Abstract
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.
Highlights
Skeletal muscle is a heterogeneous, dynamic and plastic tissue, which comprises approximately 40% of adult human body mass
Results show that Zn2+ increases cell density after 1, 3 and 5 days compared with control medium (Fig. 1c)
The zinc mitogenic effect is stronger at the initial steps of proliferation (1 day) and the trend is maintained after 3 days of culture
Summary
Skeletal muscle is a heterogeneous, dynamic and plastic tissue, which comprises approximately 40% of adult human body mass. Muscle tissue is the largest cellular compartment of the body, characterized in physiological conditions by a relatively slow turnover[3] It is composed by a combination of myofibres bound by connective tissue[1,4]. Activated satellite cells progress to become fusion-competent myoblast[6] These myoblasts proliferate and differentiate creating new myofibres and restoring tissue damage[7]. In the first steps of post-injury, muscle degeneration and posterior inflammation result in the activation of resident macrophages, which release chemoattractant molecules recruiting neutrophils and monocytes. Inflammatory mediators such as tumour necrosis factor alpha (TNFα) are released. Protein kinase Akt activation by IGF/PI3K cascade enhances the activity of the transcription factor MyoD in myoblasts cells, inducing them to terminal differentiation into myocytes and subsequent fusion into regenerating myofibres[12,13,14]
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