameliorates skeletal muscle pathology and cardiomyopathy and extends life span in mouse models of DMD.
- Antanina Voit
- , Vishwendra Patel
- & Gopal J. Babu
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Article
| Open AccessSilencing Nfix rescues muscular dystrophy by delaying muscle regeneration
Strategies aimed at promoting muscle regeneration to treat muscular dystrophy have met with limited success. Here the authors show instead that delaying muscle regeneration, by ablation of the transcription factor Nfix, ameliorates muscular dystrophy in mice.
- Giuliana Rossi
- , Chiara Bonfanti
- & Graziella Messina
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Article
| Open AccessThe giant protein titin regulates the length of the striated muscle thick filament
Thick filaments in skeletal muscle and heart are composed of myosin. The authors show that the length of thick filaments is defined by titin, and that alterations in titin length affect force generation and lead to dilated cardiomyopathy in mice.
- Paola Tonino
- , Balazs Kiss
- & Henk Granzier
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| Open AccessMyoblasts and macrophages are required for therapeutic morpholino antisense oligonucleotide delivery to dystrophic muscle
Exon skipping is a strategy for the treatment of Duchenne muscular dystrophy, but has variable efficacy. Here, the authors show that dystrophin restoration occurs preferentially in areas of myofiber regeneration, where antisense oligonucleotides are stored in macrophages and delivered to myoblasts and newly formed myotubes
- James S. Novak
- , Marshall W. Hogarth
- & Terence A. Partridge
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Article
| Open AccessMuscle pathology from stochastic low level DUX4 expression in an FSHD mouse model
Facioscapulohumeral muscular dystrophy is a severe myopathy that is caused by abnormal activation of DUX4, and for which a suitable mouse model does not exist. Here, the authors generate a novel mouse model with titratable expression of DUX4, and show that it recapitulates several features of the human pathology.
- Darko Bosnakovski
- , Sunny S. K. Chan
- & Michael Kyba
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Article
| Open AccessAmpk phosphorylation of Ulk1 is required for targeting of mitochondria to lysosomes in exercise-induced mitophagy
Exercise is associated with biogenesis and removal of dysfunctional mitochondria. Here the authors use a mitochondrial reporter gene to demonstrate the occurrence of mitophagy following exercise in mice, and show this is dependent on AMPK and ULK1 signaling.
- Rhianna C. Laker
- , Joshua C. Drake
- & Zhen Yan
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Article
| Open AccessThe Ca2+ influx through the mammalian skeletal muscle dihydropyridine receptor is irrelevant for muscle performance
In mammalian skeletal muscle, the DHPR functions as a voltage sensor to trigger muscle contraction and as a Ca2+ channel. Here the authors show that mice where Ca2+ influx through the DHPR is eliminated display no difference in skeletal muscle function, suggesting that the Ca2+ influx through this channel is vestigial.
- Anamika Dayal
- , Kai Schrötter
- & Manfred Grabner
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| Open AccessLong-term microdystrophin gene therapy is effective in a canine model of Duchenne muscular dystrophy
Duchenne muscular dystrophy is a progressive degenerative disease of muscles caused by mutations in the dystrophin gene. Here the authors use AAV vectors to deliver microdystrophin to dogs with muscular dystrophy, and show restoration of dystrophin expression and reduction of symptoms up to 26 months of age.
- Caroline Le Guiner
- , Laurent Servais
- & George Dickson
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Article
| Open AccessBioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss
Volumetric muscle loss leads to functional muscle impairment, and current stem cell-based treatments show limited efficacy. Here, the authors generate a stem cell scaffold, implant it in mice, and show that an exercise regimen enhances innervation and restoration of muscle function in mice.
- Marco Quarta
- , Melinda Cromie
- & Thomas A. Rando
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| Open AccessAntisense oligonucleotide-mediated Dnm2 knockdown prevents and reverts myotubular myopathy in mice
X-linked myotubular myopathy is caused by mutations in the gene coding for myotubularin 1, and is characterized by overexpression of dynamin 2. Here the authors develop antisense oligonucleotides to dynamin 2, and show that systemic injection leads to improved pathology in mice.
- Hichem Tasfaout
- , Suzie Buono
- & Jocelyn Laporte
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Article
| Open AccessSuccinate and its G-protein-coupled receptor stimulates osteoclastogenesis
Bone loss is common in patients with diabetes, but the underlying molecular and cellular mechanisms are unclear. Here the authors show high succinate levels in mice with type 2 diabetes and that succinate can signal through succinate receptor 1 on osteoclasts to induce bone resorption.
- Yuqi Guo
- , Chengzhi Xie
- & Xin Li
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Article
| Open AccessmiR-29b contributes to multiple types of muscle atrophy
Skeletal muscle atrophy can occur in response to stimuli such as inactivity, fasting, and ageing. Here the authors show that expression of microRNA-29b promotes muscle atrophy by targeting IGF-1 and PI3K, and that its inhibition attenuates atrophy induced by denervation and immobilization in mice.
