Search

Receptor-activator of nuclear factor-κB (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Here we show that RANK is also expressed in fully differentiated myotubes and skeletal muscle. Muscle RANK deletion has inotropic effects in denervated, but not in sham, extensor digitorum longus (EDL) muscles preventing the loss of maximum specific force while promoting muscle atrophy, fatigability, and increased proportion of fast-twitch fibers. In denervated EDL muscles, RANK deletion markedly increased stromal interaction molecule 1 content, a Ca2+ sensor, and altered activity of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) modulating Ca2+ storage. Muscle RANK deletion had no significant effects on the sham or denervated slowtwitch soleus muscles. These data identify a novel role for RANK as a key regulator of Ca2+ storage and SERCA activity, ultimately affecting denervated skeletal muscle function. [ABSTRACT FROM AUTHOR]

Muscle stem cells, termed satellite cells, are crucial for skeletal muscle growth and regeneration. In healthy adult muscle, satellite cells are quiescent but poised for activation. During muscle regeneration, activated satellite cells transiently re-enter the cell cycle to proliferate and subsequently exit the cell cycle to differentiate or self-renew. Recent studies have demonstrated that satellite cells are heterogeneous and that subpopulations of satellite stem cells are able to perform asymmetric divisions to generate myogenic progenitors or symmetric divisions to expand the satellite cell pool. Thus, a complex balance between extrinsic cues and intrinsic regulatory mechanisms is needed to tightly control satellite cell cycle progression and cell fate determination. Defects in satellite cell regulation or in their niche, as observed in degenerative conditions such as aging, can impair muscle regeneration. Here, we review recent discoveries of the intrinsic and extrinsic factors that regulate satellite cell behaviour in regenerating and degenerating muscles. [ABSTRACT FROM AUTHOR]

Muscle stem cells facilitate the long-term regenerative capacity of skeletal muscle. This self-renewing population of satellite cells has only recently been defined through genetic and transplantation experiments. Although muscle stem cells remain in a dormant quiescent state in uninjured muscle, they are poised to activate and produce committed progeny. Unlike committed myogenic progenitor cells, the self-renewal capacity gives muscle stem cells the ability to engraft as satellite cells and capitulate long-term regeneration. Similar to other adult stem cells, understanding the molecular regulation of muscle stem cells has significant implications towards the development of pharmacological or cell-based therapies for muscle disorders. This Cell Science at a Glance article and accompanying poster will review satellite cell characteristics and therapeutic potential, and provide an overview of the muscle stem cell hallmarks: quiescence, self-renewal and commitment. [ABSTRACT FROM AUTHOR]

Neutrophils phagocyte necrotic debris and release cytokines, enzymes, and oxidative factors. In the present study, we investigated the contribution of neutrophils to muscle injury, dysfunction, and recovery using an unloading and reloading model. Mice were submitted to 10 days of hindlimb unloading and were transiently depleted in neutrophils with anti-Ly6G/ Ly6C antibody prior to reloading. Leukocyte accumulation and muscle function were assessed immunohistologically and functionally in vitro. In addition, soleus muscles submitted to unloading and reloading were incubated in vitro with LPS (100 µg/ml) to determine whether exogenous stimulus would activate neutrophil response and produce extensive muscle damage. Contractile properties were recorded every hour for 6 h, and muscles were subsequently incubated in procion orange to assess muscle damage. Neutrophil depletion affected neither the loss in muscle force nor the time of recovery in atrophied and reloaded soleus muscles. However, atrophied and reloaded soleus muscles that contained high concentration of neutrophils experienced a 20% greater loss in force than atrophied and reloaded soleus muscles depleted in neutrophils following in vitro incubation with LPS. Procion orange dye also confirmed that neutrophils induced a 2.5-fold increase in muscle membrane damage in the presence of LPS. These results show that neutrophil infiltration during modified mechanical loading is highly regulated and efficiently eliminated, with no significant muscle fiber injury unless the activation state of neutrophils is modified by the presence of LPS. [ABSTRACT FROM AUTHOR]

