252 research outputs found
The Role of Skeletal Muscle in Neuromuscular Diseases: From Cellular and Molecular Players to Therapeutic Interventions
No full textGenetic and acquired defects of lower motor neurons, peripheral nerves, or skeletal muscle are responsible for several neuromuscular disorders [...
Molecular mechanisms regulating skeletal muscle homeostasis: effects of V1a AVP receptor overexpression
No full textThe maintenance of a working skeletal musculature is conferred by its capacity to regenerate after mechanical or pathological injury. Most muscle pathologies are characterized by the progressive loss of muscle tissue due to chronic degeneration combined with the inability of the regeneration machinery to replace damaged myofibers. Cachexia or muscle wasting is characterized by a loss of adipose and muscle mass associated with a compromised muscle regenerative ability. Arg-vasopressin (AVP) is a potent myogenesis promoting factor and activates both the calcineurin and CaMK pathways, whose combined activation leads to the formation of transcription factor complexes in vitro. The local over-expression of V1a AVP receptor (V1aR) in injured muscle results in enhanced regeneration. V1aR over-expressing muscle exhibits early activation of satellite cells and regeneration markers and accelerated differentiation. Here we investigated the role of V1aR over-expression in animals undergoing cachexia as a result of muscle over-expression of a specific cytokine (TNF). In these condi-tions, the local V1aR over-expression counteracts the negative effects of cachex-ia on muscle, as demonstrated by morphological and biochemical analysis. In particular, the presence of V1aR results in increased Pax-7, myogenin and myosin expression levels both in wild type and in cachectic muscles. The positive effects of V1aR on muscle homeostasis are due to the promotion of the calcineurin-IL-4 pathway and to the inhibition of atrophic genes expression mediat-ed by FOXO phosphorylation.
This study highlights a novel in vivo role for the AVP-dependent pathways which may suggest a potential gene therapy approach for many diseases affecting muscle homeostasis
Exploring the Role of Extracellular Vesicles in Skeletal Muscle Regeneration
No full textSkeletal muscle regeneration entails a multifaceted process marked by distinct phases, encompassing inflammation, regeneration, and remodeling. The coordination of these phases hinges upon precise intercellular communication orchestrated by diverse cell types and signaling molecules. Recent focus has turned towards extracellular vesicles (EVs), particularly small EVs, as pivotal mediators facilitating intercellular communication throughout muscle regeneration. Notably, injured muscle provokes the release of EVs originating from myofibers and various cell types, including mesenchymal stem cells, satellite cells, and immune cells such as M2 macrophages, which exhibit anti-inflammatory and promyogenic properties. EVs harbor a specific cargo comprising functional proteins, lipids, and nucleic acids, including microRNAs (miRNAs), which intricately regulate gene expression in target cells and activate downstream pathways crucial for skeletal muscle homeostasis and repair. Furthermore, EVs foster angiogenesis, muscle reinnervation, and extracellular matrix remodeling, thereby modulating the tissue microenvironment and promoting effective tissue regeneration. This review consolidates the current understanding on EVs released by cells and damaged tissues throughout various phases of muscle regeneration with a focus on EV cargo, providing new insights on potential therapeutic interventions to mitigate muscle-related pathologies
The beneficial effects of taurine to counteract sarcopenia
No full textAging is a multifactorial process characterized by several features including low-grade inflammation, increased oxidative stress and reduced regenerative capacity, which ultimately lead to alteration in morpho-functional properties of skeletal muscle, thus promoting sarcopenia. This condition is characterized by a gradual loss of muscle mass due to an unbalance between protein synthesis and degradation, finally conveying in functional decline and disability. The development of specific therapeutic approaches able to block or reverse this condition may represent an invaluable tool for the promotion of a healthy aging among elderly. It is well established that changes in the quantity and the quality of dietary proteins, as well as the intake of specific amino acids, are able to counteract some of the physiopathological processes related to the progression of the loss of muscle mass and may have beneficial effects in improving the anabolic response of muscle in the elderly. Taurine is a non-essential amino acid expressed in high concentration in several mammalian tissues and particularly in skeletal muscle where it is involved in the modulation of intracellular calcium concentration and ion channel regulation and where it also acts as an antioxidant and anti-inflammatory factor. The aim of this review is to summarize the pleiotropic effects of taurine on specific muscle targets and to discuss its role in regulating signaling pathways involved in the maintenance of muscle homeostasis. We also highlight the potential use of taurine as a therapeutic molecule for the amelioration of skeletal muscle function and performance severely compromised during aging
