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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.
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Células-Tronco Pluripotentes Induzidas , Animais , Diferenciação Celular , Células Endoteliais , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Camundongos , Desenvolvimento Muscular , Fosfatidilinositol 3-Quinases/metabolismo , Nicho de Células-TroncoRESUMO
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.
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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.
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Força Muscular , Músculo Esquelético , Nascimento Prematuro , Humanos , Músculo Esquelético/fisiologia , Músculo Esquelético/fisiopatologia , Recém-Nascido , Força Muscular/fisiologia , Recém-Nascido Prematuro/crescimento & desenvolvimentoRESUMO
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.
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Proteína Forkhead Box O3/metabolismo , Transdução de Sinais , Animais , Peptídeos e Proteínas de Sinalização Intracelular , Camundongos , Proteína Quinase 6 Ativada por Mitógeno/metabolismo , Músculos , Proteínas Serina-Treonina Quinases/metabolismoRESUMO
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.
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Modelos Animais de Doenças , Músculo Esquelético/metabolismo , Nascimento Prematuro , Animais , Animais Recém-Nascidos , Feminino , Hiperóxia , Masculino , Músculo Esquelético/patologia , Atrofia Muscular/etiologia , Estresse Oxidativo , Ratos Sprague-DawleyRESUMO
PURPOSE: Skeletal muscle growth and regeneration rely on muscle stem cells, called satellite cells. Specific transcription factors, particularly PAX7, are key regulators of the function of these cells. Knockout of this factor in mice leads to poor postnatal survival; however, the consequences of a lack of PAX7 in humans have not been established. METHODS: Here, we study five individuals with myopathy of variable severity from four unrelated consanguineous couples. Exome sequencing identified pathogenic variants in the PAX7 gene. Clinical examination, laboratory tests, and muscle biopsies were performed to characterize the disease. RESULTS: The disease was characterized by hypotonia, ptosis, muscular atrophy, scoliosis, and mildly dysmorphic facial features. The disease spectrum ranged from mild to severe and appears to be progressive. Muscle biopsies showed the presence of atrophic fibers and fibroadipose tissue replacement, with the absence of myofiber necrosis. A lack of PAX7 expression was associated with satellite cell pool exhaustion; however, the presence of residual myoblasts together with regenerating myofibers suggest that a population of PAX7-independent myogenic cells partially contributes to muscle regeneration. CONCLUSION: These findings show that biallelic variants in the master transcription factor PAX7 cause a new type of myopathy that specifically affects satellite cell survival.
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Doenças Musculares/genética , Fator de Transcrição PAX7/genética , Adolescente , Alelos , Criança , Pré-Escolar , Feminino , Humanos , Masculino , Desenvolvimento Muscular , Músculo Esquelético/metabolismo , Doenças Musculares/etiologia , Mioblastos , Fator de Transcrição PAX7/metabolismo , Linhagem , Regeneração , Células Satélites de Músculo Esquelético/metabolismo , Fatores de Transcrição/genética , Sequenciamento do Exoma/métodosRESUMO
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.
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Envelhecimento/fisiologia , Linhagem da Célula/fisiologia , Modelos Biológicos , Desenvolvimento Muscular/fisiologia , Músculo Esquelético/fisiologia , Regeneração/fisiologia , Células Satélites de Músculo Esquelético/fisiologia , Animais , Ciclo Celular/fisiologia , Diferenciação Celular/fisiologia , Sinais (Psicologia) , Humanos , Transdução de Sinais/fisiologiaRESUMO
Compensatory growth and regeneration of skeletal muscle is dependent on the resident stem cell population, satellite cells (SCs). Self-renewal and maintenance of the SC niche is coordinated by the paired-box transcription factor Pax7, and yet continued expression of this protein inhibits the myoblast differentiation program. As such, the reduction or removal of Pax7 may denote a key prerequisite for SCs to abandon self-renewal and acquire differentiation competence. Here, we identify caspase 3 cleavage inactivation of Pax7 as a crucial step for terminating the self-renewal process. Inhibition of caspase 3 results in elevated Pax7 protein and SC self-renewal, whereas caspase activation leads to Pax7 cleavage and initiation of the myogenic differentiation program. Moreover, in vivo inhibition of caspase 3 activity leads to a profound disruption in skeletal muscle regeneration with an accumulation of SCs within the niche. We have also noted that casein kinase 2 (CK2)-directed phosphorylation of Pax7 attenuates caspase-directed cleavage. Together, these results demonstrate that SC fate is dependent on opposing posttranslational modifications of the Pax7 protein.
