1,721,025 research outputs found
Counteracting sarcopenia: The role of IGF-1 isoforms
Full text linkSarcopenia, the age-related loss of muscle mass and strength, represents one of the main causes of impaired physical performance and reduced mobility. Thus, understanding the pathogenetic mechanisms of muscle wasting associated with aging has been the objective of numerous studies and represents an important first step for the development of therapeutic approaches [1,2].
Among growth factors, the insulin-like growth factor-1 (IGF-1) have been implicated in the control of skeletal muscle growth, differentiation, and regeneration and has emerged as a growth factor with a remarkably wide range of actions and a tremendous potential as a therapeutic factor in attenuating the atrophy and frailty associated with muscle ageing and diseases [3,4]. In the adult mammals, IGF-1 is principally synthesized in the liver, acting as a systemic growth factor; however, it is also produced in extrahepatic tissues, including skeletal muscle, where it mainly plays an autocrine/paracrine role. The IGF-1 protein is produced by different pre-pro-peptides, whereas two different promoters and differential splicing of the IGF-1 gene create several IGF-1 isoforms, which differ in the N-terminal signal-peptide (Class 1 or 2) and the C-terminal Extension peptide (E-peptide Ea or Eb) [3]. Given the conflicting and still unclear data on effects of different IGF-1 isoforms, a recent study investigated whether the muscle overexpression of either propeptides IGF-1Ea or IGF-1Eb isoform impacts sarcopenia and through which mechanisms each isoform acts [5]. Muscle restricted over-expression of both IGF-1Ea and IGF-1Eb isoforms did not induce any significant change in the circulating IGF-1 levels in young mice compared to age-matched wild type animals. Interestingly, consistent with the physiological decline of IGF-1 plasma levels during aging, a strong reduction of IGF-1 levels was observed in old wild type mice [5]. On the contrary, aged transgenic animals showed unchanged levels of circulating IGF-1 compared to young counterparts, thus resulting higher compared to old wild type mice. It is possible to speculate that IGF-1 isoforms, locally expressed, exert an indirect systemic effect, contributing to the maintenance of circulating IGF-1 levels during postnatal life. Indeed, skeletal muscle has recently been identified as an endocrine organ, able to produce and release cytokines and other peptides, such as the myokines, that act in paracrine, autocrine, or endocrine manner [6]. In this context, muscle can be also a source of circulating IGF-1, based on the evidences that IGF-1 is released from exercising muscle into the blood stream [6]. Thus, we can speculate that the reduction of circulating IGF-1 levels in aged wild type mice could be the result of the morpho-functional alterations occurred in muscle. Conversely, transgenic mice, guaranteeing the muscle expression levels of IGF-1 isoforms even at late post-natal life, preserve the capability of muscle to function as endocrine organ, thus contributing to maintain unaltered the circulating IGF-1 levels.
Of note, IGF-1Ea but not IGF-1Eb was able to promote a pronounced muscle hypertrophy and strength in both young and aged mice [5]. Nevertheless, beside the promotion of muscle growth, both IGF-1Ea and IGF-1Eb were able to counteract sarcopenia, negatively modulating the inflame-aging process and activating relevant pathways considered part of a molecular antiaging system, such as autophagy and PGC-1-mediated signaling, which alteration induces neuromuscular junction degeneration and precocious aging [5,7]. Of interest, and in some way paradoxically, the increased levels of IGF-1Ea, but not IGF-1Eb, was correlated with high ROS production [5]. This data suggests that ROS production is part of the promotion and maintenance of a functional hypertrophic phenotype, induced by IGF-1Ea, and supports the evidence that reactive oxygen species are not merely damaging agent but useful signaling molecules to regulate growth, proliferation, differentiation, and adaptation, at least within physiological concentration. Of note, the IGF-1Ea mice were able to minimize oxidative damage in senescent muscle up-regulating, through PGC1-α activation, NRF-2 protein, the master regulator of antioxidant defense [8] and Sirt-1, a factor involved in growth regulation, stress response, endocrine signaling, and extended lifespan.
