Search

Vitamin E (Vit E) deficiency studies underline the relevance of this vitamin in skeletal muscle (SkM) homeostasis. The knowledge of the effectors and modulators of Vit E action in SkM cells is limited, especially in aging and chronic diseases characterized by a decline in musculoskeletal health. Vit E comprises eight fat-soluble compounds grouped into tocopherols and tocotrienols, which share the basic chemical structure but show different biological properties and potentials to prevent diseases. Vit E has antioxidant and non-antioxidant activities and both favorable and adverse effects depending on the specific conditions and tissues. In this review, we focus on the actual knowledge of Vit E forms in SkM functions and new potential signaling effectors (i.e., bioactive sphingolipids and myokines). The possible advantages of Vit E supplementation in counteracting SkM dysfunctions in sarcopenia and under microgravity will also be discussed. [ABSTRACT FROM AUTHOR]

Castanea sativa Mill. is a valuable species with historical and economic importance in Europe, particularly in the Mediterranean area. In Italy, chestnut cultivation has been developed for centuries, leading to the recognition of more than 300 varieties. Nevertheless, a profusion of local names has been assigned by growers, causing the occurrence of synonyms and homonyms across the country. This research focused on genetic characterization and identification using 21 single sequence repeats (SSRs) for four chestnut varieties (i.e., Pastinese, Nerattino, Carpinese, and Rossola) commonly used for flour production in the Tuscan Apennine Mountains (Pistoia Province). A comprehensive number of 55 accessions identified by local growers as belonging to the four varieties were analyzed, in addition to a few "Marrone" accessions as outgroups. The 21 microsatellites were highly informative, detecting 98 alleles and displaying an average polymorphism information content (PIC) equal to 0.582. In addition, a considerable amount of genetic diversity was revealed, as shown by the heterozygosity levels (He = 0.634 and Ho = 0.475). The STRUCTURE analysis provided clear distinctions among the different varieties, splitting them into four separate groups. This result was also confirmed by UPGMA dendrogram and principal co-ordinates analysis (PCoA). However, one accession (Carp_5), previously identified as Carpinese, showed an allelic profile attributable to Pastinese, suggesting that farmers might have performed mislabeling or grafting propagation errors. Thus, our results confirm the use of SSRs to allocate the accessions of different varieties, uncovering possible synonyms and homonyms. Specifically, in the context of the Pistoiese mountain region, this tool can favor the traceability of processed products, such as flour, enhancing the quality and economic value of the local market. Lastly, our findings have revealed a considerable genetic variability within the Tuscan chestnut varieties whose preservation is mandatory to face climate change challenges through sustainable forest management practices. [ABSTRACT FROM AUTHOR]

Irisin is a hormone-like myokine produced in abundance by skeletal muscle (SkM) in response to exercise. This myokine, identical in humans and mice, is involved in many signaling pathways related to metabolic processes. Despite much evidence on the regulators of irisin and the relevance of sphingolipids for SkM cell biology, the contribution of these latter bioactive lipids to the modulation of the myokine in SkM is missing. In particular, we have examined the potential involvement in irisin formation/release of sphingosine-1-phosphate (S1P), an interesting bioactive molecule able to act as an intracellular lipid mediator as well as a ligand of specific G-protein-coupled receptors (S1PR). We demonstrate the existence of distinct intracellular pools of S1P able to affect the expression of the irisin precursor FNDC. In addition, we establish the crucial role of the S1P/S1PR axis in irisin formation/release as well as the autocrine/paracrine effects of irisin on myoblast proliferation and myogenic differentiation. Altogether, these findings provide the first evidence for a functional crosstalk between the S1P/S1PR axis and irisin signaling, which may open new windows for potential therapeutic treatment of SkM dysfunctions. [ABSTRACT FROM AUTHOR]

