A unique property of skeletal muscle is its ability to adapt its mass to changes in activity. Inactivity, as in disuse or aging, causes atrophy, the loss of muscle mass and strength, leading to ...physical incapacity and poor quality of life. Here, through a combination of transcriptomics and transgenesis, we identify sestrins, a family of stress-inducible metabolic regulators, as protective factors against muscle wasting. Sestrin expression decreases during inactivity and its genetic deficiency exacerbates muscle wasting; conversely, sestrin overexpression suffices to prevent atrophy. This protection occurs through mTORC1 inhibition, which upregulates autophagy, and AKT activation, which in turn inhibits FoxO-regulated ubiquitin-proteasome-mediated proteolysis. This study reveals sestrin as a central integrator of anabolic and degradative pathways preventing muscle wasting. Since sestrin also protected muscles against aging-induced atrophy, our findings have implications for sarcopenia.
Repair of damaged tissue requires the coordinated action of inflammatory and tissue-specific cells to restore homeostasis, but the underlying regulatory mechanisms are poorly understood. In this ...paper, we report new roles for MKP-1 (mitogen-activated protein kinase MAPK phosphatase-1) in controlling macrophage phenotypic transitions necessary for appropriate muscle stem cell-dependent tissue repair. By restricting p38 MAPK activation, MKP-1 allows the early pro- to antiinflammatory macrophage transition and the later progression into a macrophage exhaustion-like state characterized by cytokine silencing, thereby permitting resolution of inflammation as tissue fully recovers. p38 hyperactivation in macrophages lacking MKP-1 induced the expression of microRNA-21 (miR-21), which in turn reduced PTEN (phosphatase and tensin homologue) levels, thereby extending AKT activation. In the absence of MKP-1, p38-induced AKT activity anticipated the acquisition of the antiinflammatory gene program and final cytokine silencing in macrophages, resulting in impaired tissue healing. Such defects were reversed by temporally controlled p38 inhibition. Conversely, miR-21-AKT interference altered homeostasis during tissue repair. This novel regulatory mechanism involving the appropriate balance of p38, MKP-1, miR-21, and AKT activities may have implications in chronic inflammatory degenerative diseases.
Tissue regeneration declines with ageing but little is known about whether this arises from changes in stem-cell heterogeneity. Here, in homeostatic skeletal muscle, we identify two quiescent ...stem-cell states distinguished by relative CD34 expression: CD34
, with stemness properties (genuine state), and CD34
, committed to myogenic differentiation (primed state). The genuine-quiescent state is unexpectedly preserved into later life, succumbing only in extreme old age due to the acquisition of primed-state traits. Niche-derived IGF1-dependent Akt activation debilitates the genuine stem-cell state by imposing primed-state features via FoxO inhibition. Interventions to neutralize Akt and promote FoxO activity drive a primed-to-genuine state conversion, whereas FoxO inactivation deteriorates the genuine state at a young age, causing regenerative failure of muscle, as occurs in geriatric mice. These findings reveal transcriptional determinants of stem-cell heterogeneity that resist ageing more than previously anticipated and are only lost in extreme old age, with implications for the repair of geriatric muscle.
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.
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 p16(INK4a) (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. p16(INK4a) 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 p16(INK4a) is dysregulated in human geriatric satellite cells, these findings provide the basis for stem-cell rejuvenation in sarcopenic muscles.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Normal homeostatic functions of adult stem cells have rhythmic daily oscillations that are believed to become arrhythmic during aging. Unexpectedly, we find that aged mice remain behaviorally ...circadian and that their epidermal and muscle stem cells retain a robustly rhythmic core circadian machinery. However, the oscillating transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses, such as DNA damage or inefficient autophagy. Importantly, deletion of circadian clock components did not reproduce the hallmarks of this reprogramming, underscoring that rewiring, rather than arrhythmia, is associated with physiological aging. While age-associated rewiring of the oscillatory diurnal transcriptome is not recapitulated by a high-fat diet in young adult mice, it is significantly prevented by long-term caloric restriction in aged mice. Thus, stem cells rewire their diurnal timed functions to adapt to metabolic cues and to tissue-specific age-related traits.
