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). Zinc uptake promotes myoblast differentiation via Zip7 transporter and activation of Akt signalling transduction pathway. Scientific Reports. 8:1-14. https://doi.org/10.1038/s41598-018-32067-0S1148Frontera, W. R. & Ochala, J. Skeletal muscle: a brief review of structure and function. Calcif. Tissue Int. 96, 183–195 (2015).Wolfe, R. R., Frontera, W. R. & Ochala, J. The underappreciated role of muscle in health and disease. Am. J. Clin. Nutr. 84, 475–82 (2006).Sciorati, C., Rigamonti, E., Manfredi, A. A. & Rovere-Querini, P. Cell death, clearance and immunity in the skeletal muscle. Cell Death Differ. 23, 927–937 (2016).Wang, Y. X. & Rudnicki, M. A. Satellite cells, the engines of muscle repair. Nat. Rev. Mol. Cell Biol. 13, 127–133 (2011).Yin, H., Price, F. & Rudnicki, M. A. Satellite cells and the muscle stem cell niche. Physiol. Rev. 93, 23–67 (2013).Dhawan, J. & Rando, T. A. Stem cells in postnatal myogenesis: Molecular mechanisms of satellite cell quiescence, activation and replenishment. Trends Cell Biol. 15, 666–673 (2005).Yun, K. & Wold, B. Skeletal muscle determination and differentiation: Story of a core regulatory network and its context. Curr. Opin. Cell Biol. 8, 877–889 (1996).Gharaibeh, B. et al. Biological approaches to improve skeletal muscle healing after injury and disease. Birth Defects Res. Part C Embryo Today Rev. 96, 82–94 (2012).Schiaffino, S. & Mammucari, C. Regulation of skeletal muscle growth by the IGF1-Akt/PKB pathway: insights from genetic models. Skelet. Muscle 1, 4 (2011).Sandri, M. Signaling in muscle atrophy and hypertrophy. Physiology (Bethesda). 23, 160–70 (2008).Karalaki, M., Fili, S., Philippou, A. & Koutsilieris, M. Muscle regeneration: cellular and molecular events. In Vivo 23, 779–96 (2009).Fujio, Y. et al. Cell cycle withdrawal promotes myogenic induction of Akt, a positive modulator of myocyte survival. Mol. Cell. Biol. 19, 5073–82 (1999).Wilson, E. M. & Rotwein, P. Control of MyoD function during initiation of muscle differentiation by an autocrine signaling pathway activated by insulin-like growth factor-II. J. Biol. Chem. 281, 29962–29971 (2006).Sun, L., Liu, L., Yang, X. & Wu, Z. Akt binds prohibitin 2 and relieves its repression of MyoD and muscle differentiation. J. Cell Sci. 117, 3021–3029 (2004).Milner, D. & Cameron, J. Muscle repair and regeneration: stem cells, scaffolds, and the contributions of skeletal muscle to amphibian limb regeneration. Curr. Top. Microbiol. Immunol. 367, 133–159 (2013).Liu, C. et al. PI3K/Akt signaling transduction pathway is involved in rat vascular smooth muscle cell proliferation induced by apelin-13. Acta Biochim Biophys Sin 42, 396–402 (2010).Eriksson, M., Taskinen, M. & Leppä, S. Mitogen Activated Protein Kinase-Dependent Activation of c-Jun and c-Fos is required for Neuronal differentiation but not for Growth and Stress Reposne in PC12 cells. J. Cell. Physiol. 207, 12–22 (2006).Arsic, N. et al. Vascular endothelial growth factor stimulates skeletal muscle regeneration in Vivo. Mol. Ther. 10, 844–854 (2004).Borselli, C. et al. Functional muscle regeneration with combined delivery of angiogenesis and myogenesis factors. Proc. Natl. Acad. Sci. USA 107, 3287–3292 (2010).Hanft, J. R. et al. Phase I trial on the safety of topical rhVEGF on chronic neuropathic diabetic foot ulcers. J. Wound Care 17(30–2), 34–7 (2008).Simón-Yarza, T. et al. Vascular endothelial growth factor-delivery systems for cardiac repair: An overview. Theranostics 2, 541–552 (2012).Briquez, P. S., Hubbell, J. A. & Martino, M. M. Extracellular Matrix-Inspired Growth Factor Delivery Systems for Skin Wound Healing. Adv. Wound Care 4, 479–489 (2015).Barthel, A., Ostrakhovitch, E. A., Walter, P. L., Kampkötter, A. & Klotz, L. O. Stimulation of phosphoinositide 3-kinase/Akt signaling by copper and zinc ions: Mechanisms and consequences. Arch. Biochem. Biophys. 463, 175–182 (2007).Ostrakhovitch, E. A., Lordnejad, M. R., Schliess, F., Sies, H. & Klotz, L.-O. Copper ions strongly activate the phosphoinositide-3-kinase/Akt pathway independent of the generation of reactive oxygen species. Arch. Biochem. Biophys. 