SARS-CoV-2 virus infection is the cause of the coronavirus disease 2019 (COVID-19), which is still spreading over the world. The manifestation of this disease can range from mild to severe and can be limited in time (weeks) or persist for months in about 30–50% of patients. COVID-19 is considered a multiple organ dysfunction syndrome and the musculoskeletal system manifestations are beginning to be considered of absolute importance in both COVID-19 patients and in patients recovering from the SARS-CoV-2 infection. Musculoskeletal manifestations of COVID-19 and other coronavirus infections include loss of muscle mass, muscle weakness, fatigue or myalgia, and muscle injury. The molecular mechanisms by which SARS-CoV-2 can cause damage to skeletal muscle (SkM) cells are not yet well understood. Sphingolipids (SLs) represent an important class of eukaryotic lipids with structural functions as well as bioactive molecules able to modulate crucial processes, including inflammation and viral infection. In the last two decades, several reports have highlighted the role of SLs in modulating SkM cell differentiation, regeneration, aging, response to insulin, and contraction. This review summarizes the consequences of SARS-CoV-2 infection on SkM and the potential involvement of SLs in the tissue responses to virus infection. In particular, we highlight the role of sphingosine 1-phosphate signaling in order to aid the prediction of novel targets for preventing and/or treating acute and long-term musculoskeletal manifestations of virus infection in COVID-19. [ABSTRACT FROM AUTHOR]

Simple Summary: Skeletal muscle (SkM) represents the largest "organ" in the human body as it constitutes at least 40% of the body mass. SkM mass wasting is a serious conditions since pathological tissue degeneration significantly worsens the prognosis of the associated disease and significantly reduces the quality and life expectancy with an incidence of 10–50% in patients suffering of cancer, chronic infection and inflammation. Therefore, it is urgent to investigate the molecular basis of SkM mass wasting and identify potential therapeutic targets. Apart from cytokines and chemokines, also sphingolipid mediators, particularly sphingosine-1-phosphate and ceramide 1-phosphate (C1P), contribute to cancer and inflammation, however, the contribution of  ceramide kinase (CerK), and its product ceramide 1-phosphate (C1P), to SkM mass wasting in these conditions is missing. The present study was developed using mice bearing the C26, or Lewis lung carcinoma (LLC) tumors, well characterized models of cancer-associated SkM atrophy, and in murine and human myotubes treated with conditioned media obtained from C26 or LLC-cells or with the corticosteroid dexamethasone. The results obtained reveal that CerK protein expression and the Ceramide/C1P axis are markedly impaired in all experimental models, demonstrating that the CerK/C1P axis plays a crucial role as molecular regulator of SkM mass associated to cancer or corticosteroids. Apart from cytokines and chemokines, sphingolipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide 1-phosphate (C1P), contribute to cancer and inflammation. Cancer, as well as other inflammatory conditions, are associated with skeletal muscle (SkM) atrophy, which is characterized by the unbalance between protein synthesis and degradation. Although the signaling pathways involved in SkM mass wasting are multiple, the regulatory role of simple sphingolipids is limited. Here, we report the impairment of ceramide kinase (CerK), the enzyme responsible for the phosphorylation of ceramide to C1P, associated with the accomplishment of atrophic phenotype in various experimental models of SkM atrophy: in vivo animal model bearing the C26 adenocarcinoma or Lewis lung carcinoma tumors, in human and murine SkM cells treated with the conditioned medium obtained from cancer cells or with the glucocorticoid dexamethasone. Notably, we demonstrate in all the three experimental approaches a drastic decrease of CerK expression. Gene silencing of CerK promotes the up-regulation of atrogin-1/MAFbx expression, which was also observed after cell treatment with C8-ceramide, a biologically active ceramide analogue. Conversely, C1P treatment significantly reduced the corticosteroid's effects. Altogether, these findings provide evidence that CerK, acting as a molecular modulator, may be a new possible target for SkM mass regulation associated with cancer or corticosteroids. [ABSTRACT FROM AUTHOR]