Moreover, the maintenance of hypertrophic phenotype by IGF-1Ea promoted the activation of additional pathways, such as AMPK, a factor involved in the maintenance of whole-body energy balance and an energy sensor controlling glucose and lipid metabolism. These data are consistent with a model (Figure 1) in which muscle expression of either IGF-1Ea or IGF-1Eb, activating a series of anabolic and compensatory pathways, are able to counteract sarcopenia, preventing muscle loss, strength, and alteration in muscle-nerve interaction. It is also plausible that muscle expression of IGF-1 isoforms, preserving skeletal muscle, might maintain the youth not only of muscle tissue but also of the entire organism, by promoting a local effort activity for a global impact benefit
Muscle Homeostasis and Regeneration: From Molecular Mechanisms to Therapeutic Opportunities
Full text linkThe capacity of adult muscle to regenerate in response to injury stimuli represents an important homeostatic process. Regeneration is a highly coordinated program that partially recapitulates the embryonic developmental program and involves the activation of the muscle compartment of stem cells, namely satellite cells, as well as other precursor cells, whose activity is strictly dependent on environmental signals. However, muscle regeneration is severely compromised in several pathological conditions due to either the progressive loss of stem cell populations or to missing signals that limit the damaged tissues from efficiently activating a regenerative program. It is, therefore, plausible that the loss of control over these cells’ fate might lead to pathological cell differentiation, limiting the ability of a pathological muscle to sustain an efficient regenerative process. This Special Issue aims to bring together a collection of original research and review articles addressing the intriguing field of the cellular and molecular players involved in muscle homeostasis and regeneration and to suggest potential therapeutic approaches for degenerating muscle disease
The physiopathologic interplay between stem cells and tissue niche in muscle regeneration and the role of IL-6 on muscle homeostasis and diseases
No full textSkeletal muscle is a complex, dynamic tissue characterized by an elevated plasticity. Although the adult muscle is mainly composed of multinucleated fibers with post mitotic nuclei, it retains a remarkable ability to regenerate in response to traumatic events. The regenerative potential of the adult skeletal muscle relies in the activity of satellite cells, mononucleated cells residing within the muscle in intimate association with myofibers. Satellite cells normally remain quiescent in their sublaminar position, sporadically entering the cell cycle to guarantee an efficient cellular turnover, by fusing with pre-existing myofibers, and to maintain the stem cell pool. However, after muscle injury satellite cells undergo an extensive increase of their activity in response to environmental stimuli, thereby participating to the regeneration of a functional muscle tissue. Nevertheless, regeneration is affected in several pathologic conditions and by a wide range of environmental signals that are highly variable, not only through time, but also depending on the physiological or pathological conditions of the musculature. Among these factors, the interleukin-6 (IL-6) plays a critical physiopathologic role on muscle homeostasis and diseases. The basis of muscle regeneration and the impact of IL-6 on the physiopathology of skeletal muscle will be discussed
Growth factor enhancement of cardiac regeneration
No full textThe potential for endogenous or supplementary stem cells to restore the form and function of damaged tissues is particularly promising for overcoming the restricted regenerative capacity of the mammalian heart. To maintain blood circulation, this essential organ needs to launch a rapid response to repair damage of the muscle wall and to prevent muscle loss. The capacity of growth factors to supplement the repair process has been successfully applied to restore the integrity of damaged skeletal muscle, reducing the fibrotic response to injury, and recruiting local populations of self-renewing precursor cells and circulating stem cells. We review the recent evidence that extension of growth factor supplementation to the heart may overcome its inherent regenerative impediments through improvement of the local tissue environment and stimulation of cell replacement, and we speculate on future research directions for treatment of myocardial damage. Copyright © 2006 Cognizant Comm. Corp
Metabolic reprogramming as therapeutic strategy to ameliorate skeletal muscle tissue engineering procedures
No full textBackground: Stem cells and regenerative medicine raise great expectations
because of the promise to reconstitute aged, injured and diseased tissues. While
success has been achieved for hematological and epithelial diseases, several hur-
dles remain for diseases affecting skeletal and cardiac muscle. Maximizing the sur-
vival and the myogenic activity of the engrafted cells used for tissue engineering
by preconditioning with suitable bioactive molecules would allow better therapeu-
tic outcomes. Notably, energy management and metabolic reprogramming seem to
play a key role in stem cell differentiation. We, therefore, propose that myogenic
precursors preconditioning by metabolic shift induction might potentiate and ame-
liorate the efficacy of reconstructive muscular tissue strategies.
Methodology: We will evaluate the effect of metabolic reprogramming on stem cell
myogenic capabilities and survival and on 3D artificial muscle generation in vitro and in vivo.
Results: Our data show that TMZ exert a profound effect on stem cells, altering
their gene expression profile. It stimulates differentiation of both C2C12 and satel-
lite cells as shown by enhanced expression of muscle-specific genes and proteins
and by higher myotube size and fusion index. Moreover we developed a biotech-
nology demonstrating the possibility to build in vitro and in vivo a complete and
functional artificial muscle in mice.
Conclusions: We expect to select metabolic remodeling agents able to improve
the generation and implantation of artificial muscles. We will also clarify the key
metabolic changes occurring during muscle differentiation, and this will allow further specific therapeutic approaches for muscle replacement
Insights into the pathogenic secondary symptoms caused by the primary loss of dystrophin
No full textDuchenne muscular dystrophy (DMD) is an X-linked genetic disease in which the dystrophin gene is mutated, resulting in dysfunctional dystrophin protein. Without dystrophin, the dystrophin-glycoprotein complex (DGC) is unstable, leading to an increase in muscle damage. Moreover, the imbalance between muscle damage and repair leads to a chronic inflammatory response and an increase in the amount of fibrosis over time. The absence of dystrophin at the sarcolemma also delocalizes and downregulates nitric oxide synthase (nNOS) and alters enzymatic antioxidant responses, leading to an increase in oxidative stress. In this review, we analyze the pathogenic role of both inflammation and oxidative stress in muscular dystrophy
Mechanisms regulating muscle regeneration: insights into the interrelated and time-dependent phases of tissue healing
Full text linkDespite a massive body of knowledge which has been produced related to the mechanisms guiding muscle regeneration, great interest still moves the scientific community toward the study of different aspects of skeletal muscle homeostasis, plasticity, and regeneration. Indeed, the lack of effective therapies for several physiopathologic conditions suggests that a comprehensive knowledge of the different aspects of cellular behavior and molecular pathways, regulating each regenerative stage, has to be still devised. Hence, it is important to perform even more focused studies, taking the advantage of robust markers, reliable techniques, and reproducible protocols. Here, we provide an overview about the general aspects of muscle regeneration and discuss the different approaches to study the interrelated and time-dependent phases of muscle healing
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Full text link“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
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