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•Tissue stem cells retain a rhythmic circadian machinery during aging•Daily rhythms are reprogrammed in aged SCs to cope with tissue-specific stress•Rewiring of daily rhythms in aged SCs is prevented by caloric restriction•Deletion of core clock genes does not recapitulate age-related reprogramming
The daily rhythmic transcriptome is extensively reprogrammed in aged stem cells, switching from genes involved in homeostasis to those involved in tissue-specific stresses.
Preservation of cell identity is necessary for homeostasis of most adult tissues. This process is challenged every time a tissue undergoes regeneration after stress or injury. In the lethal Duchenne ...muscular dystrophy (DMD), skeletal muscle regenerative capacity declines gradually as fibrosis increases. Using genetically engineered tracing mice, we demonstrate that, in dystrophic muscle, specialized cells of muscular, endothelial, and hematopoietic origins gain plasticity toward a fibrogenic fate via a TGFβ-mediated pathway. This results in loss of cellular identity and normal function, with deleterious consequences for regeneration. Furthermore, this fibrogenic process involves acquisition of a mesenchymal progenitor multipotent status, illustrating a link between fibrogenesis and gain of progenitor cell functions. As this plasticity also was observed in DMD patients, we propose that mesenchymal transitions impair regeneration and worsen diseases with a fibrotic component.
•Regeneration declines as fibrosis increases in Duchenne muscular dystrophy (DMD)•Myogenic, endothelial, and hematopoietic cells acquire fibrogenic plasticity in DMD•This fibrogenic plasticity in DMD is induced by TGFβ and blunts muscle regeneration•Fibrogenesis occurs through an intermediate mesenchymal progenitor multipotent state
The cellular pathways driving fibrosis in dystrophic skeletal muscle are largely unknown. Muñoz-Cánoves and colleagues found that a significant number of muscle stem cells, endothelial cells, and hematopoietic cells gain plasticity as Duchenne muscular dystrophy (DMD) progresses, and convert into fibrotic collagen-producing cells, with negative consequences on regeneration. An association between fibrogenesis and mesenchymal transitions in DMD also is demonstrated.
ResumenAnte la llegada masiva en las últimas décadas de personas solicitantes de protección internacional en el territorio europeo, el Derecho Europeo ha debido encontrar respuestas legislativas y ...jurisprudenciales para regularla. Los cambios y avances en materia de protección de las personas desplazadas, de las demandantes de asilo, de las refugiadas y de las apátridas en el Derecho Europeo y especialmente en el derecho de la Unión Europea han sido constantes. En este trabajo se analiza hasta qué punto estos cambios han afectado la vida familiar de estas personas.El TEDH, interpretando el Convenio y sirviéndose de la normativa del Consejo de Europa en la materia, no ha querido en sus construcciones pretorianas crear obligaciones positivas directas para los Estados.Su análisis es casuístico y si las personas afectadas pueden continuar su vida familiar fuera del Estado que les ha acogido, no considera que exista ninguna violación del derecho al respeto de la vida familiar.En cambio, cuando el Estado no cumple con sus obligaciones de asistencia mínimas, realiza malas prácticas, es el causante de la pérdida deresidencia o nacionalidad o se injiere inadecuadamente en el desarrollo de la vida familiar, existe violación del artículo 8 del Convenio. En el Derecho de la Unión Europea, con la voluntad de crear una política común de asilo, Directivas y Reglamentos se han sucedido rápidamente.Las personas desplazadas en caso de afluencia masiva cuentan con la posibilidad de reagrupar a los miembros de la familia y de interponer recurso ante la denegación de su derecho a la reunificación familiar.En relación con los demandantes de asilo, las nuevas normativas han realizado avances en el derecho al respeto de la vida familiar. Entre otros, han ampliado los sujetos considerados como miembros de la familia, incluyendo a los familiares del solicitante menor que podrá pedir reagrupación familiar; se han mejorado las condiciones de internamiento posibilitando más contactos con los familiares e incluyendo la posibilidad de facilitar a las familias internadas un alojamiento separado y se ha creado la obligación de realizar una entrevista personal con el solicitante. Asimismo, se han realizado modificaciones paramejorar la cooperación entre autoridades nacionales a todos los niveles, incluyendo la cooperación en materia de reagrupación familiar enel caso de menores no acompañados y personas dependientes, la realizaciónde traslados y el intercambio de información cuando la familia esté dispersa. Además, se prestará asistencia y apoyo a la familia de los menores víctimas de la trata de seres humanos cuando aquella se encuentre en el territorio del Estado miembros. Respecto a los miembros de las familias de las personas refugiadas y de las apátridas estas podrán ser beneficiarias del estatuto de refugiado si se encuentran