Denervation does not induce muscle atrophy through oxidative stress

Denervation leads to the activation of the catabolic pathways, such as the ubiquitin-proteasome and autophagy, resulting in skeletal muscle atrophy and weakness. Furthermore, denervation induces oxidative stress in skeletal muscle, which is thought to contribute to the induction of skeletal muscle atrophy. Several muscle diseases are characterized by denervation, but the molecular pathways contributing to muscle atrophy have been only partially described. Our study delineates the kinetics of activation of oxidative stress response in skeletal muscle following denervation. Despite the denervation-dependent induction of oxidative stress in skeletal muscle, treatments with anti-oxidant drugs do not prevent the reduction of muscle mass. Our results indicate that, although oxidative stress may contribute to the activation of the response to denervation, it is not responsible by itself of oxidative damage or neurogenic muscle atrophy

Peroxynitrite activates the NLRP3 inflammasome cascade in SOD1(G93A) mouse model of amyotrophic lateral sclerosis

Neuroinflammation, characterized by the appearance of reactive microglial and astroglial cells, is one of the several pathogenic mechanisms of amyotrophic lateral sclerosis (ALS), a fast-progressing and fatal neurodegenerative disease. Cerebrospinal fluid and spinal cord of ALS patients and SOD1 mutant mice show high concentrations of IL-1β. This interleukin, expressed as an inactive precursor, undergoes a proteolytic maturation by caspase1, whose activation, in turn, depends on inflammasomes. Whether and how inflammasome is activated in ALS models is still to be clarified. The mechanism of inflammasome activation was studied in murine microglial cells overexpressing hSOD1(G93A) and verified in the spinal cord of hSOD1(G93A) mice. Murine microglial hSOD1(G93A) cells express all the inflammasome components and LPS activates caspase1 leading to an increase in the secretion of IL-1β. By activating NF-κB, LPS increases ROS and NO levels that spontaneously react to form peroxynitrite, thus leading to protein nitration. Reduction in peroxynitrite levels results in a decrease in caspase1 activity. Protein nitration and caspase1 activity are concomitantly increased in the spinal cord of pre-symptomatic SOD1(G93A) mice. Oxidative/nitrosative stress induces peroxynitrite formation that may be a key trigger of caspase1/inflammasome activation. Peroxynitrite formation may play a critical role in inflammasome activation and might be exploited as potential therapeutic target for ALS

Oxidative stress-induced S100B accumulation in myoblasts converts myoblasts into brown preadipocytes via an NF-κB/YY1/MIR-133 axis and NF-κB/YY1/BMP7 axis

Muscles of sarcopenic people show hypotrophic myofibers and infiltration with adipose and, at later stages, fibrotic tissue. The origin of infiltrating adipocytes resides in fibro-adipogenic precursors, nonmyogenic mesenchymal progenitor cells, and satellite cells, the adult stem cells of skeletal muscles. Myoblasts and brown adipocytes share a common Myf5+ progenitor cell, and cell fate decision depends on levels of BMP7, a TGF-β family member; high BMP7 levels cause Myf5+ progenitor cells to differentiate in brown adipocytes. When expressed at relatively high levels as observed in myoblasts from sarcopenic humans, intracellular S100B, a Ca2+-binding protein of the EF-hand type (1), exerts anti-myogenic effects that are reversed by S100B knockdown (2,3). We show that ROS-activated NF-κB induces accumulation of S100B that causes myoblasts to convert into brown preadipocytes via 1) an NF-κB/YY1 axis that negatively regulates the promyogenic and anti-brown adipogenic miR-133 with consequent accumulation of the pro-brown adipogenic transcription factor, PRDM16, and 2) an NF-κB/YY1/BMP7 axis with resultant BMP7 autocrine activity. Also, culturing L6C8 (S100b-overexpressing) myoblasts (2) in adipocyte differentiation medium causes NF-κB-dependent upregulation of S100B expression, which precedes and is required for lipid droplet formation. Lastly, S100B knockdown in myoblast-derived brown adipocytes reconvert them into fusion competent myoblasts. Thus, S100B is a major molecular determinant of cell fate decision of proliferating myoblasts; while modulating myoblast differentiation (2,3), at high levels S100B promotes myoblast-brown adipocyte transition, which might have pathophysiological implications in sarcopenia.This work was supported by grants from MIUR FIRB RBFR12BUMH_003 and Fondazione CRP 2016.0136.021

Natriuretic Peptides: The Case of Prostate Cancer

Cardiac natriuretic peptides have long been known to act as main players in the homeostatic control of blood pressure, salt and water balance. However, in the last few decades, new properties have been ascribed to these hormones. A systematic review of English articles using MEDLINE Search terms included prostate cancer, inflammation, cardiac hormones, atrial natriuretic peptide, and brain natriuretic peptide. Most recent publications were selected. Natriuretic peptides are strongly connected to the immune system, whose two branches, innate and adaptive, are finely tuned and organized to kill invaders and repair injured tissues. These peptides control the immune response and act as anti-inflammatory and immune-modulatory agents. In addition, in cancers, natriuretic peptides have anti-proliferative effects by molecular mechanisms based on the inhibition/regulation of several pathways promoting cell proliferation and survival. Nowadays, it is accepted that chronic inflammation is a crucial player in prostate cancer development and progression. In this review, we summarize the current knowledge on the link between prostate cancer and inflammation and the potential use of natriuretic peptides as anti-inflammatory and anticancer agents

