Reversing Cellular Senescence in Satellite cells by Targeting P16INK4a-Inducing Pathways

William Choi

 Introduction. Sarcopenia is an age-related process with a loss of function due to atrophy of muscle mass. Skeletal muscle accounts for nearly 40% of body mass and its decay can progress as individuals enter later stages of their lives. It can be debilitating on individuals, impairing normal routines that require use of muscles such as lifting, carrying objects, walking, and climbing stairs1. In skeletal muscle, there are muscle stem cells known as satellite cells that are responsible for restoring muscle mass. They are normally in a reversible quiescent G0 phase and enter the cell cycle only when stimulated from events such as an injury or daily wear and tear2. In sarcopenia, these satellite cells fail to activate and are arrested in permanent irreversible G0 phase3. Studies have found that targeting P16ink4a inducing pathway such as p38α/β MAPK can restore function in aged satellite cells, creating a potential therapeutic impact4. Methods. Old satellite cells from mouse models were treated with biophysical and biochemical cues. The cells were placed in soft hydrogel substrates which mimicked the soft elasticity biophysical property of muscle tissue. The cells were also treated with SB202190, a potent protein kinase inhibitor blocking the p38α/β MAPK activity4. Results. There was a restoration in function in satellite cells that were treated compared to the control group. Function of the cells were measured by inducing activity in muscle cells and measuring the twitch force in millinewtons. The treated satellite cells showed same twitch force as the ones measured in young cells. P16 levels were also measured and the treated cells showed decreased levels of p16, suggesting reversal of cellular senescence.Conclusion. By placing aged satellite cells in a soft hydrogel and treating it with a protein kinase inhibitor, the cells showed reversal of cellular senescence and restoration in function. With current treatment methods of sarcopenia only being supportive measures through diet and physical exercise supplementation5, MAPK inhibition stem cell therapy provides a promising potential future treatment option in combating sarcopenia.

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