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Dive into the research topics where Pura Muñoz-Cánoves is active.

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Featured researches published by Pura Muñoz-Cánoves.


Cell Metabolism | 2008

Interleukin-6 is an essential regulator of satellite cell-mediated skeletal muscle hypertrophy

Antonio Serrano; Bernat Baeza-Raja; Eusebio Perdiguero; Mercè Jardí; Pura Muñoz-Cánoves

Skeletal muscles adapt to increasing workload by augmenting their fiber size, through mechanisms that are poorly understood. This study identifies the cytokine interleukin-6 (IL-6) as an essential regulator of satellite cell (muscle stem cell)-mediated hypertrophic muscle growth. IL-6 is locally and transiently produced by growing myofibers and associated satellite cells, and genetic loss of IL-6 blunted muscle hypertrophy in vivo. IL-6 deficiency abrogated satellite cell proliferation and myonuclear accretion in the preexisting myofiber by impairing STAT3 activation and expression of its target gene cyclin D1. The growth defect was indeed muscle cell intrinsic, since IL-6 loss also affected satellite cell behavior in vitro, in a STAT3-dependent manner. Myotube-produced IL-6 further stimulated cell proliferation in a paracrine fashion. These findings unveil a role for IL-6 in hypertrophic muscle growth and provide mechanistic evidence for the contribution of satellite cells to this process.


Skeletal Muscle | 2011

Aberrant repair and fibrosis development in skeletal muscle

Christopher J. Mann; Eusebio Perdiguero; Yacine Kharraz; Susana Aguilar; Patrizia Pessina; Antonio Serrano; Pura Muñoz-Cánoves

The repair process of damaged tissue involves the coordinated activities of several cell types in response to local and systemic signals. Following acute tissue injury, infiltrating inflammatory cells and resident stem cells orchestrate their activities to restore tissue homeostasis. However, during chronic tissue damage, such as in muscular dystrophies, the inflammatory-cell infiltration and fibroblast activation persists, while the reparative capacity of stem cells (satellite cells) is attenuated. Abnormal dystrophic muscle repair and its end stage, fibrosis, represent the final common pathway of virtually all chronic neurodegenerative muscular diseases. As our understanding of the pathogenesis of muscle fibrosis has progressed, it has become evident that the muscle provides a useful model for the regulation of tissue repair by the local microenvironment, showing interplay among muscle-specific stem cells, inflammatory cells, fibroblasts and extracellular matrix components of the mammalian wound-healing response. This article reviews the emerging findings of the mechanisms that underlie normal versus aberrant muscle-tissue repair.


Nature | 2014

Geriatric muscle stem cells switch reversible quiescence into senescence

Pedro Sousa-Victor; Susana Gutarra; Laura García-Prat; Javier Rodríguez-Ubreva; Laura Ortet; Vanessa Ruiz-Bonilla; Mercè Jardí; Esteban Ballestar; Susana Gonzalez; Antonio Serrano; Eusebio Perdiguero; Pura Muñoz-Cánoves

Regeneration of skeletal muscle depends on a population of adult stem cells (satellite cells) that remain quiescent throughout life. Satellite cell regenerative functions decline with ageing. Here we report that geriatric satellite cells are incapable of maintaining their normal quiescent state in muscle homeostatic conditions, and that this irreversibly affects their intrinsic regenerative and self-renewal capacities. In geriatric mice, resting satellite cells lose reversible quiescence by switching to an irreversible pre-senescence state, caused by derepression of p16INK4a (also called Cdkn2a). On injury, these cells fail to activate and expand, undergoing accelerated entry into a full senescence state (geroconversion), even in a youthful environment. p16INK4a silencing in geriatric satellite cells restores quiescence and muscle regenerative functions. Our results demonstrate that maintenance of quiescence in adult life depends on the active repression of senescence pathways. As p16INK4a is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.


