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1.
Genet Med ; 21(11): 2521-2531, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31092906

RESUMO

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.

2.
Cell Stem Cell ; 24(3): 419-432.e6, 2019 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-30713094

RESUMO

Loss of dystrophin expression in Duchenne muscular dystrophy (DMD) causes progressive degeneration of skeletal muscle, which is exacerbated by reduced self-renewing asymmetric divisions of muscle satellite cells. This, in turn, affects the production of myogenic precursors and impairs regeneration and suggests that increasing such divisions may be beneficial. Here, through a small-molecule screen, we identified epidermal growth factor receptor (EGFR) and Aurora kinase A (Aurka) as regulators of asymmetric satellite cell divisions. Inhibiting EGFR causes a substantial shift from asymmetric to symmetric division modes, whereas EGF treatment increases asymmetric divisions. EGFR activation acts through Aurka to orient mitotic centrosomes, and inhibiting Aurka blocks EGF stimulation-induced asymmetric division. In vivo EGF treatment markedly activates asymmetric divisions of dystrophin-deficient satellite cells in mdx mice, increasing progenitor numbers, enhancing regeneration, and restoring muscle strength. Therefore, activating an EGFR-dependent polarity pathway promotes functional rescue of dystrophin-deficient satellite cells and enhances muscle force generation.

3.
Phys Ther ; 97(8): 807-817, 2017 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-28789470

RESUMO

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.


Assuntos
Músculo Esquelético/lesões , Músculo Esquelético/patologia , Regeneração/fisiologia , Cicatrização/fisiologia , Animais , Anti-Inflamatórios/uso terapêutico , Humanos , Inflamação/etiologia , Inflamação/fisiopatologia , Inflamação/terapia , Músculo Esquelético/fisiopatologia , Miosite/etiologia , Miosite/patologia , Miosite/terapia
4.
Methods Mol Biol ; 1560: 179-188, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28155153

RESUMO

Muscle stem cells, named satellite cells, are quiescent in resting skeletal muscle. Following injury, satellite cells are activated and become proliferating myoblasts that either self-renew or differentiate. Several markers are used to identify the different myogenic populations, such as Pax7 (quiescent and activated satellite cells), MyoD (proliferating myoblasts), and myogenin (differentiating myoblasts). Immunodetection of these markers is a very useful tool to analyze myogenic cells and muscle regeneration. Here, we describe a method for immunodetection of satellite cells and their myogenic progeny in resting and regenerating skeletal muscles.


Assuntos
Músculo Esquelético/metabolismo , Regeneração , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/metabolismo , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Antígenos de Diferenciação/metabolismo , Imunofluorescência , Imuno-Histoquímica/métodos , Camundongos , Microscopia de Fluorescência/métodos , Desenvolvimento Muscular/fisiologia
6.
Med Sci (Paris) ; 32(6-7): 591-7, 2016 Jun-Jul.
Artigo em Francês | MEDLINE | ID: mdl-27406769

RESUMO

Muscle injuries are very frequent and are associated with an inflammatory reaction that varies in intensity. Classically the inflammatory process was considered harmful for muscle regeneration and anti-inflammatory agents are still part of a conventional therapy. Over the last decades, it has been demonstrated under some conditions that the inflammatory response could be detrimental for the musculoskeletal tissue. However, accumulating evidence indicate that controlled and efficient inflammatory response is necessary for an optimal muscle recovery. Among the resident and infiltrating leukocytes that participate into the inflammatory process, macrophages play a critical role in muscle regeneration due to their ability to switch from pro-inflammatory to anti-inflammatory phenotypes depending on their microenvironment. The present review synthesizes the recent advances regarding the interactions of the different infiltrating and resident leukocytes on myogenic cell function and muscle regeneration.


Assuntos
Inflamação/fisiopatologia , Músculo Esquelético/fisiologia , Doenças Musculares/etiologia , Regeneração/fisiologia , Animais , Anti-Inflamatórios/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Macrófagos/imunologia , Macrófagos/metabolismo , Desenvolvimento Muscular/fisiologia , Doenças Musculares/imunologia
7.
Nat Med ; 22(8): 897-905, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27376579

RESUMO

Age-related changes in the niche have long been postulated to impair the function of somatic stem cells. Here we demonstrate that the aged stem cell niche in skeletal muscle contains substantially reduced levels of fibronectin (FN), leading to detrimental consequences for the function and maintenance of muscle stem cells (MuSCs). Deletion of the gene encoding FN from young regenerating muscles replicates the aging phenotype and leads to a loss of MuSC numbers. By using an extracellular matrix (ECM) library screen and pathway profiling, we characterize FN as a preferred adhesion substrate for MuSCs and demonstrate that integrin-mediated signaling through focal adhesion kinase and the p38 mitogen-activated protein kinase pathway is strongly de-regulated in MuSCs from aged mice because of insufficient attachment to the niche. Reconstitution of FN levels in the aged niche remobilizes stem cells and restores youth-like muscle regeneration. Taken together, we identify the loss of stem cell adhesion to FN in the niche ECM as a previously unknown aging mechanism.