Arthrogryposis is a clinical feature defined by congenital joint contractures in two or more different body areas which occurs in between 1/3000 and 1/5000 live births. Variants in multiple genes have been associated with distal arthrogryposis syndromes. Heterozygous variants in MYH3 have been identified to cause the dominantly‐inherited distal arthrogryposis conditions, Freeman–Sheldon syndrome, Sheldon–Hall syndrome, and multiple pterygium syndrome. In contrast, MYH3 variants underlie both dominantly and recessively inherited Contractures, Pterygia, and Spondylocarpotarsal Fusion syndromes (CPSFS) which are characterized by extensive bony abnormalities in addition to congenital contractures. Here we report two affected sibs with distal arthrogryposis born to unaffected, distantly related parents. Sequencing revealed that both sibs were homozygous for two ultra‐rare MYH3 variants, c.3445G>A (p.Glu1149Lys) and c.4760T>C (p.Leu1587Pro). Sequencing and deletion/duplication analysis of 169 other arthrogryposis genes yielded no other compelling candidate variants. This is the first report of biallelic variants in MYH3 being implicated in a distal arthrogryposis phenotype without the additional features of CPSFS. Thus, akin to CPSFS, both dominant and recessively inherited distal arthrogryposis can be caused by variants in MYH3. [ABSTRACT FROM AUTHOR]

Individuals born preterm present lower exercise capacity. Along with the cardiopulmonary responses and activity level, muscle strength is a key determinant of exercise capacity. This systematic review aimed to summarize the current knowledge on the impact of preterm birth on skeletal muscle mass and function across the lifespan. The databases PubMed, MEDLINE, EBM, Embase, CINAHL Plus, Global Index Medicus, and Google Scholar were searched using keywords and MeSH terms related to skeletal muscle, preterm birth, and low birth weight. Two independent reviewers undertook study selection, data extraction, and quality appraisal using Covidence review management. Data were pooled to estimate the prematurity effect on muscle mass and function using the R software. From 4378 studies retrieved, 132 were full-text reviewed and 25 met the inclusion/exclusion criteria. Five studies presented a low risk of bias, and 5 had a higher risk of bias due to a lack of adjustment for confounding factors and presenting incomplete outcomes. Meta-analyses of pooled data from homogenous studies indicated a significant reduction in muscle thickness and jump test (muscle power) in individuals born preterm versus full-term with standardized mean difference and confidence interval of − 0.58 (0.27, 0.89) and − 0.45 (0.21, 0.69), respectively. Conclusion: Overall, this systematic review summarizing the existing literature on the impact of preterm birth on skeletal muscle indicates emerging evidence that individuals born preterm, display alteration in the development of their skeletal muscle mass and function. This work also highlights a clear knowledge gap in understanding the effect of preterm birth on skeletal muscle development. What is Known: • Preterm birth, which occurs at a critical time of skeletal muscle development and maturation, impairs the development of different organs and tissues leading to a higher risk of comorbidities such as cardiovascular diseases. • Preterm birth is associated with reduced exercise capacity. What is New: • Individuals born preterm display alterations in muscle mass and function compared to individuals born at term from infancy to adulthood. • There is a need to develop preventive or curative interventions to improve skeletal muscle health in preterm-born individuals. [ABSTRACT FROM AUTHOR]