Nature | 2016

Autophagy maintains stemness by preventing senescence

Laura García-Prat; Martínez-Vicente M; Eusebio Perdiguero; Ortet L; Javier Rodríguez-Ubreva; Rebollo E; Ruiz-Bonilla; Susana Gutarra; Esteban Ballestar; Antonio Serrano; Sandri M; Pura Muñoz-Cánoves

During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.During ageing, muscle stem-cell regenerative function declines. At advanced geriatric age, this decline is maximal owing to transition from a normal quiescence into an irreversible senescence state. How satellite cells maintain quiescence and avoid senescence until advanced age remains unknown. Here we report that basal autophagy is essential to maintain the stem-cell quiescent state in mice. Failure of autophagy in physiologically aged satellite cells or genetic impairment of autophagy in young cells causes entry into senescence by loss of proteostasis, increased mitochondrial dysfunction and oxidative stress, resulting in a decline in the function and number of satellite cells. Re-establishment of autophagy reverses senescence and restores regenerative functions in geriatric satellite cells. As autophagy also declines in human geriatric satellite cells, our findings reveal autophagy to be a decisive stem-cell-fate regulator, with implications for fostering muscle regeneration in sarcopenia.


FEBS Journal | 2013

Interleukin‐6 myokine signaling in skeletal muscle: a double‐edged sword?

Pura Muñoz-Cánoves; Camilla Scheele; Bente Klarlund Pedersen; Antonio Serrano

Interleukin (IL)‐6 is a cytokine with pleiotropic functions in different tissues and organs. Skeletal muscle produces and releases significant levels of IL‐6 after prolonged exercise and is therefore considered as a myokine. Muscle is also an important target of the cytokine. IL‐6 signaling has been associated with stimulation of hypertrophic muscle growth and myogenesis through regulation of the proliferative capacity of muscle stem cells. Additional beneficial effects of IL‐6 include regulation of energy metabolism, which is related to the capacity of actively contracting muscle to synthesize and release IL‐6. Paradoxically, deleterious actions for IL‐6 have also been proposed, such as promotion of atrophy and muscle wasting. We review the current evidence for these apparently contradictory effects, the mechanisms involved and discuss their possible biological implications.


The EMBO Journal | 2007

Genetic analysis of p38 MAP kinases in myogenesis: fundamental role of p38α in abrogating myoblast proliferation

Eusebio Perdiguero; Vanessa Ruiz-Bonilla; Lionel Gresh; Lijian Hui; Esteban Ballestar; Pedro Sousa-Victor; Bernat Baeza-Raja; Mercè Jardí; Anna Bosch-Comas; Manel Esteller; Carme Caelles; Antonio Serrano; Erwin F. Wagner; Pura Muñoz-Cánoves

The p38 mitogen‐activated protein kinase (MAPK) pathway plays a critical role in skeletal muscle differentiation. However, the relative contribution of the four p38 MAPKs (p38α, p38β, p38γ and p38δ) to this process is unknown. Here we show that myoblasts lacking p38α, but not those lacking p38β or p38δ, are unable to differentiate and form multinucleated myotubes, whereas p38γ‐deficient myoblasts exhibit an attenuated fusion capacity. The defective myogenesis in the absence of p38α is caused by delayed cell‐cycle exit and continuous proliferation in differentiation‐promoting conditions. Indeed, activation of JNK/cJun was enhanced in p38α‐deficient myoblasts leading to increased cyclin D1 transcription, whereas inhibition of JNK activity rescued the proliferation phenotype. Thus, p38α controls myogenesis by antagonizing the activation of the JNK proliferation‐promoting pathway, before its direct effect on muscle differentiation‐specific gene transcription. More importantly, in agreement with the defective myogenesis of cultured p38αΔ/Δ myoblasts, neonatal muscle deficient in p38α shows cellular hyperproliferation and delayed maturation. This study provides novel evidence of a fundamental role of p38α in muscle formation in vitro and in vivo.


The EMBO Journal | 2005

E47 phosphorylation by p38 MAPK promotes MyoD/E47 association and muscle‐specific gene transcription

Frederic Lluı́s; Esteban Ballestar; Mònica Suelves; Manel Esteller; Pura Muñoz-Cánoves

Selective recognition of the E‐box sequences on muscle gene promoters by heterodimers of myogenic basic helix–loop–helix (bHLH) transcription factors, such as MyoD, with the ubiquitous bHLH proteins E12 and E47 is a key event in skeletal myogenesis. However, homodimers of MyoD or E47 are unable of binding to and activating muscle chromatin targets, suggesting that formation of functional MyoD/E47 heterodimers is pivotal in controlling muscle transcription. Here we show that p38 MAPK, whose activity is essential for myogenesis, regulates MyoD/E47 heterodimerization. Phosphorylation of E47 at Ser140 by p38 induces MyoD/E47 association and activation of muscle‐specific transcription, while the nonphosphorylatable E47 mutant Ser140Ala fails to heterodimerize with MyoD and displays impaired myogenic potential. Moreover, inhibition of p38 activity in myocytes precludes E47 phosphorylation at Ser140, which results in reduced MyoD/E47 heterodimerization and inefficient muscle differentiation, as a consequence of the impaired binding of the transcription factors to the E regulatory regions of muscle genes. These findings identify a novel pro‐myogenic role of p38 in regulating the formation of functional MyoD/E47 heterodimers that are essential for myogenesis.