Assuntos
Envelhecimento/metabolismo , Fibronectinas/genética , Proteína-Tirosina Quinases de Adesão Focal/metabolismo , Músculo Esquelético/metabolismo , Regeneração/genética , Nicho de Células-Tronco , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Animais , Western Blotting , Matriz Extracelular/metabolismo , Fibronectinas/metabolismo , Citometria de Fluxo , Integrinas/metabolismo , Camundongos , Músculo Esquelético/citologia , Reação em Cadeia da Polimerase
8.
Am J Physiol Cell Physiol ; 310(8): C663-72, 2016 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-26825123

RESUMO

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.


Assuntos
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 C57BL
9.
Artigo em Inglês | MEDLINE | ID: mdl-29188075

RESUMO

Duchenne muscular dystrophy (DMD) is a genetic disease characterised by skeletal muscle degeneration and progressive muscle wasting, which is caused by loss-of-function mutations in the DMD gene that encodes for the protein dystrophin. Dystrophin has critical roles in myofiber stability and integrity by connecting the actin cytoskeleton to the extracellular matrix. Absence of dystrophin leads to myofiber fragility and contributes to skeletal muscle degeneration in DMD patients, however, accumulating evidence also indicate that muscle stem cells (also known as satellite cells) are defective in dystrophic muscles, which leads to impaired muscle regeneration. Our recent work demonstrated that dystrophin is expressed in activated satellite cells, where it regulates the establishment of satellite cell polarity and asymmetric cell division. These findings indicate that dystrophin-deficient satellite cells have intrinsic dysfunctions that contribute to muscle wasting and progression of the disease. This discovery suggests that satellite cells could be targeted to treat DMD. Here we discuss how these new findings affect regenerative therapies for muscular dystrophies. Therapies targeting satellite cells hold great potential and could have long-term efficiency owing to the high self-renewal ability of these cells.

10.
Nat Med ; 21(12): 1455-63, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26569381

RESUMO

Dystrophin is expressed in differentiated myofibers, in which it is required for sarcolemmal integrity, and loss-of-function mutations in the gene that encodes it result in Duchenne muscular dystrophy (DMD), a disease characterized by progressive and severe skeletal muscle degeneration. Here we found that dystrophin is also highly expressed in activated muscle stem cells (also known as satellite cells), in which it associates with the serine-threonine kinase Mark2 (also known as Par1b), an important regulator of cell polarity. In the absence of dystrophin, expression of Mark2 protein is downregulated, resulting in the inability to localize the cell polarity regulator Pard3 to the opposite side of the cell. Consequently, the number of asymmetric divisions is strikingly reduced in dystrophin-deficient satellite cells, which also display a loss of polarity, abnormal division patterns (including centrosome amplification), impaired mitotic spindle orientation and prolonged cell divisions. Altogether, these intrinsic defects strongly reduce the generation of myogenic progenitors that are needed for proper muscle regeneration. Therefore, we conclude that dystrophin has an essential role in the regulation of satellite cell polarity and asymmetric division. Our findings indicate that muscle wasting in DMD not only is caused by myofiber fragility, but also is exacerbated by impaired regeneration owing to intrinsic satellite cell dysfunction.


Assuntos
Divisão Celular Assimétrica , Polaridade Celular , Distrofina/metabolismo , Músculo Esquelético/citologia , Células-Tronco/citologia , Células-Tronco/metabolismo , Animais , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células , Separação Celular , Distrofina/deficiência , Citometria de Fluxo , Camundongos Endogâmicos mdx , Análise de Sequência com Séries de Oligonucleotídeos , Ligação Proteica , Proteínas Serina-Treonina Quinases/metabolismo , Regeneração , Células Satélites de Músculo Esquelético/citologia , Células Satélites de Músculo Esquelético/metabolismo , Fuso Acromático/metabolismo
11.
Proc Natl Acad Sci U S A ; 112(38): E5246-52, 2015 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-26372956

RESUMO

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.