397, 232–239 (2002).Kaur, K., Gupta, R., Saraf, S. A. & Saraf, S. K. Zinc: The metal of life. Compr. Rev. Food Sci. Food Saf. 13, 358–376 (2014).Coleman, J. E. Zinc proteins: enzymes, storage proteins, transcription factors, and replication proteins. Annu. Rev. Biochem. 61, 897–946 (1992).Fukada, T. & Kambe, T. Molecular and genetic features of zinc transporters in physiology and pathogenesis. Metallomics 3, 662–674 (2011).Murakami, M. & Hirano, T. Intracellular zinc homeostasis and zinc signaling. Cancer Sci. 99, 1515–1522 (2008).Hogstrand, C., Kille, P., Nicholson, R. I. & Taylor, K. M. Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation. Trends Mol. Med. 15, 101–111 (2009).Kolenko, V., Teper, E., Kutikov, A. & Uzzo, R. Zinc and zinc transporters in prostate carcinogenesis. Nat. Rev. Urol. 10, 219–26 (2013).Myers, S. A., Nield, A., Chew, G. S. & Myers, M. A. The zinc transporter, Slc39a7 (Zip7) is implicated in glycaemic control in skeletal muscle cells. Plos One 8 (2013).Kambe, T., Tsuji, T., Hashimoto, A. & Itsumura, N. The Physiological, Biochemical, and Molecular Roles of Zinc Transporters in Zinc Homeostasis and Metabolism. Physiol. Rev. 95, 749–784 (2015).Jinno, N., Nagata, M. & Takahashi, T. Marginal zinc deficiency negatively affects recovery from muscle injury in mice. Biol. Trace Elem. Res. 158, 65–72 (2014).Taylor, K. M., Hiscox, S., Nicholson, R. I., Hogstrand, C. & Kille, P. Protein Kinase CK2 Triggers Cytosolic Zinc Signaling Pathways by Phosphorylation of Zinc Channel ZIP7. Sci. Signal. 5, ra11–ra11 (2012).Yamasaki, S. et al. Zinc is a novel intracellular second messenger. J. Cell Biol. 177, 637–45 (2007).Sumitani, S., Goya, K., Testa, J. R., Kouhara, H. & Kasayama, S. Akt1 and Akt2 differently regulate muscle creatine kinase and myogenin gene transcription in insulin-induced differentiation of C2C12 myoblasts. Endocrinology 143, 820–828 (2002).Ohashi, K. et al. Zinc promotes proliferation and activation of myogenic cells via the PI3K/Akt and ERK signaling cascade. Exp. Cell Res. 333, 228–237 (2015).Chesters, J. K. In Zinc in human biology 53, 109–118 (1989).Burattini, S. et al. C2C12 murine myoblasts as a model of skeletal muscle development: Morpho-functional characterization. Eur. J. Histochem. 48, 223–233 (2004).Mnatsakanyan, H. et al. Controlled Assembly of Fibronectin Nanofibrils Triggered by Random Copolymer Chemistry. ACS Appl. Mater. Interfaces 7, 18125–18135 (2015).Jeong, J. & Eide, D. J. The SLC39 family of zinc transporters. Molecular Aspects of Medicine 34, 612–619 (2013).Huang, L., Kirschke, C. P., Zhang, Y. & Yan, Y. Y. The ZIP7 gene (Slc39a7) encodes a zinc transporter involved in zinc homeostasis of the Golgi apparatus. J. Biol. Chem. 280, 15456–15463 (2005).Vallee, B. L. & Falchuk, K. H. The biochemical basis of zinc physiology. Physiological reviews 73 (1993).Ganju, N. & Eastman, A. Zinc inhibits Bax and Bak activation and cytochrome c release induced by chemical inducers of apoptosis but not by death-receptor-initiated pathways. Cell Death Differ. 10, 652–61 (2003).Chai, F., Truong-Tran, A. Q., Ho, L. H. & Zalewski, P. D. Regulation of caspase activation and apoptosis by cellular zinc fluxes and zinc deprivation: A review. Immunol. Cell Biol. 77, 272–278 (1999).Smith, P. J., Wiltshire, M., Furon, E., Beattie, J. H. & Errington, R. J. Impact of overexpression of metallothionein-1 on cell cycle progression and zinc toxicity. Am. J. Physiol. Cell Physiol. 295, C1399–C1408 (2008).Bozym, R. A. et al. Free zinc ions outside a narrow concentration range are toxic to a variety of cells in vitro. Exp. Biol. Med. (Maywood). 235, 741–50 (2010).Plum, L. M., Rink, L. & Hajo, H. The essential toxin: Impact of zinc on human health. Int. J. Environ. Res. Public Health 7, 1342–1365 (2010).Chen, C.-J. & Liao, S.-L. Zinc toxicity on neonatal cortical neurons: involvement of glutathione chelation. J. Neurochem. 