en el mismo estado que el solicitante y la familia ya existía en el país de origen. Sin embargo, no se han producido todos los avances que eran necesarios. Por ejemplo, en relación con las familias LGBTI, su protección aún depende de las normas internas del Estado miembro de acogida, lo que continúa dando pie a discriminaciones.AbstractEuropean law, in response to the massive arrival of persons applying for international protection within the territory of the EU over the past decades, has been obliged to provide legislative and jurisprudential solutions to regulate this phenomenon. The changes and advances in the protection of displaced persons, asylum applicants, refugees, and stateless persons in European law and particularly EU law have therefore been constant. In this paper we analyze to which extent these changes have affected the family life of these persons.The ECtHR, in its interpretation of the Convention, in reference to all the relevant regulations of Council of Europe, has not been keen to use its case law to create direct positive obligations for the contracting parties. Its decisions are essentially based on a case-by-case analysis. If the persons concerned are able to continue their family life outside the State of reception, it considers no violation of the right to respect for family life has occurred. On the other hand, when the State fails to meet the minimum obligations of assistance, is engagedin bad practices, causes a loss of residence or nationality, or unduly interferes with the development of family life, a violation of Article 8 of the Convention exists. In EU law, reflecting the desire to create a common asylum policy, directives and regulations have rapidly succeeded one another. In case of mass influx, displaced persons have the possibility to request reunification with family members and the right to appeal the denial of these requests. With regard to asylum applicants, the new regulations include several advances in relationto the right to respect to family life. Among others, the number of persons considered family members has been extended, including the relatives of underage applicants who may request family reunification; the conditions for detention have been improved, allowing for more contacts with family members and the possibility to facilitate separate accommodation to families in detention. An obligation has been introduced to carry out a personal interview with the applicant. Moreover, modifications have been implemented to improve the cooperation between national authorities at all levels, including the cooperation regarding family reunification in the case of unaccompanied minors and dependant persons, the performance of transfers, and the exchange of information when families are dispersed. In addition, assistance and support will be provided to the family members of minors who are victims of human trafficking when they find themselves within the territory of the Member States. With regard to the family members of refugees and stateless persons, these may now be granted refugee status if they find themselves in the same State as the applicant, provided the family already existed in the country of origin. Nonetheless, not on all relevant issues necessary headway was made. For instance, with regard to LGBTI families, their protection still essentially depends on the national rules of the host State, which continues to give cause to discrimination.
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.
Adult skeletal muscle is a very stable tissue containing a small population of myofiber-associated quiescent satellite cells compared with late embryonic/neonatal skeletal muscle, which contains ...highly proliferating myoblasts and small actively growing myofibers, suggesting that specific regulatory pathways may control myogenesis at distinct developmental stages. The p38 MAPK signaling pathway is central for myogenesis, based on studies using immortalized and neonatal primary myoblasts in vitro. However, the contribution of this pathway to adult myogenesis has never been investigated. Four p38 isoforms (p38α, p38β, p38γ and p38δ) exist in mammalian cells, being p38α and p38γ the most abundantly expressed isoforms in adult skeletal muscle. Given the embryonic/neonatal lethality of p38α-deficient mice, here we investigate the relative contribution of p38β, p38γ and p38δ to adult myogenesis. Regeneration and myofiber growth of adult muscle proceeds with similar efficiency in mice lacking p38β, p38γ and p38δ as in wild-type control mice. In agreement with this, there is no difference in adult satellite cell behavior in vitro among the different genotypes. Importantly, the pattern of p38 activation (ascribed to p38α) remains unperturbed during satellite myogenesis in vitro and adult muscle regeneration in wild type and p38β-, p38γ- and p38δ-deficient mice, rendering p38α as the essential p38 isoform sustaining adult myogenesis. This study constitutes the first analysis addressing the functionality of p38β, p38γ and p38δ in satellite cell-dependent adult muscle regeneration and growth.
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