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Caspase 3/metabolismo , Músculo Esquelético/metabolismo , Fator de Transcrição PAX7/metabolismo , Células Satélites de Músculo Esquelético/citologia , Sequência de Aminoácidos , Animais , Sítios de Ligação , Caseína Quinases/metabolismo , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Imuno-Histoquímica , Camundongos , Camundongos Endogâmicos C57BL , Dados de Sequência Molecular , Fosforilação , Proteínas Recombinantes/metabolismo , Regeneração , Homologia de Sequência de Aminoácidos , Células-Tronco/citologiaRESUMO
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 Ca(2+)sensor, and altered activity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) modulating Ca(2+)storage. Muscle RANK deletion had no significant effects on the sham or denervated slow-twitch soleus muscles. These data identify a novel role for RANK as a key regulator of Ca(2+)storage and SERCA activity, ultimately affecting denervated skeletal muscle function.
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Sinalização do Cálcio/fisiologia , Cálcio/metabolismo , Contração Isométrica/fisiologia , Fibras Musculares de Contração Rápida/fisiologia , Receptor Ativador de Fator Nuclear kappa-B/metabolismo , ATPases Transportadoras de Cálcio do Retículo Sarcoplasmático/metabolismo , Animais , Células Cultivadas , Masculino , Camundongos , Camundongos Endogâmicos C57BLRESUMO
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.
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Músculo Esquelético/citologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Diferenciação Celular/fisiologia , Células Cultivadas , Imuno-Histoquímica , Camundongos , Fator de Transcrição PAX7/metabolismo , Células Satélites de Músculo Esquelético/citologiaRESUMO
Receptor-activator of NF-κB, its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Although there is a strong association between osteoporosis and skeletal muscle atrophy/dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology still is elusive. Here, we show that muscle cells can produce and secrete osteoprotegerin and pharmacologic treatment of dystrophic mdx mice with recombinant osteoprotegerin muscles. (Recombinant osteoprotegerin-Fc mitigates the loss of muscle force in a dose-dependent manner and preserves muscle integrity, particularly in fast-twitch extensor digitorum longus.) Our data identify osteoprotegerin as a novel protector of muscle integrity, and it potentially represents a new therapeutic avenue for both muscular diseases and osteoporosis.
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Distrofia Muscular Animal/metabolismo , Distrofia Muscular Animal/prevenção & controle , Osteoprotegerina/metabolismo , Animais , Linhagem Celular , Fragmentos Fc das Imunoglobulinas/metabolismo , Técnicas In Vitro , Inflamação/patologia , Leucócitos/efeitos dos fármacos , Leucócitos/metabolismo , Lipopolissacarídeos/farmacologia , Masculino , Camundongos Endogâmicos C57BL , Fibras Musculares Esqueléticas/efeitos dos fármacos , Fibras Musculares Esqueléticas/metabolismo , Músculos/efeitos dos fármacos , Músculos/metabolismo , Músculos/patologia , Músculos/fisiopatologia , Distrofia Muscular Animal/fisiopatologiaRESUMO
Satellite cells, the quintessential skeletal muscle stem cells, reside in a specialized local environment whose anatomy changes dynamically during tissue regeneration. The plasticity of this niche is attributable to regulation by the stem cells themselves and to a multitude of functionally diverse cell types. In particular, immune cells, fibrogenic cells, vessel-associated cells and committed and differentiated cells of the myogenic lineage have emerged as important constituents of the satellite cell niche. Here, we discuss the cellular dynamics during muscle regeneration and how disease can lead to perturbation of these mechanisms. To define the role of cellular components in the muscle stem cell niche is imperative for the development of cell-based therapies, as well as to better understand the pathobiology of degenerative conditions of the skeletal musculature.
