Zinc uptake promotes myoblast differentiation via Zip7 transporter and activation of Akt signalling transduction pathway

[EN] Myogenic regeneration occurs through a chain of events beginning with the output of satellite cells from quiescent state, formation of competent myoblasts and later fusion and differentiation into myofibres. Traditionally, growth factors are used to stimulate muscle regeneration but this involves serious off-target effects, including alterations in cell homeostasis and cancer. In this work, we have studied the use of zinc to trigger myogenic differentiation. We show that zinc promotes myoblast proliferation, differentiation and maturation of myofibres. We demonstrate that this process occurs through the PI3K/Akt pathway, via zinc stimulation of transporter Zip7. Depletion of zinc transporter Zip7 by RNA interference shows reduction of both PI3K/Akt signalling and a significant reduction of multinucleated myofibres and myotubes development. Moreover, we show that mature myofibres, obtained through stimulation with high concentrations of zinc, accumulate zinc and so we hypothesise their function as zinc reservoirs into the cell.P.R. and R.S. acknowledges support from the Spanish Ministry of Economy and Competitiveness (MINECO) (MAT2015-69315-C3-1-R). P.R. acknowledges the Fondo Europeo de Desarrollo Regional (FEDER). CIBER-BBN is an initiative funded by the VI National R&D&I Plan 2008-2011, Iniciativa Ingenio 2010, Consolider Program, CIBER Actions and financed by the Instituto de Salud Carlos III with assistance from the European Regional Development Fund. R.S. acknowledges the support from the Spanish MECD through the PRX16/00208 grant. MSS acknowledges support from the European Research Council (ERC - HealInSynergy 306990) and the UK Engineering and Physical Sciences Research Council (EPSRC - EP/P001114/1)Mnatsakanyan, H.; Sabater I Serra, R.; Rico Tortosa, PM.; Salmerón Sánchez, M. (2018). 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Electrical Stimulation Influences Satellite Cell Proliferation and Apoptosis in Unloading-Induced Muscle Atrophy in Mice

Muscle atrophy caused by disuse is accompanied by adverse physiological and functional consequences. Satellite cells are the primary source of skeletal muscle regeneration. Satellite cell dysfunction, as a result of impaired proliferative potential and/or increased apoptosis, is thought to be one of the causes contributing to the decreased muscle regeneration capacity in atrophy. We have previously shown that electrical stimulation improved satellite cell dysfunction. Here we test whether electrical stimulation can also enhance satellite cell proliferative potential as well as suppress apoptotic cell death in disuse-induced muscle atrophy. Eight-week-old male BALB/c mice were subjected to a 14-day hindlimb unloading procedure. During that period, one limb (HU-ES) received electrical stimulation (frequency: 20 Hz; duration: 3 h, twice daily) while the contralateral limb served as control (HU). Immunohistochemistry and western blotting techniques were used to characterize specific proteins in cell proliferation and apoptosis. The HU-ES soleus muscles showed significant improvement in muscle mass, cross-sectional area, and peak tetanic force relative to the HU limb (p<0.05). The satellite cell proliferative activity as detected within the BrdU+/Pax7+ population was significantly higher (p<0.05). The apoptotic myonuclei (detected by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling) and the apoptotic satellite cells (detected by cleaved Poly [ADP-ribose] polymerase co-labeled with Pax7) were reduced (p<0.05) in the HU-ES limb. Furthermore the apoptosis-inducing factor and cleaved caspase-3 were down-regulated while the anti-apoptotic Bcl-2 protein was up-regulated (p<0.05), in the HU-ES limb. These findings suggest that the electrical stimulation paradigm provides an effective stimulus to rescue the loss of myonuclei and satellite cells in disuse muscle atrophy, thus maintaining a viable satellite cell pool for subsequent muscle regeneration. Optimization of stimulation parameters may enhance the outcome of the intervention

