Harnessing the power of muscle regeneration

Cecilia Jiménez

Resum


After birth, skeletal muscle retains its ability to regenerate from a population of muscle stem cells (MuSC) often referred to as satellite cells. These are quiescent cells that upon activation activate, migrate from their niche (between the muscle plasma membrane and the basal lamina), proliferate and differentiate into a mononuclear myocyte and become a mature myotube. In certain conditions, skeletal muscle regeneration is impaired. Duchenne Muscular Dystrophy (DMD), caused by mutations in the DMD gene in the X chromosome. This leads to deficiency of dystrophin, a sub-sarcolemmal protein that protects the muscle membrane from damage. Muscle pathology in DMD is associated with insufficient regenerative capacity of MuSCs due to numerous cell autonomous (intrinsic) and extrinsic changes in satellite cells and their environment or niche. In addition to muscular dystrophies there are other circumstances when adult myogenesis deteriorates. We focused on sarcopenia, the loss of muscle mass and function that accompanies advanced age. Autophagy is essential for the stemness of the satellite cell pool, to prevent senescence and apoptosis. Satellite cells from geriatric mice have a reduction in the autophagic flux and an increase in apoptosis due to defects in the AMPK/p27kipI axis. Autophagy in MuSCs can be boosted by caloric restriction, exercise, rapamycin and spermidine treatment. The environment of the satellite cell also plays an important role (myostatin and wnt ligands, and locally secreted factors such as TGFB, FGF2 and Ang1). MuSCs themselves can be utilized in cell therapy as the source of new muscle and to replace defective proteins such as dystrophin if combined with gene therapy. Many attempts have been made with myoblasts, mesangioblasts, CD133+ cells and pericytes but so far the effects have been modest. However, technologies such as iPS cells, tissue bioengineering and gene editing (CRISPR/Cas) hold great promise to improve the efficiency and translation into clinical practice of therapies for muscle diseases and muscle deterioration. Students were asked to argue a potential combined strategy to enhance MuSCs activity andmuscle regeneration for the treatment of muscle injury, disease or age-related dysfunction based on the information discussed in the seminar.

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