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Desenvolvimento Muscular , Músculo Esquelético/fisiologia , Regeneração , Células Satélites de Músculo Esquelético/metabolismo , Nicho de Células-Tronco , Animais , Humanos , Músculo Esquelético/citologia , Músculo Esquelético/crescimento & desenvolvimento , Células Satélites de Músculo Esquelético/fisiologiaRESUMO
Skeletal muscle injury and regeneration are closely associated with an inflammatory reaction that is usually characterized by sequential recruitment of neutrophils and monocytes or macrophages. Selective macrophage depletion models have shown that macrophages are essential for complete regeneration of muscle fibers after freeze injuries, toxin injuries, ischemia-reperfusion, and hindlimb unloading and reloading. Although there is growing evidence that macrophages possess major myogenic capacities, it is not known whether the positive effects of macrophages can be optimized to stimulate muscle regrowth. We used in vivo and in vitro mouse models of atrophy to investigate the effects of stimulating macrophages with macrophage colony-stimulating factor (M-CSF) on muscle regrowth. When atrophied soleus muscles were injected intramuscularly with M-CSF, we observed a 1.6-fold increase in macrophage density and a faster recovery in muscle force (20%), combined with an increase in muscle fiber diameter (10%), after 7 days of reloading, compared with PBS-injected soleus muscles. Furthermore, coculture of atrophied myotubes with or without bone marrow-derived macrophages (BMDM) and/or M-CSF revealed that the combination of BMDMs and M-CSF was required to promote myotube growth (15%). More specifically, M-CSF promoted the anti-inflammatory macrophage phenotype, which in turn decreased protein degradation and MuRF-1 expression by 25% in growing myotubes. These results indicate that specific macrophage subsets can be stimulated to promote muscle cell regrowth after atrophy.
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Diferenciação Celular/efeitos dos fármacos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Macrófagos/patologia , Fibras Musculares Esqueléticas/patologia , Músculo Esquelético/patologia , Atrofia Muscular/patologia , Animais , Células da Medula Óssea/efeitos dos fármacos , Células da Medula Óssea/patologia , Células Cultivadas , Técnicas de Cocultura , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Contração Muscular/efeitos dos fármacos , Desenvolvimento Muscular/efeitos dos fármacos , Fibras Musculares Esqueléticas/efeitos dos fármacos , Músculo Esquelético/efeitos dos fármacos , Músculo Esquelético/fisiopatologia , Atrofia Muscular/fisiopatologia , Neutrófilos/efeitos dos fármacos , Neutrófilos/patologia , Fenótipo , Biossíntese de Proteínas/efeitos dos fármacos , Proteólise/efeitos dos fármacosRESUMO
As monitoring and diagnostic tools for long COVID-19 cases, wearable systems and supervised learning-based medical image analysis have proven to be useful. Current research on these two technical roadmaps has various drawbacks, despite their respective benefits. Wearable systems allow only the real-time monitoring of physiological parameters (heart rate, temperature, blood oxygen saturation, or SpO2). Therefore, they are unable to conduct in-depth investigations or differentiate COVID-19 from other illnesses that share similar symptoms. Medical image analysis using supervised learning-based models can be used to conduct in-depth analyses and provide precise diagnostic decision support. However, these methods are rarely used for real-time monitoring. In this regard, we present an intelligent garment combining the precision of supervised learning-based models with real-time monitoring capabilities of wearable systems. Given the relevance of electrocardiogram (ECG) signals to long COVID-19 symptom severity, an explainable data fusion strategy based on multiple machine learning models uses heart rate, temperature, SpO2, and ECG signal analysis to accurately assess the patient's health status. Experiments show that the proposed intelligent garment achieves an accuracy of 97.5 %, outperforming most of the existing wearable systems. Furthermore, it was confirmed that the two physiological indicators most significantly affected by the presence of long COVID-19 were SpO2 and the ST intervals of ECG signals.
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Myotonic dystrophy type 1 (DM1) is a rare autosomal dominant genetic disorder. Although DM1 is primarily characterized by progressive muscular weakness, it exhibits many multisystemic manifestations, such as cognitive deficits, cardiac conduction abnormalities, and cataracts, as well as endocrine and reproductive issues. Additionally, the gastrointestinal (GI) tract is frequently affected, encompassing the entire digestive tract. However, the underlying causes of these GI symptoms remain uncertain, whether it is biomechanical problems of the intestine, involvement of bacterial communities, or both. The primary objective of this study is to investigate the structural changes in the gut microbiome of DM1 patients. To achieve this purpose, 35 patients with DM1 were recruited from the DM-Scope registry of the neuromuscular clinic in the Saguenay-Lac-St-Jean region of the province of Québec, Canada. Stool samples from these 35 patients, including 15 paired samples with family members living with them as controls, were collected. Subsequently, these samples were sequenced by 16S MiSeq and were analyzed with DADA2 to generate taxonomic signatures. Our analysis revealed that the DM1 status correlated with changes in gut bacterial community. Notably, there were differences in the relative abundance of Bacteroidota, Euryarchaeota, Fusobacteriota, and Cyanobacteria Phyla compared to healthy controls. However, no significant shift in gut microbiome community structure was observed between DM1 phenotypes. These findings provide valuable insights into how the gut bacterial community, in conjunction with biomechanical factors, could potentially influence the gastrointestinal tract of DM1 patients.