Pour-on eprinomectin was recently registered for lactating small ruminants. Given the high prevalence of benzimidazole resistance in gastrointestinal nematodes in dairy goats, many farmers use eprinomectin exclusively to treat their animals. On a French dairy goat farm, a veterinary practitioner noted a poor response to two types of eprinomectin treatment (pour-on application and injectable formulation). Therefore, we evaluated the efficacy of both formulations of eprinomectin, as well as moxidectin and fenbendazole, using the fecal egg count reduction test (FECRT) according to the World Association for the Advancement of Veterinary Parasitology (WAAVP) guidelines. Nematode species were identified at days 0 and post-treatment days 14 after bulk larval cultures, by morphology and real-time PCR. Plasma concentrations of eprinomectin were analyzed by high-performance liquid chromatography (HPLC) at post-treatment days 2 and 5 in the eprinomectin-treated groups. Egg count reductions were poor in animals treated with topical (−16.7%; 95% CI:[−237; 59]) or subcutaneous (21.5%; 95% CI:[−126; 73]) eprinomectin, and with fenbendazole (−5.8%; 95% CI:[−205; 63]). Haemonchus contortus was the main species identified by morphology and by real-time PCR before and after treatment. The plasma concentrations of eprinomectin were determined in all eprinomectin-treated animals and were above 2 ng/ml at post-treatment day 2, indicating that the lack of effect was not due to low exposure of the worms to the drug. Interestingly, moxidectin remained effective in all infected animals. This is the first report of multiple resistance to eprinomectin and benzimidazole in H. contortus on a French dairy goat farm with moxidectin as a relevant alternative. Unlabelled Image • First report of resistance to eprinomectin and benzimidazole on a French goat farm • On this farm, Haemonchus contortus is the multiple-resistant species. • The lack of efficacy of eprinomectin is not due to a low exposure of the worms to the drug. • Moxidectin retained its full effectiveness on this Haemonchus contortus population. [ABSTRACT FROM AUTHOR]

• Randomized Quasi-Monte Carlo method is assessed in 3D configurations involving radiative heat transfer in participating media. • The use of Randomized Quasi-Monte Carlo method reduces the computational time of the radiative heat transfer simulations of all the investigated cases compared to Monte Carlo method. • Randomized Quasi-Monte Carlo is combined to a technique of importance sampling to further improve the efficiency. Radiation can play a central role in turbulent reactive flows where heat transfer is enhanced in applications with high temperature and pressure. The Monte Carlo method is a successful technique to solve the radiative transfer equation accurately with relative ease while retaining detailed properties. However, its drawback is associated to a slow convergence rate. One strategy to improve the efficiency of Monte Carlo method consists in replacing the pseudo-random sequences with an alternative sampling: the low-discrepancy sequences. The introduction of such sequences in Monte Carlo leads to Quasi-Monte Carlo methods. Their advantage lies in a higher convergence rate compared to MC methods which have however not been assessed in 3D participating media. Additionally, in order to get an error estimation which is necessary in practical applications, a randomization of Quasi-Monte Carlo is needed (Randomized-QMC). Such Randomized-QMC methods have not been considered for simulations of radiative heat transfer in participating media before. In the present study, Monte Carlo and Randomized Quasi-Monte Carlo methods are assessed in terms of efficiency and computational cost in radiative heat transfer simulations of three practical 3D configurations. Comparisons in terms of local standard deviation, convergence rate, and final computational cost show that Randomized Quasi-Monte Carlo outperforms Monte Carlo in all the investigated cases. [ABSTRACT FROM AUTHOR]

The possibility that inflammatory changes affect dystrophin expression has been proposed in a recent myositis mouse model study where miRNA-mediated dystrophin deficiency correlated with myositis severity [[3]]. To explore whether decreased dystrophin may be a feature of dystrophic IMNM, we performed dystrophin immunofluorescence on three control cases of adult anti-HMGCR IMNM and noted reductions in dystrophin staining similar to those observed in our patient (Supplementary Fig. The role of dystrophin-targeting miRNAs in IMNM is currently elusive but these first data in patient biopsies raise the possibility of a new potential pathophysiological mechanism and warrant further exploration. [Extracted from the article]