Therapeutic implications of osteoprotegerin

Osteoprotegerin (OPG), a member of the tumor necrosis factor (TNF) receptor superfamily, contributes determinatively to the bone remodeling as well as to the pathogenetic mechanism of bone malignancies and disorders of mineral metabolism. There is additional evidence that OPG can promote cell survival by inhibiting TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. A number of recent in vitro, in vivo and clinical studies have defined the role of the RANK/RANKL/OPG pathway in skeletal and vascular diseases. These works were the milestone of the deep understanding of the mechanism of OPG. This review provides an overview of the potential innovative therapeutic strategies of OPG in metastatic breast and prostate carcinoma, multiple myeloma, postmenopausal osteoporosis, glucocorticoid-induced osteoporosis and rheumatoid arthritis. Special reference is given to the increasing evidence that RANKL and OPG may link the skeletal with the vascular system. © 2009 Fili et al; licensee BioMed Central Ltd

Mechanism of bone metastasis: The role of osteoprotegerin and of the host-tissue microenvironment-related survival factors

Osteoprotegerin (OPG), member of tumor necrosis factor (TNF) receptor superfamily, has various biological functions including bone remodeling. OPG binds to receptor activator of nuclear factor-kB ligand (RANKL) and prevents osteoclastic bone resorption. Recently, OPG has gained more clinical interest as its role in cancer-mediated bone destruction and the potential of RANKL inhibition could act as a novel treatment in tumor-induced bone disease. OPG protects prostate cancer cells from apoptotic effects of TRAIL and therefore provides tumor cells producing OPG with survival advantages. Additionally, the increased RANKL/OPG ratio in metastatic breast cancer results in severe osteolysis. Thus, bone formation and resorption are the crux of cancer metastasis, resulting in bone pain and pathological fractures. This review provides an overview of the role of OPG in cancer-induced bone disease. © 2009 Elsevier Ireland Ltd. All rights reserved

Common pathophysiological mechanisms involved in luteal phase deficiency and polycystic ovary syndrome. Impact on fertility

Luteal phase deficiency (LPD) is a consequence of the corpus luteum (CL) inability to produce and preserve adequate levels of progesterone. This is clinically manifested by short menstrual cycles and infertility. Abnormal follicular development, defects in neo-angiogenesis or inadequate steroidogenesis in the lutein cells of the CL have been implicated in CL dysfunction and LPD. LPD and polycystic ovary syndrome (PCOS) are independent disorders sharing common pathophysiological profiles. Factors such as hyperinsulinemia, AMH excess, and defects in angiogenesis of CL are at the origin of both LPD and PCOS. In PCOS ovulatory cycles, infertility could result from dysfunctional CL. The aim of this review was to investigate common mechanisms of infertility in CL dysfunction and PCOS. © 2012 Springer Science+Business Media, LLC

Papillary thyroid carcinoma of the isthmus: Total thyroidectomy or isthmusectomy?

Background: Papillary thyroid carcinoma (PTC) is the most common histological type of differentiated thyroid malignancy. Although the majority of PTC is located in the thyroid lobes, a small minority arise from the thyroid isthmus. The reported incidence of PTC arising in the thyroid isthmus ranges from 1% to 9.2%, probably reflecting variation in the study populations. Purpose: This review aimed to analyze the data about the optimal management of PTC arising in the isthmus. Data sources: We performed a systematic review of PubMed, MEDLINE, EMBASE, Scopus, and Cochrane Central Register of Controlled Trials to identify eligible studies analyzing surgical management strategies and published outcomes of isthmic PTC. Results: Most reports support that papillary thyroid carcinomas originating in the isthmus are more likely to have multiple foci, invasion of thyroid capsule and adjacent tissues with increased rate of central node involvement, compared to carcinomas located in other parts of the thyroid. Conclusions: The extent of the surgical resection, the role of prophylactic central neck dissection and the extent of central neck dissection in surgery for isthmic PTC remain highly controversial. However, total thyroidectomy and central node dissection may be an appropriate treatment for these patients. © 2017 Elsevier Inc