Assuntos
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/citologia
12.
Compr Physiol ; 5(3): 1027-59, 2015 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-26140708

RESUMO

Skeletal muscles are essential for vital functions such as movement, postural support, breathing, and thermogenesis. Muscle tissue is largely composed of long, postmitotic multinucleated fibers. The life-long maintenance of muscle tissue is mediated by satellite cells, lying in close proximity to the muscle fibers. Muscle satellite cells are a heterogeneous population with a small subset of muscle stem cells, termed satellite stem cells. Under homeostatic conditions all satellite cells are poised for activation by stimuli such as physical trauma or growth signals. After activation, satellite stem cells undergo symmetric divisions to expand their number or asymmetric divisions to give rise to cohorts of committed satellite cells and thus progenitors. Myogenic progenitors proliferate, and eventually differentiate through fusion with each other or to damaged fibers to reconstitute fiber integrity and function. In the recent years, research has begun to unravel the intrinsic and extrinsic mechanisms controlling satellite cell behavior. Nonetheless, an understanding of the complex cellular and molecular interactions of satellite cells with their dynamic microenvironment remains a major challenge, especially in pathological conditions. The goal of this review is to comprehensively summarize the current knowledge on satellite cell characteristics, functions, and behavior in muscle regeneration and in pathological conditions.


Assuntos
Diferenciação Celular , Músculo Esquelético/citologia , Regeneração , Células Satélites de Músculo Esquelético/citologia , Animais , Humanos , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Células Satélites de Músculo Esquelético/metabolismo
13.
Development ; 142(9): 1572-81, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25922523

RESUMO

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.


Assuntos
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/fisiologia
15.
Am J Pathol ; 185(4): 920-6, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25708645

RESUMO

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.


Assuntos
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/fisiopatologia
16.
J Cell Sci ; 127(Pt 21): 4543-8, 2014 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-25300792

RESUMO

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.


Assuntos
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/citologia
17.
Nat Med ; 20(10): 1174-81, 2014 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25194569

RESUMO

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 3-week [corrected] 18-month-old mice [corrected]. 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.


Assuntos
Janus Quinases/antagonistas & inibidores , Fatores de Transcrição STAT/antagonistas & inibidores , Células Satélites de Músculo Esquelético/fisiologia , Envelhecimento/patologia , Envelhecimento/fisiologia , Animais , Feminino , Técnicas de Silenciamento de Genes , Janus Quinase 2/antagonistas & inibidores , Janus Quinase 2/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos mdx , Camundongos Transgênicos , RNA Interferente Pequeno/genética , Regeneração/efeitos dos fármacos , Regeneração/fisiologia , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Células Satélites de Músculo Esquelético/transplante , Transdução de Sinais
18.
J Cell Biol ; 205(1): 97-111, 2014 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-24711502

RESUMO

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 Rac1. 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.


Assuntos
Movimento Celular , Força Muscular , Músculo Esquelético/cirurgia , Distrofias Musculares/cirurgia , Mioblastos Esqueléticos/metabolismo , Mioblastos Esqueléticos/transplante , Proteínas Wnt/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Animais , Fusão Celular , Linhagem Celular , Polaridade Celular , Modelos Animais de Doenças , Proteínas Desgrenhadas , Endocitose , Receptores Frizzled/metabolismo , Genes Reporter , Proteínas de Fluorescência Verde/genética , Proteínas de Fluorescência Verde/metabolismo , Humanos , Hipertrofia , Proteínas Luminescentes/genética , Proteínas Luminescentes/metabolismo , Camundongos , Camundongos Endogâmicos mdx , Camundongos Knockout , Camundongos Transgênicos , Músculo Esquelético/metabolismo , Músculo Esquelético/patologia , Músculo Esquelético/fisiopatologia , Distrofias Musculares/genética , Distrofias Musculares/metabolismo , Distrofias Musculares/patologia , Distrofias Musculares/fisiopatologia , Mioblastos Esqueléticos/patologia , Neuropeptídeos/metabolismo , Fator de Transcrição PAX7/genética , Fosfoproteínas/metabolismo , Regiões Promotoras Genéticas , Receptores Acoplados a Proteínas-G/deficiência , Receptores Acoplados a Proteínas-G/genética , Proteínas Recombinantes de Fusão/metabolismo , Transdução de Sinais , Proteínas Wnt/genética , Proteínas rac1 de Ligação ao GTP/metabolismo
19.
EMBO Rep ; 14(12): 1062-72, 2013 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-24232182

RESUMO

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.


Assuntos
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/fisiologia
20.
Am J Pathol ; 182(2): 505-15, 2013 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-23201131

RESUMO

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.


Assuntos
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 fármacos
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