In skeletal muscle, muscle stem cells (MuSC) are the main cells responsible for regeneration upon injury. In diseased skeletal muscle, it would be therapeutically advantageous to replace defective MuSCs, or rejuvenate them with drugs to enhance their self-renewal and ensure long-term regenerative potential. One limitation of the replacement approach has been the inability to efficiently expand MuSCs ex vivo, while maintaining their stemness and engraftment abilities. Herein, we show that inhibition of type I protein arginine methyltransferases (PRMTs) with MS023 increases the proliferative capacity of ex vivo cultured MuSCs. Single cell RNA sequencing (scRNAseq) of ex vivo cultured MuSCs revealed the emergence of subpopulations in MS023-treated cells which are defined by elevated Pax7 expression and markers of MuSC quiescence, both features of enhanced self-renewal. Furthermore, the scRNAseq identified MS023-specific subpopulations to be metabolically altered with upregulated glycolysis and oxidative phosphorylation (OxPhos). Transplantation of MuSCs treated with MS023 had a better ability to repopulate the MuSC niche and contributed efficiently to muscle regeneration following injury. Interestingly, the preclinical mouse model of Duchenne muscular dystrophy had increased grip strength with MS023 treatment. Our findings show that inhibition of type I PRMTs increased the proliferation capabilities of MuSCs with altered cellular metabolism, while maintaining their stem-like properties such as self-renewal and engraftment potential. [ABSTRACT FROM AUTHOR]

Anti-inflammatory modalities are commonly used for the treatment of various musculoskeletal injuries. Although inflammation was originally believed to interfere with skeletal muscle regeneration, several recent studies have highlighted the beneficial effects of inflammatory cells on muscle healing. This discrepancy is attributable to an evolving understanding of the complex inflammatory process. To better appreciate the paradoxical roles of inflammation, clinicians must have a better comprehension of the fundamental mechanisms regulating the inflammatory response. In this perspective article, cellular, animal, and human studies were analyzed to summarize recent knowledge regarding the impact of inflammation on muscle regeneration in acute or chronic conditions. The effect of anti-inflammatory drugs on the treatment of various muscle injuries was also considered. Overall, this work aims to summarize the current state of the literature on the inflammatory process associated with muscle healing in order to give clinicians the necessary tools to have a more efficient and evidence-based approach to the treatment of muscle injuries and disorders. [ABSTRACT FROM AUTHOR]

Skeletal muscle possesses a high plasticity and a remarkable regenerative capacity that relies mainly on muscle stem cells (MuSCs). Molecular and cellular components of the MuSC niche, such as immune cells, play key roles to coordinate MuSC function and to orchestrate muscle regeneration. An abnormal infiltration of immune cells and/or imbalance of pro- and anti-inflammatory cytokines could lead to MuSC dysfunctions that could have long lasting effects on muscle function. Different genetic variants were shown to cause muscular dystrophies that intrinsically compromise MuSC function and/or disturb their microenvironment leading to impaired muscle regeneration that contributes to disease progression. Alternatively, many acquired myopathies caused by comorbidities (e.g., cardiopulmonary or kidney diseases), chronic inflammation/infection, or side effects of different drugs can also perturb MuSC function and their microenvironment. The goal of this review is to comprehensively summarize the current knowledge on acquired myopathies and their impact on MuSC function. We further describe potential therapeutic strategies to restore MuSC regenerative capacity. [ABSTRACT FROM AUTHOR]

Fate decisions in the embryo are controlled by a plethora of microenvironmental interactions in a three‐dimensional niche. To investigate whether aspects of this microenvironmental complexity can be engineered to direct myogenic human‐induced pluripotent stem cell (hiPSC) differentiation, we here screened murine cell types present in the developmental or adult stem cell niche in heterotypic suspension embryoids. We identified embryonic endothelial cells and fibroblasts as highly permissive for myogenic specification of hiPSCs. After two weeks of sequential Wnt and FGF pathway induction, these three‐component embryoids are enriched in Pax7‐positive embryonic‐like myogenic progenitors that can be isolated by flow cytometry. Myogenic differentiation of hiPSCs in heterotypic embryoids relies on a specialized structural microenvironment and depends on MAPK, PI3K/AKT, and Notch signaling. After transplantation in a mouse model of Duchenne muscular dystrophy, embryonic‐like myogenic progenitors repopulate the stem cell niche, reactivate after repeated injury, and, compared to adult human myoblasts, display enhanced fusion and lead to increased muscle function. Altogether, we provide a two‐week protocol for efficient and scalable suspension‐based 3D derivation of Pax7‐positive myogenic progenitors from hiPSCs. Synopsis: Skeletal progenitors offer extensive self‐renewal capacity for muscle regeneration, but their niche context remains unclear and derivatization inefficient. This resource reports a novel heterotypic embryoid model for the generation of induced pluripotent stem cell (iPSC)‐derived human myogenic progenitors in a defined microenvironment, suggesting new therapeutic avenues and opportunities for in vitro screenings. A cell type screen identifies mouse growth‐arrested embryonic fibroblasts and endothelial cells as permissive niche components for the induction of Pax7+ myogenic cells.WNT/FGF stimulation supports hiPSC commitment to the mesodermal lineage.Heterotypic culture‐derived Pax7+ cells display embryonic characteristics, resist differentiation, and function as stem cells in vivo.Heterotypic culture‐induced Pax7+ cell production is scalable to bioreactor level. [ABSTRACT FROM AUTHOR]