85, 443–453 (2003).Chassot, A. A. et al. Confluence-induced cell cycle exit involves pre-mitotic CDK inhibition by p27Kip1 and cyclin D1 downregulation. Cell Cycle 7, 2038–2046 (2008).Spencer, S. L. et al. XThe proliferation-quiescence decision is controlled by a bifurcation in CDK2 activity at mitotic exit. Cell 155, 369–383 (2013).Walsh, K. & Perlman, H. Cell cycle exit upon myogenic differentiation. Curr. Opin. Genet. Dev. 7, 597–602 (1997).Puri, P. L. & Sartorelli, V. Regulation of muscle regulatory factors by DNA-binding, interacting proteins, and post-transcriptional modifications. Journal of Cellular Physiology 185, 155–173 (2000).Zammit, P. S., Partridge, T. A. & Yablonka-Reuveni, Z. The skeletal muscle satellite cell: the stem cell that came in from the cold. J Histochem Cytochem 54, 1177–1191 (2006).McCord, M. C. & Aizenman, E. The role of intracellular zinc release in aging, oxidative stress, and Alzheimer’s disease. Front. Aging Neurosci. 6, 1–16 (2014).Dirksen, R. T. Sarcoplasmic reticulum–mitochondrial through-space coupling in skeletal muscle. This paper is one of a selection of papers published in this Special Issue, entitled 14th International Biochemistry of Exercise Conference – Muscles as Molecular and Metabolic. Appl. Physiol. Nutr. Metab. 34, 389–395 (2009).Groth, C., Sasamura, T., Khanna, M. R., Whitley, M. & Fortini, M. E. Protein trafficking abnormalities in Drosophila tissues with impaired activity of the ZIP7 zinc transporter Catsup. Development 140, 3018–3027 (2013).Ellis, C. D. et al. Zinc and the Msc2 zinc transporter protein are required for endoplasmic reticulum function. J. Cell Biol. 166, 325–335 (2004).Koch, U., Lehal, R. & Radtke, F. Stem cells living with a Notch. Development 140, 689–704 (2013).Gardner, S., Anguiano, M. & Rotwein, P. Defining Akt actions in muscle differentiation. Am. J. Physiol. Physiol. 303, C1292–C1300 (2012).Knight, J. D. & Kothary, R. The myogenic kinome: protein kinases critical to mammalian skeletal myogenesis. Skelet. Muscle 1, 29 (2011).Roth, S. M. Genetic aspects of skeletal muscle strength and mass with relevance to sarcopenia. Bonekey Rep. 1, 1–7 (2012).Mebratu, Y. & Tesfaigzi, Y. How ERK1/2 Activation Controls Cell Proliferation and Cell Death Is Subcellular Localization the Answer? Cell Cycle 8, 1168–1175 (2009)

Laminin heparin-binding peptides bind to several growth factors and enhance diabetic wound healing

Laminin, as a key component of the basement membrane extracellular matrix (ECM), regulates tissue morphogenesis. Here, we show that multiple laminin isoforms promiscuously bind to growth factors (GFs) with high affinity, through their heparin-binding domains (HBDs) located in the α chain laminin-type G (LG) domains. These domains also bind to syndecan cell-surface receptors, promoting attachment of fibroblasts and endothelial cells. We explore the application of these multifunctional laminin HBDs in wound healing in the type-2 diabetic mouse. We demonstrate that covalent incorporation of laminin HBDs into fibrin matrices improves retention of GFs and significantly enhances the efficacy of vascular endothelial cell growth factor (VEGF-A165) and platelet-derived growth factor (PDGF-BB) in promoting wound healing in vivo, under conditions where the GFs alone in fibrin are inefficacious. This laminin HBD peptide may be clinically useful by improving biomaterial matrices as both GF reservoirs and cell scaffolds, leading to effective tissue regeneration

Hydrogels with precisely controlled integrin activation dictate vascular patterning and permeability

Integrin binding to bioengineered hydrogel scaffolds is essential for tissue regrowth and regeneration, yet not all integrin binding can lead to tissue repair. Here, we show that through engineering hydrogel materials to promote α3/α5β1 integrin binding, we can promote the formation of a space-filling and mature vasculature compared with hydrogel materials that promote αvβ3 integrin binding. In vitro, α3/α5β1 scaffolds promoted endothelial cells to sprout and branch, forming organized extensive networks that eventually reached and anastomosed with neighbouring branches. In vivo, α3/α5β1 scaffolds delivering vascular endothelial growth factor (VEGF) promoted non-tortuous blood vessel formation and non-leaky blood vessels by 10 days post-stroke. In contrast, materials that promote αvβ3 integrin binding promoted endothelial sprout clumping in vitro and leaky vessels in vivo. This work shows that precisely controlled integrin activation from a biomaterial can be harnessed to direct therapeutic vessel regeneration and reduce VEGF-induced vascular permeability in vivo