Nrf2 and NF-κB and Their Concerted Modulation in Cancer Pathogenesis and Progression

Reactive oxygen species, produced by oxidative stress, are implicated in the initiation, promotion, and malignant conversion of carcinogenesis through activation/suppression of redox-sensitive transcription factors. NF-E2-related factor 2 (Nrf2) encodes for antioxidant and general cytoprotection genes, while NF-κB regulates the expression of pro-inflammatory genes. A variety of anti-inflammatory or anti-carcinogenic phyto-chemicals suppress NF-κB signalling and activate the Nrf2-ARE pathway. In this review we consider the role of Nrf2 and NF-κB in cancer pathogenesis and progression, focusing on their concerted modulation and potential cross-talk

Oxidative status and semen characteristics of rabbit buck as affected by dietary

The aim of this study was to investigate the effect of dietary supplementation of long chain fatty acids (C $\geq$ 20 LCP) of the n-3 series, vitamin E and vitamin C on the antioxidant capacity of rabbit buck and on semen characteristics. Fifty male rabbits at 30 days were randomly assigned to five different diets: Control (50 mg$\cdot$kg$^{-1}$ diet $\alpha$-tocopheryl acetate), Vitamin E (200 mg$\cdot$kg$^{-1}$ diet $\alpha$-tocopheryl acetate), n-3 (2% ROPUFA oil + 50 mg$\cdot$kg$^{-1}$ diet $\alpha$-tocopheryl acetate), n-3 + E (2% ROPUFA oil + 200 mg$\cdot$kg$^{-1}$ diet $\alpha$-tocopheryl acetate) and n-3 + E C (2% ROPUFA oil + 200 mg$\cdot$kg$^{-1}$ diet $\alpha$-tocopheryl acetate + 0.5 g$\cdot$L$^{-1}$ vitamin C in the drinking water). The levels of vitamins E and C and reactive oxygen metabolites (ROMs) in the blood plasma were evaluated at different ages. The antioxidant capacity and ROMs of seminal plasma, the fatty acid profile of sperm phospholipids, the semen traits and the oxidative processes during storage (24 h at + 4 °C) were carried out weekly for 5 wk starting from the 5th month of age. Vitamin E addition showed enough antioxidant protection only when associated with no lipid enriched diets. The n-3 supplementation modified the fatty acid profile of the spermatozoa membrane and simultaneously enhanced oxidative processes. Only the association with supranutritional levels of vitamins E and C inhibited the oxidative processes and improved the characteristics of fresh and stored rabbit semen

ROS-independent Nrf2 activation in prostate cancer

In prostate cancer, oxidative stress and the subsequent Nrf2 activation promote the survival of cancer cells and acquired chemoresistance. Nrf2 links prostate cancer to endoplasmic reticulum stress, an event that triggers the unfolded protein response, aiming to restore cellular homeostasis as well as an adaptive survival mechanism. Glucose-regulated protein of 78 kD /immunoglobulin heavy chain binding protein (GRP78/BiP) is a key molecular chaperone in the endoplasmic reticulum that, when expressed at the cell surface, acts as a receptor for several signaling pathways enhancing antiapoptotic and proliferative signals. We showed GRP78/BiP translocation to PC3 cell surface in the presence of tunicamycin, an ER stress inductor, and demonstrated the existence of a GRP78/BiP-dependent non-canonical Nrf2 activation, responsible for increased resistance to ER-stress induced apoptosis. We found that, even in the absence of ROS production, tunicamycin causes Nrf2 activation, and activates Akt signaling, events bulnted by anti-GRP78/BiP antibody treatment. The presence of GRP78/BiP at the cell surface might be exploited for the immunotherapeutic strategy of prostate cancer since its blockage by anti-GRP78/BiP antibodies might promote cancer death by suppressing some of the several molecular protective mechanisms found in aggressive cancer cells

Cellular and molecular mechanisms of sarcopenia: the S100B perspective

Abstract Primary sarcopenia is a condition of reduced skeletal muscle mass and strength, reduced agility, and increased fatigability and risk of bone fractures characteristic of aged, otherwise healthy people. The pathogenesis of primary sarcopenia is not completely understood. Herein, we review the essentials of the cellular and molecular mechanisms of skeletal mass maintenance; the alterations of myofiber metabolism and deranged properties of muscle satellite cells (the adult stem cells of skeletal muscles) that underpin the pathophysiology of primary sarcopenia; the role of the Ca2+‐sensor protein, S100B, as an intracellular factor and an extracellular signal regulating cell functions; and the functional role of S100B in muscle tissue. Lastly, building on recent results pointing to S100B as to a molecular determinant of myoblast–brown adipocyte transition, we propose S100B as a transducer of the deleterious effects of accumulation of reactive oxygen species in myoblasts and, potentially, myofibers concurring to the pathophysiology of sarcopenia