Homeostasis of satellite cells during aging
Final Report Abstract
Skeletal muscle has a remarkable ability to regenerate. The regeneration process is depending on muscle stem cells, also termed satellite cells. This population of stem cells is heterogeneous, for instance for the lineage expression of myf5. Thereby, muscle stem cells can be divided in satellite stem cells and committed progenitor cells. Of note, both subpopulations of muscle stem cells are positive for the canonical marker Pax7. During aging the regenerative capacity of skeletal muscle significantly declines concomitant with a decrease in numbers and functionality of muscle stem cells. We found a reduction in numbers of muscle stem cells with increasing age as well as a reduction in the intrinsic capacity of aged muscle stem cells to contribute to regeneration and repopulation of the stem cell niche. Gene expression analyses identified significant changes between muscle stem cells from young and aged mice. For instance, we could show a higher expression of JAK-STAT signaling targets in muscle stem cells from aged mice. Genetic knockdown or chemical inhibition of JAK2 or STAT3 resulted in increased engraftment potential of aged muscle stem cells and ultimately in increased regeneration in aged mice. Together these results reveal agedependent intrinsic changes that functionally distinguish muscle stem cells from young and aged mice. Other genes of interest which show differential expression between young and aged muscle stem cells are endomucin and galanin, whose function we analyzed in more detail. Here, we could demonstrate that expression of endomucin is aberrantly high in aged muscle stem cells and that reduction of this aberrant expression increases the differentiation potential of aged muscle stem cells and ultimately improves regeneration in the aged. Furthermore, we were able to demonstrate that expression of the neuropeptide galanin is decreased in aged muscle stem cells and that galanin expression plays an important role in apical basal muscle stem cell divisions. Furthermore, we identified upregulation of Hoxa9 in activated muscle stem cells from aged mice resulting in activation of JAK/STAT signaling and impairments of muscle stem cell functionality. Inhibition of Hoxa9 expression resulted in restored muscle stem cell functionality in the aged, e.g. increased engraftment potential and increased regenerative capacity of aged skeletal muscle. In a study in collaboration with the laboratory of C.Florian Bentzinger in Lausanne we investigated the effect of the niche factor fibronectin on muscle stem cells during aging. We found that the aged stem cell niche contains substantially less fibronectin leading to detrimental effects on stem cell functionality. Reconstitution of fibronectin levels in the aged niche restores youth-like regeneration of skeletal muscle. Additionally, we investigated the role of the anti-aging hormone klotho on muscle stem cell functionality. Here, we demonstrated that klotho hypomorphic mice display severely impaired regeneration of skeletal muscle as well as decreased muscle stem cell numbers. Furthermore, we show that addition of recombinant klotho protein to aged muscle stem cells improves their functionality through counteracting the aberrant canonical Wnt signaling described in aged muscle stem cells. Skeletal muscle has diverse functions in the organism and a remarkable ability to adapt to physiological demands such as growth, training or injury, which are all reduced with increasing age. Regeneration of skeletal muscle is depending on muscle stem cells, also called satellite cells. They are characterized by the expression of the transcription factor Pax7. During aging the regenerative capacity of skeletal muscle declines significantly. We found that also the number of muscle stem cells declines with increasing age. Additionally, muscle stem cells isolated from aged skeletal muscle display intrinsic differences, which are causative for their decreased functionality. The muscle stem cell population is heterogeneous based on the expression of cell surface markers and the lineage expression of myf5. Genetic analyses using the ROSA-YFP;myf5-cre mouse line established that approximately 10% of muscle stem cells (Pax7 positive) have never expressed myf5 shown by the lack of YFP expression. The study by Kuang et al. (2007) also demonstrated that the myf5-lineage negative muscle stem cells represent the satellite stem cell population while the myf5-lineage positive cells are more committed cells therefore also called committed progenitor cells.
Publications
- (2014). Inhibition of JAK-STAT signaling stimulates adult satellite cell function. Nat Med 20, 1174-1181
Price, F.D., von Maltzahn, J., Bentzinger, C.F., Dumont, N.A., Yin, H., Chang, N.C., Wilson, D.H., Frenette, J., and Rudnicki, M.A.
(See online at https://doi.org/10.1038/nm.3655) - (2016). Epigenetic stress responses induce muscle stem-cell ageing by Hoxa9 developmental signals. Nature 540, 428-432
Schworer, S., Becker, F., Feller, C., Baig, A.H., Kober, U., Henze, H., Kraus, J.M., Xin, B., Lechel, A., Lipka, D.B Varghese, C. S., Schmidt, M.; Rohs, R., Aebersold, R., Medina, K. L., Kestler, H. A., Neri, F., von Maltzahn, J., Tumpel, S., Rudolph, K. L.
(See online at https://doi.org/10.1038/nature20603) - (2016). Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice. Nat Med 22, 897-905
Lukjanenko, L., Jung, M.J., Hegde, N., Perruisseau-Carrier, C., Migliavacca, E., Rozo, M., Karaz, S., Jacot, G., Schmidt, M., Li, L., Metairon, S., Raymond, F., Lee, U., Sizzano, F., Wilson, D. H., Dumont, N. A., Palini, A., Fassler, R., Steiner, P., Descombes, P., Rudnicki, M. A., Fan, C. M., von Maltzahn, J., Feige, J. N., Bentzinger, C. F.
(See online at https://doi.org/10.1038/nm.4126) - Klotho expression is a prerequisite for proper muscle stem cell function and regeneration of skeletal muscle, 2018, Skelet Muscle, 8:20
Ahrens HE, Huettemeister J, Schmidt M, Kaether C and von Maltzahn J
(See online at https://doi.org/10.1186/s13395-018-0166-x) - Adult stem cells at work: regenerating skeletal muscle, 2019, Cell Mol Life Sci, 76(13):2559-2570
Schmidt M, Schüler SC, Hüttner SS, von Eyss B and von Maltzahn J
(See online at https://doi.org/10.1007/s00018-019-03093-6) - Analyzing Satellite Cell Function During Skeletal Muscle Regeneration by Cardiotoxin Injury and Injection of Self-Delivering siRNA In Vivo, 2019, JoVE, 18:(151)
Ahrens HE, Henze H, Schüler SC, Schmidt M and von Maltzahn J
(See online at https://doi.org/10.3791/60194)