The physiological functions and downstream effectors of the atypical mitogen‐activated protein kinase extracellular signal‐regulated kinase 3 (ERK3) remain to be characterized. We recently reported that mice expressing catalytically‐inactive ERK3 (Mapk6KD/KD) exhibit a reduced postnatal growth rate as compared to control mice. Here, we show that genetic inactivation of ERK3 impairs postnatal skeletal muscle growth and adult muscle regeneration after injury. Loss of MAPK‐activated protein kinase 5 (MK5) phenocopies the muscle phenotypes of Mapk6KD/KD mice. At the cellular level, genetic or pharmacological inactivation of ERK3 or MK5 induces precocious differentiation of C2C12 or primary myoblasts, concomitant with MyoD activation. Reciprocally, ectopic expression of activated MK5 inhibits myogenic differentiation. Mechanistically, we show that MK5 directly phosphorylates FoxO3, promoting its degradation and reducing its association with MyoD. Depletion of FoxO3 rescues in part the premature differentiation of C2C12 myoblasts observed upon inactivation of ERK3 or MK5. Our findings reveal that ERK3 and its substrate MK5 act in a linear signaling pathway to control postnatal myogenic differentiation. [ABSTRACT FROM AUTHOR]

Wnt7a/Fzd7 signaling stimulates skeletal muscle growth and repair by inducing the symmetric expansion of satellite stem cells through the planar cell polarity pathway and by activating the Akt/mTOR growth pathway in muscle fibers. Here we describe a third level of activity where Wnt7a/Fzd7 increases the polarity and directional migration of mouse satellite cells and human myogenic progenitors through activation of Dvl2 and the small GTPase Racl. Importantly, these effects can be exploited to potentiate the outcome of myogenic cell transplantation into dystrophic muscles. We observed that a short Wnt7a treatment markedly stimulated tissue dispersal and engraftment, leading to significantly improved muscle function. Moreover, myofibers at distal sites that fused with Wnt7a-treated cells were hypertrophic, suggesting that the transplanted cells deliver activated Wnt7a/Fzd7 signaling complexes to recipient myofibers. Taken together, we describe a viable and effective ex vivo cell modulation process that profoundly enhances the efficacy of stem cell therapy for skeletal muscle. [ABSTRACT FROM AUTHOR]

