In this review, we are going to explore the consequences of ageing in satellite cell numbers and their ability to maintain and preserve muscle tissue. Steps involved when skeletal muscle is damaged: The homeostatic process that allows muscle regeneration in response to an injury stimulus, involves four interrelated steps: degeneration, inflammation, regeneration and remodelling repair. When myofibers are damaged, extracellular calcium flows into the cell, initiating proteolysis, which causes necrosis.
The necrosis of myofibers brings about an inflammatory response where neutrophils and macrophages infiltrate the injured site. Neutrophils are the first to arrive; they remove cell debris by releasing free radicals and proteases as well as secreting pro-inflammatory cytokines that stimulate the arrival of macrophages. There two different classes of macrophages arriving at the injured site: M1 (expressing CD68) and M2 (expressing CD163). The M1 class is responsible for producing a high concentration of pro-inflammatory cytokines, which promote further tissue inflammation.
Arriving next, is the M2 class of macrophages that induce angiogenesis and tissue remodelling and repair, by activating stem cells. This phase of inflammation is critical to the muscle regeneration process. Experiments have shown that if the inflammation response is inhibited, then muscle repair cannot occur at all. Nevertheless, there must be a balance between insufficient and excessive inflammation response. The regenerative phase is achieved by the activation, proliferation and differentiation of satellite cells that fuse together to form multinucleated myotubes.
This is regulated by the presence of a number of growth factors such as insulin-like growth factor-1 (IGF-1), hepatocyte growth factor (HGF) and others. The final phase of the regenerative process is ‘remodelling and repair’ and it involves the remodelling of connective tissue, angiogenesis and functional recovery of the skeletal muscle. How does this happen? Well, once the muscle is injured, there is an excessive production of collagens that promote scar tissue to form.
This is so-called fibrosis formation is activated by transforming growth factor-? 1 (TGF-? 1), which plays a major role in this cascade. This phase is over once the injured muscle has been replaced by a functional and contractile apparatus. Figure 1: [pic] Fig. 1 shows the steps involved for a satellite cell to form a myotube. (www. bioscience. org) The role of satellite cells: Satellite cells (identified using electron microscopy) are located under the basal lamina and are a type of muscle stem cells.
They are present in muscle tissue in the quiescent form and can be activated by both physiological stimuli (such as extensive exercise), as well as pathological conditions (injury or degenerative disease). Their main function is to create a population of myoblasts that can fuse with each other or with other myofibers and differentiate, so as to repair muscle tissue. Both quiescent and active satellite cells express the transcription factor Pax-7 that is thought to drive transcription and maintain proliferation.
Even though the role of Pax-7 is not completely understood, it is evident that without it, we would not have satellite cells. In fact, an experiment showed that mice lacking Pax-7, did not survive beyond 2 weeks. In addition, activated satellite cells express a protein called myogenic regulatory factor (MyoD), which is a crucial factor in regulating the differentiation of muscle cells. Impact of ageing in muscle degeneration: Hypothetically, even though the number of satellite cells decreases with age, the few cells remaining should be enough to initiate the regenerative mechanism.
However, experiments have shown that the surrounding tissue and systemic environment to which the satellite cells were placed, were far more important factors for muscle regeneration than the number of cells present. This hypothesis was supported by the fact that old muscle tissue could be regenerated when it was placed in a young animal, but the opposite did not occur. Therefore, the hypothesis that the decrease in satellite cell numbers due to ageing was the major factor that affected regeneration was proved to be wrong. Figure 2: [pic] Fig. illustrates the difference between a normal myofiber and a regenerating myofiber. (www. bioscience. org) Conclusion: All in all, sarcopenia alters the regeneration and repair of muscle, which can cause structural abnormalities. Ageing causes a dramatic decrease in satellite cell numbers and reduces their ability to repair damaged muscle. Even though young stem cells applied to aged or damaged skeletal muscle seem to be promising for therapeutic applications, we must gain a better understanding of satellite cell biology in order to use regenerative medicine to treat sarcopenia.
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