The mitotic clock in skeletal muscle regeneration, disease and cell mediated gene therapy

• Published in: Acta physiologica Scandinavica Vol. 184; no. 1; pp. 3 - 15
• Main Authors: Mouly, V., Aamiri, A., Bigot, A., Cooper, R. N., Di Donna, S., Furling, D., Gidaro, T., Jacquemin, V., Mamchaoui, K., Negroni, E., Périé, S., Renault, V., Silva-Barbosa, S. D., Butler-Browne, G. S.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Science Ltd 01-05-2005; Blackwell Science; Wiley-Blackwell
• Subjects: Adult; Aging - physiology; Animals; Biological and medical sciences; Biotechnology; Cell Differentiation; Cellular Senescence - physiology; Fundamental and applied biological sciences. Psychology; Gene therapy; Genetic Therapy; Health. Pharmaceutical industry; Humans; Immunologic Deficiency Syndromes - physiopathology; Industrial applications and implications. Economical aspects; Insulin-Like Growth Factor I - physiology; insulin-like growth factor-1; Life Sciences; Mice; Mitosis - physiology; muscle regeneration; Muscle, Skeletal - growth & development; myoblast transplantation; Myoblasts - physiology; Satellite Cells, Skeletal Muscle - physiology; Striated muscle. Tendons; telomerase; Telomerase - analysis; Telomere - physiology; telomeres; Vertebrates: osteoarticular system, musculoskeletal system; Human; Senescence; Enzyme; Mitosis; Ageing; telomeres; insulin-like growth factor-1; Transplantation; muscle regeneration; Insulin like growth factor 1; Striated muscle; Telomere; Biological clock; Regeneration; Myoblast; myoblast transplantation; Satellite cell; Gene therapy; Telomerase
• ISSN: 0001-6772; 1365-201X
• DOI: 10.1111/j.1365-201X.2005.01417.x

The regenerative capacity of skeletal muscle will depend on the number of available satellite cells and their proliferative capacity. We have measured both parameters in ageing, and have shown that although the proliferative capacity of satellite cells is decreasing during muscle growth, it then stabilizes in the adult, whereas the number of satellite cells decreases during ageing. We have also developed a model to evaluate the regenerative capacity of human satellite cells by implantation into regenerating muscles of immunodeficient mice. Using telomere measurements, we have shown that the proliferative capacity of satellite cells is dramatically decreased in muscle dystrophies, thus hampering the possibilities of autologous cell therapy. Immortalization by telomerase was unsuccessful, and we currently investigate the factors involved in cell cycle exits in human myoblasts. We have also observed that insulin‐like growth factor‐1 (IGF‐1), a factor known to provoke hypertrophy, does not increase the proliferative potential of satellite cells, which suggests that hypertrophy is provoked by increasing the number of satellite cells engaged in differentiation, thus possibly decreasing the compartment of reserve cells. We conclude that autologous cell therapy can be applied to specific targets when there is a source of satellite cells which is not yet exhausted. This is the case of Oculo–Pharyngeal Muscular Dystrophy (OPMD), a late onset muscular dystrophy, and we participate to a clinical trial using autologous satellite cells isolated from muscles spared by the disease.