Breast cancer MCF-7 cell-line-derived mammospheres were shown to be enriched in cells with a CD44+/CD24– surface profile, consistent with breast cancer stem cells (BCSC). These BCSC were previously reported to express key sphingolipid signaling effectors, including pro-oncogenic sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate receptor 3 (S1P3). In this study, we explored intracellular trafficking and localization of SphK1 and S1P3 in parental MCF-7 cells, and MCF-7 derived BCSC-enriched mammospheres treated with growth- or apoptosis-stimulating agents. Intracellular trafficking and localization were assessed using confocal microscopy and cell fractionation, while CD44+/CD24- marker status was confirmed by flow cytometry. Mammospheres expressed significantly higher levels of S1P3 compared to parental MCF-7 cells (p < 0.01). Growth-promoting agents (S1P and estrogen) induced SphK1 and S1P3 translocation from cytoplasm to nuclei, which may facilitate the involvement of SphK1 and S1P3 in gene regulation. In contrast, pro-apoptotic cytokine tumor necrosis factor α (TNFα)-treated MCF-7 cells demonstrated increased apoptosis and no nuclear localization of SphK1 and S1P3, suggesting that TNFα can inhibit nuclear translocation of SphK1 and S1P3. TNFα inhibited mammosphere formation and induced S1P3 internalization and degradation. No nuclear translocation of S1P3 was detected in TNFα-stimulated mammospheres. Notably, SphK1 and S1P3 expression and localization were highly heterogenous in mammospheres, suggesting the potential for a large variety of responses. The findings provide further insights into the understanding of sphingolipid signaling and intracellular trafficking in BCs. Our data indicates that the inhibition of SphK1 and S1P3 nuclear translocation represents a novel method to prevent BCSCs proliferation. [ABSTRACT FROM AUTHOR]

The recent coronavirus disease (COVID-19) is still spreading worldwide. The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the virus responsible for COVID-19, binds to its receptor angiotensin-converting enzyme 2 (ACE2), and replicates within the cells of the nasal cavity, then spreads along the airway tracts, causing mild clinical manifestations, and, in a majority of patients, a persisting loss of smell. In some individuals, SARS-CoV-2 reaches and infects several organs, including the lung, leading to severe pulmonary disease. SARS-CoV-2 induces neurological symptoms, likely contributing to morbidity and mortality through unknown mechanisms. Sphingosine 1-phosphate (S1P) is a bioactive sphingolipid with pleiotropic properties and functions in many tissues, including the nervous system. S1P regulates neurogenesis and inflammation and it is implicated in multiple sclerosis (MS). Notably, Fingolimod (FTY720), a modulator of S1P receptors, has been approved for the treatment of MS and is being tested for COVID-19. Here, we discuss the putative role of S1P on viral infection and in the modulation of inflammation and survival in the stem cell niche of the olfactory epithelium. This could help to design therapeutic strategies based on S1P-mediated signaling to limit or overcome the host–virus interaction, virus propagation and the pathogenesis and complications involving the nervous system. [ABSTRACT FROM AUTHOR]

The bioactive sphingolipid metabolite, sphingosine 1-phosphate (S1P), and the signaling pathways triggered by its binding to specific G protein-coupled receptors play a critical regulatory role in many pathophysiological processes, including skeletal muscle and nervous system degeneration. The signaling transduced by S1P binding appears to be much more complex than previously thought, with important implications for clinical applications and for personalized medicine. In particular, the understanding of S1P/S1P receptor signaling functions in specific compartmentalized locations of the cell is worthy of being better investigated, because in various circumstances it might be crucial for the development or/and the progression of neuromuscular diseases, such as Charcot–Marie–Tooth disease, myasthenia gravis, and Duchenne muscular dystrophy. [ABSTRACT FROM AUTHOR]

Tissue damage, irrespective from the underlying etiology, destroys tissue structure and, eventually, function. In attempt to achieve a morpho-functional recover of the damaged tissue, reparative/regenerative processes start in those tissues endowed with regenerative potential, mainly mediated by activated resident stem cells. These cells reside in a specialized niche that includes different components, cells and surrounding extracellular matrix (ECM), which, reciprocally interacting with stem cells, direct their cell behavior. Evidence suggests that ECM stiffness represents an instructive signal for the activation of stem cells sensing it by various mechanosensors, able to transduce mechanical cues into gene/protein expression responses. The actin cytoskeleton network dynamic acts as key mechanotransducer of ECM signal. The identification of signaling pathways influencing stem cell mechanobiology may offer therapeutic perspectives in the regenerative medicine field. Sphingosine 1-phosphate (S1P)/S1P receptor (S1PR) signaling, acting as modulator of ECM, ECM-cytoskeleton linking proteins and cytoskeleton dynamics appears a promising candidate. This review focuses on the current knowledge on the contribution of S1P/S1PR signaling in the control of mechanotransduction in stem/progenitor cells. The potential contribution of S1P/S1PR signaling in the mechanobiology of skeletal muscle stem cells will be argued based on the intriguing findings on S1P/S1PR action in this mechanically dynamic tissue. [ABSTRACT FROM AUTHOR]