Mediators of Inflammation | 2013

Macrophage plasticity and the role of inflammation in skeletal muscle repair.

Yacine Kharraz; Joana Guerra; Christopher J. Mann; Antonio Serrano; Pura Muñoz-Cánoves

Effective repair of damaged tissues and organs requires the coordinated action of several cell types, including infiltrating inflammatory cells and resident cells. Recent findings have uncovered a central role for macrophages in the repair of skeletal muscle after acute damage. If damage persists, as in skeletal muscle pathologies such as Duchenne muscular dystrophy (DMD), macrophage infiltration perpetuates and leads to progressive fibrosis, thus exacerbating disease severity. Here we discuss how dynamic changes in macrophage populations and activation states in the damaged muscle tissue contribute to its efficient regeneration. We describe how ordered changes in macrophage polarization, from M1 to M2 subtypes, can differently affect muscle stem cell (satellite cell) functions. Finally, we also highlight some of the new mechanisms underlying macrophage plasticity and briefly discuss the emerging implications of lymphocytes and other inflammatory cell types in normal versus pathological muscle repair.


Genes & Development | 2008

Fibrinogen drives dystrophic muscle fibrosis via a TGFβ/alternative macrophage activation pathway

Berta Vidal; Antonio Serrano; Marc Tjwa; Mònica Suelves; Esther Ardite; Roberta De Mori; Bernat Baeza-Raja; María Martínez de Lagrán; Peggy Lafuste; Vanessa Ruiz-Bonilla; Mercè Jardí; Romain K. Gherardi; Christo Christov; Mara Dierssen; Peter Carmeliet; Jay L. Degen; Mieke Dewerchin; Pura Muñoz-Cánoves

In the fatal degenerative Duchenne muscular dystrophy (DMD), skeletal muscle is progressively replaced by fibrotic tissue. Here, we show that fibrinogen accumulates in dystrophic muscles of DMD patients and mdx mice. Genetic loss or pharmacological depletion of fibrinogen in these mice reduced fibrosis and dystrophy progression. Our results demonstrate that fibrinogen-Mac-1 receptor binding, through induction of IL-1beta, drives the synthesis of transforming growth factor-beta (TGFbeta) by mdx macrophages, which in turn induces collagen production in mdx fibroblasts. Fibrinogen-produced TGFbeta further amplifies collagen accumulation through activation of profibrotic alternatively activated macrophages. Fibrinogen, by engaging its alphavbeta3 receptor on fibroblasts, also directly promotes collagen synthesis. These data unveil a profibrotic role of fibrinogen deposition in muscle dystrophy.


Molecular and Cellular Biology | 2003

Role of HuR in skeletal myogenesis through coordinate regulation of muscle differentiation genes

Angélica Figueroa; Ana Cuadrado; Jinshui Fan; Ulus Atasoy; George E. O. Muscat; Pura Muñoz-Cánoves; Myriam Gorospe; Alberto Muñoz

ABSTRACT In this report, we investigate the role of the RNA-binding protein HuR during skeletal myogenesis. At the onset of myogenesis in differentiating C2C12 myocytes and in vivo in regenerating mouse muscle, HuR cytoplasmic abundance increased dramatically, returning to a predominantly nuclear presence upon completion of myogenesis. mRNAs encoding key regulators of myogenesis-specific transcription (myogenin and MyoD) and cell cycle withdrawal (p21), bearing AU-rich regions, were found to be targets of HuR in a differentiation-dependent manner. Accordingly, mRNA half-lives were highest during differentiation, declining when differentiation was completed. Importantly, HuR-overexpressing C2C12 cells displayed increased target mRNA expression and half-life and underwent precocious differentiation. Our findings underscore a critical function for HuR during skeletal myogenesis linked to HuRs coordinate regulation of muscle differentiation genes.

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Antonio Serrano

Spanish National Research Council

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Pedro Sousa-Victor

Buck Institute for Research on Aging

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Laura García-Prat

Centro Nacional de Investigaciones Cardiovasculares

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Berta Vidal

Pompeu Fabra University

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