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Impaired skeletal muscle stem cell (MuSC) function has long been suspected to contribute to the pathogenesis of muscular dystrophy (MD). Here, we showed that defects in the endothelial cell (EC) compartment of the vascular stem cell niche in mouse models of Duchenne MD, laminin α2-related MD, and collagen VI-related myopathy were associated with inefficient mobilization of MuSCs after tissue damage. Using chemoinformatic analysis, we identified the 13-amino acid form of the peptide hormone apelin (AP-13) as a candidate for systemic stimulation of skeletal muscle ECs. Systemic administration of AP-13 using osmotic pumps generated a pro-proliferative EC-rich niche that supported MuSC function through angiocrine factors and markedly improved tissue regeneration and muscle strength in all three dystrophic mouse models. Moreover, EC-specific knockout of the apelin receptor led to regenerative defects that phenocopied key pathological features of MD, including vascular defects, fibrosis, muscle fiber necrosis, impaired MuSC function, and reduced force generation. Together, these studies provide in vivo proof of concept that enhancing endogenous skeletal muscle repair by targeting the vascular niche is a viable therapeutic avenue for MD and characterized AP-13 as a candidate for further study for the systemic treatment of MuSC dysfunction.
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Distrofia Muscular de Duchenne , Nicho de Células-Tronco , Camundongos , Animais , Apelina/metabolismo , Músculo Esquelético/metabolismo , Distrofia Muscular de Duchenne/metabolismo , Transdução de SinaisRESUMO
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.
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Doenças Musculares , Humanos , Doenças Musculares/genética , Músculo Esquelético/fisiologia , Mioblastos , Desenvolvimento Muscular/genética , InflamaçãoRESUMO
Introduction: Muscle wasting in Duchenne Muscular Dystrophy is caused by myofiber fragility and poor regeneration that lead to chronic inflammation and muscle replacement by fibrofatty tissue. Our recent findings demonstrated that Resolvin-D2, a bioactive lipid derived from omega-3 fatty acids, has the capacity to dampen inflammation and stimulate muscle regeneration to alleviate disease progression. This therapeutic avenue has many advantages compared to glucocorticoids, the current gold-standard treatment for Duchenne Muscular Dystrophy. However, the use of bioactive lipids as therapeutic drugs also faces many technical challenges such as their instability and poor oral bioavailability. Methods: Here, we explored the potential of PSB-KD107, a synthetic agonist of the resolvin-D2 receptor Gpr18, as a therapeutic alternative for Duchenne Muscular Dystrophy. Results and discussion: We showed that PSB-KD107 can stimulate the myogenic capacity of patient iPSC-derived myoblasts in vitro. RNAseq analysis revealed an enrichment in biological processes related to fatty acid metabolism, lipid biosynthesis, small molecule biosynthesis, and steroid-related processes in PSB-KD107-treated mdx myoblasts, as well as signaling pathways such as Peroxisome proliferator-activated receptors, AMP-activated protein kinase, mammalian target of rapamycin, and sphingolipid signaling pathways. In vivo, the treatment of dystrophic mdx mice with PSB-KD107 resulted in reduced inflammation, enhanced myogenesis, and improved muscle function. The positive impact of PSB-KD107 on muscle function is similar to the one of Resolvin-D2. Overall, our findings provide a proof-of concept that synthetic analogs of bioactive lipid receptors hold therapeutic potential for the treatment of Duchenne Muscular Dystrophy.
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Percutaneous paravalvular leak closure seems a safe alternative to surgery in frail patients. However, it is a challenging procedure that should be tailored to each patient with optimal imaging guidance. Transesophageal echocardiography during the procedure and computed tomography scan/fluoroscopy fusion provide guidance for critical steps, such as PVL localization and crossing. (Level of Difficulty: Advanced.).