Individuals born preterm show reduced exercise capacity and increased risk for pulmonary and cardiovascular diseases, but the impact of preterm birth on skeletal muscle, an inherently critical part of cardiorespiratory fitness, remains unknown. We evaluated the impacts of preterm birth-related conditions on the development, growth, and function of skeletal muscle using a recognized preclinical rodent model in which newborn rats are exposed to 80% oxygen from days 3 to 10 of life. We analyzed different hindlimb muscles of male and female rats at 10 days (neonatal), 4 weeks (juvenile), and 16 weeks (young adults). Neonatal high oxygen exposure increased the generation of reactive oxygen species (ROS) and the signs of inflammation in skeletal muscles, which was associated with muscle fiber atrophy, fiber type shifting (reduced proportion of type I slow fibers and increased proportion of type IIb fast-fatigable fibers), and impairment in muscle function. These effects were maintained until adulthood. Fast-twitch muscles were more vulnerable to the effects of hyperoxia than slow-twitch muscles. Male rats, which expressed lower antioxidant defenses, were more susceptible than females to oxygen-induced myopathy. Overall, preterm birth-related conditions have long-lasting effects on the composition, morphology, and function of skeletal muscles; and these effects are sex-specific. Oxygen-induced changes in skeletal muscles could contribute to the reduced exercise capacity and to increased risk of diseases of preterm born individuals. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) still needs effective treatments, and myoblast transplantation (MT) is considered as an approach to repair damaged skeletal muscles. DMD is due to the complete loss of dystrophin from muscles. The lack of link between the contracting apparatus and the extracellular matrix leads to frequent damage to the sarcolemma triggering muscle fiber necrosis. Laminins are major proteins in the extracellular matrix. Laminin-111 is normally present in skeletal and cardiac muscles in mice and humans but only during embryonic development. In this study, we showed that intramuscular injection of laminin-111 increased muscle strength and resistance in mdx mice. We also used laminin-111 as a coadjuvant in MT, and we showed this protein decreased considerably the repetitive cycles of degeneration, inflammatory reaction, and regeneration. Moreover, MT is significantly improved. To explain the improvement, we confirmed with the same myoblast cell batch that laminin-111 improves proliferation and drastically increases migration in vitro. These results are extremely important because DMD could be treated only by the injection of a recombinant protein, a simple and safe therapy to prevent loss of muscle function. Moreover, the improvement in MT would be significant to treat the muscles of DMD patients who are already weak. [ABSTRACT FROM AUTHOR]

Muscle regeneration is a closely regulated process that involves a variety of cell types such as satellite cells, myofibers, fibroadipogenic progenitors, endothelial cells, and inflammatory cells. Among these different cell types, macrophages emerged as a central actor coordinating the different cellular interactions and biological processes. Particularly, the transition of macrophages from their proinflammatory to their anti-inflammatory phenotype was shown to regulate inflammation, myogenesis, fibrosis, vascularization, and return to homeostasis. On the other hand, deregulation of macrophage accumulation or polarization in chronic degenerative muscle disorders was shown to impair muscle regeneration. Considering the key roles of macrophages in skeletal muscle, they represent an attractive target for new therapeutic approaches aiming at mitigating various muscle disorders. This review aims at summarizing the novel insights into macrophage heterogeneity, plasticity, and functions in skeletal muscle homeostasis, regeneration, and disease. [ABSTRACT FROM AUTHOR]

Diminished regenerative capacity of skeletal muscle occurs during adulthood. We identified a reduction in the intrinsic capacity of mouse adult satellite cells to contribute to muscle regeneration and repopulation of the niche. Gene expression analysis identified higher expression of JAK-STAT signaling targets in 18-month-old relative to 3-week-old mice. Knockdown of Jak2 or Stat3 significantly stimulated symmetric satellite stem cell divisions on cultured myofibers. Genetic knockdown of Jak2 or Stat3 expression in prospectively isolated satellite cells markedly enhanced their ability to repopulate the satellite cell niche after transplantation into regenerating tibialis anterior muscle. Pharmacological inhibition of Jak2 and Stat3 activity similarly stimulated symmetric expansion of satellite cells in vitro and their engraftment in vivo. Intramuscular injection of these drugs resulted in a marked enhancement of muscle repair and force generation after cardiotoxin injury. Together these results reveal age-related intrinsic properties that functionally distinguish satellite cells and suggest a promising therapeutic avenue for the treatment of muscle-wasting diseases. [ABSTRACT FROM AUTHOR]

A correction to the article "Inhibition of JAK-STAT signaling stimulates adult satellite cell function" that was published online in the September 22, 2014 issue, after correction, is presented.

A correction to the article "Inhibition of JAK-STAT signaling stimulates adult satellite cell function" is presented.