- Jin Li
- , Mun Chun Chan
- & Junjie Xiao
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Article
| Open AccessJoint morphogenetic cells in the adult mammalian synovium
The stem cells that maintain and repair adult joint tissues in mammals, including articular cartilage, remain incompletely defined. Here the authors perform lineage tracing studies in adult mice and find an ontogenetically defined progenitor cell population that is functional in the synovial joint and distinct from previously reported mesenchymal stem cell populations.
- Anke J. Roelofs
- , Janja Zupan
- & Cosimo De Bari
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Article
| Open AccessActivin A more prominently regulates muscle mass in primates than does GDF8
Inhibition of GDF8 increases muscle mass in mice, but is less effective in monkeys and humans. Here the authors show that activin A also inhibits muscle hypertrophy and that concomitant inhibition of activin A and GDF8 synergistically increases muscle mass in mice and non-human primates.
- Esther Latres
- , Jason Mastaitis
- & Jesper Gromada
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Article
| Open AccessLnc-mg is a long non-coding RNA that promotes myogenesis
Long non-coding mRNAs play important roles in muscle development and regeneration. Here the authors identify a long non-coding mRNA that promotes myogenesis by sequestering miR-125b, leading to increased expression of insulin-like growth factor 2.
- Mu Zhu
- , Jiafan Liu
- & Xiaogang Wang
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Article
| Open AccessSequence variant at 8q24.21 associates with sciatica caused by lumbar disc herniation
Lumbar disc herniation (LDH) can cause persistent sciatica, and in some cases surgery is required to relieve symptoms. Here, the authors carry out a genome-wide association study using microdiscectomy as an indicator of severe LDH, and find a locus on chromosome 8 associated with this condition.
- Gyda Bjornsdottir
- , Stefania Benonisdottir
- & Kari Stefansson
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Article
| Open AccessGα13 negatively controls osteoclastogenesis through inhibition of the Akt-GSK3β-NFATc1 signalling pathway
Osteoclasts are bone resorptive cells and an attractive target to treat diseases characterized by excessive bone loss, but little is known about osteoclast inhibition. Here the authors identify Gα13 as an intracellular inhibitor of osteoclastogenesis that can prevent bone loss in mice via Akt activation and inhibition of RhoA signalling.
- Mengrui Wu
- , Wei Chen
- & Yi-Ping Li
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Article
| Open AccessPten is necessary for the quiescence and maintenance of adult muscle stem cells
Pten is known to regulate haematopoietic stem cell functions. Here the authors show that Ptenalteration of Notch signalling has stage-specific muscle regenerative functions in muscle stem cells by preventing premature differentiation of quiescent cells and enhancing the self-renewal of activated cells.
- Feng Yue
- , Pengpeng Bi
- & Shihuan Kuang
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Article
| Open AccessThe transcription factor Prox1 is essential for satellite cell differentiation and muscle fibre-type regulation
Skeletal muscle has remarkable adaptive and regenerative capacity. Here the authors show that the transcription factor Prox1 is necessary for maintenance of slow muscle fibre types via activation of NFAT signalling, and for myoblast differentiation via cross-talk with the Notch signalling pathway.
- Riikka Kivelä
- , Ida Salmela
- & Kari Alitalo
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Article
| Open AccessExploiting endogenous fibrocartilage stem cells to regenerate cartilage and repair joint injury
A potentially superior tissue regenerative strategy to stem cell transplantation is modulation of endogenous stem cells. Here the authors show fibrocartilage stem cells exist in the temporomandibular joint that contribute to cartilage regeneration and can be manipulated to enhance regeneration through canonical Wnt signalling.
- Mildred C. Embree
- , Mo Chen
- & Jeremy J. Mao
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Article
| Open AccessMohawk promotes the maintenance and regeneration of the outer annulus fibrosus of intervertebral discs
Homeobox protein Mohwak (Mkx) is involved in tendon and ligament development. Here the authors show that Mkx in the outer annulus fibrosus of the intervertebral disc plays a role in maintenance of the IVD, showing that stem cells overexpressing Mkx enhance therapeutic IVD regeneration in mice.
- Ryo Nakamichi
- , Yoshiaki Ito
- & Hiroshi Asahara
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Article
| Open AccessMRF4 negatively regulates adult skeletal muscle growth by repressing MEF2 activity
Mrf4 is a transcription factor important for muscle development, but despite high expression its function in adults is unknown. Here the authors show that interfering with Mrf4 in adult mice leads to muscle hypertrophy by activating MEF2-dependent transcription and promoting protein synthesis.
- Irene Moretti
- , Stefano Ciciliot
- & Stefano Schiaffino
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Article
| Open AccessThe genetic regulatory signature of type 2 diabetes in human skeletal muscle
More than 90% of genetic variants associated with type 2 diabetes occur in non-coding regions. Scott et al. report genomes, epigenomes and transcriptomes of skeletal muscle from 271 participants with a range of glucose tolerances, revealing a genetic regulatory architecture enriched in muscle stretch/super enhancers.
- Laura J. Scott
- , Michael R. Erdos
- & Stephen C. J. Parker