Molecular mechanisms regulating skeletal muscle homeostasis: effects of V1a AVP receptor over-expression
No full textThe maintenance of a working skeletal musculature is conferred by its capacity to regenerate after mechanical or pathological injury. Most muscle pathologies are characterized by the progressive loss of muscle tissue due to chronic degeneration combined with the inability of the regeneration machinery to replace damaged myofibers. Cachexia or muscle wasting is characterized by a loss of adipose and muscle mass associated with a compromised muscle regenerative ability. Arg-vasopressin (AVP) is a potent myogenesis promoting factor and activates both the calcineurin and CaMK pathways, whose combined activation leads to the formation of transcription factor complexes in vitro. The local over-expression of V1a AVP receptor (V1aR) in injured muscle results in enhanced regeneration. V1aR over-expressing muscle exhibits early activation of satellite cells and regeneration markers and accelerated differentiation. Here we investigated the role of V1aR over-expression in animals undergoing cachexia as a result of muscle over-expression of a specific cytokine (TNF). In these conditions, the local V1aR over-expression counteracts the negative effects of cachexia on muscle, as demonstrated by morphological and biochemical analysis. In particular, the presence of V1aR results in increased Pax-7, myogenin and myosin expression levels both in wild type and in cachectic muscles. The positive effects of V1aR on muscle homeostasis are due to the promotion of the calcineurin-IL-4 pathway and to the inhibition of atrophic genes expression mediated by FOXO phosphorylation. This study highlights a novel in vivo role for the AVP-dependent pathways which may suggest a potential gene therapy approach for many diseases affecting muscle homeostasis
Signals from the Niche: Insights into the Role of IGF-1 and IL-6 in Modulating Skeletal Muscle Fibrosis
No full textAbstract
Muscle regeneration, characterized by the activation and proliferation of satellite cells and other precursors, is accompanied by an inflammatory response and the remodeling of the extracellular matrix (ECM), necessary to remove cellular debris and to mechanically support newly generated myofibers and activated satellite cells. Muscle repair can be considered concluded when the tissue architecture, vascularization, and innervation have been restored. Alterations in these connected mechanisms can impair muscle regeneration, leading to the replacement of functional muscle tissue with a fibrotic scar. In the present review, we will discuss the cellular mediators of fibrosis and how the altered expression and secretion of soluble mediators, such as IL-6 and IGF-1, can modulate regulatory networks involved in the altered regeneration and fibrosis during aging and diseases
Molecular and cellular mechanisms of muscle aging and sarcopenia and effects of electrical stimulation in seniors
No full textThe prolongation of skeletal muscle strength in aging and neuromuscular disease has been the objective of numerous studies employing a variety of approaches. It is generally accepted that cumulative failure to repair damage related to an overall decrease in anabolic processes is a primary cause of functional impairment in muscle. The functional performance of skeletal muscle tissues declines during post- natal life and it is compromised in different diseases, due to an alteration in muscle fiber composition and an overall decrease in muscle integrity as fibrotic invasions replace functional contractile tissue. Characteristics of skeletal muscle aging and diseases include a conspicuous reduction in myofiber plasticity (due to the progressive loss of muscle mass and in particular of the most powerful fast fibers), alteration in muscle-specific transcriptional mechanisms, and muscle atrophy. An early decrease in protein synthetic rates is followed by a later increase in protein degradation, to affect biochemical, physiological, and morphological parameters of muscle fibers during the aging process. Alterations in regenerative pathways also compromise the functionality of muscle tissues. In this review we will give an overview of the work on molecular and cellular mechanisms of aging and sarcopenia and the effects of electrical stimulation in seniors
Exploring the Role of Extracellular Vesicles in Skeletal Muscle Regeneration
No full textSkeletal muscle regeneration entails a multifaceted process marked by distinct phases, encompassing inflammation, regeneration, and remodeling. The coordination of these phases hinges upon precise intercellular communication orchestrated by diverse cell types and signaling molecules. Recent focus has turned towards extracellular vesicles (EVs), particularly small EVs, as pivotal mediators facilitating intercellular communication throughout muscle regeneration. Notably, injured muscle provokes the release of EVs originating from myofibers and various cell types, including mesenchymal stem cells, satellite cells, and immune cells such as M2 macrophages, which exhibit anti-inflammatory and promyogenic properties. EVs harbor a specific cargo comprising functional proteins, lipids, and nucleic acids, including microRNAs (miRNAs), which intricately regulate gene expression in target cells and activate downstream pathways crucial for skeletal muscle homeostasis and repair. Furthermore, EVs foster angiogenesis, muscle reinnervation, and extracellular matrix remodeling, thereby modulating the tissue microenvironment and promoting effective tissue regeneration. This review consolidates the current understanding on EVs released by cells and damaged tissues throughout various phases of muscle regeneration with a focus on EV cargo, providing new insights on potential therapeutic interventions to mitigate muscle-related pathologies
Expression of Reelin in cancer stem cells isolated from human glioblastoma
No full textReelin is a large secreted extracellular matrix glycoprotein which contributes to positioning, migration and laminar organization of several central nervous system structures during neurodevelopment. Recent studies reported the expression of Reelin and its intracellular adapter protein DAB1 in neuroblastoma, where it appears to be involved in cell motility and invasiveness. Interestingly, our data obtained by immunolocalization analysis show the expression of Reelin in both tumor and peritumoral area of glioblastoma (GBM). It is known that many solid tumors may originate from cancer stem cells (CSC) which are usually resistant to common therapies and might be involved in tumor progression. Therefore, we evaluated the expression of Reelin in CSC neurospheres isolated from both tumor (GCSC) and peritumoral area (PCSC) of GBM. Immunocytochemistry analysis showed the expression of Reelin in both cell types, suggesting that this protein may contribute to neurosphere tridimensional organization and possibly to cell migration during tumor progression. This is the first evidence of Reelin expression in human GBM which might indicate a pivotal role of this protein in the regulation of tumor development. Our data may open potential avenues for GBM treatment by targeting Reelin signaling activity
Exploiting Vasopressin signaling in muscular atrophy and dystrophies
No full textArginine-Vasopressin (AVP) is a neurohypophyseal hormone able to induce differentiation in myogenic cell lines and primary satellite cells. V1aR is the only AVP receptor expressed in skeletal muscle. By interacting with V1aR, AVP activates phospholipases C and D, increases cytosolic Ca2+ concentrations and regulates cAMP levels. The AVP-dependent increase in cytosolic calcium activates CaMK and calcineurin pathways resulting in the formation of multifactor complexes on the promoter of muscle specific genes. Our previous data demonstrate that V1aR expression is modulated during muscle regeneration and the stimulation of AVP signaling strongly enhances regeneration of injured muscles. In an experimental model of muscular atrophy induced by TNF over-expression, stimulation of AVP pathways counteracts the negative effects of TNF both enhancing regeneration and inhibiting inflammation. The molecular analysis for the expression levels of early and late regeneration markers (Pax7 and MyoD or myogenin and MHC, respectively) suggested an impairment of regeneration in muscles over-expressing TNF. This effect was counteracted by V1aR overexpression. The positive effects of V1aR on muscle homeostasis are due to the promotion of the calcinuerin-IL-4 pathway and by the inhibition of atrophic genes expression mediated by FOXO phosphorylation via Akt-dependant pathway. By all the above we are analyzing the effects of AVP signaling stimulation in mouse models of muscular dystrophies. Preliminary data demonstrate that stimulation of AVP-dependent pathways ameliorates inflammation and regeneration processes. This study highlights a novel in vivo role for the AVP-dependent pathways which may represent a potential gene therapy approach for many diseases affecting muscle homeostasis
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