This application aims at deciphering the molecular pathways supporting satellite cell function and at understanding how these are influenced during aging. Age-related skeletal muscle deterioration (sarcopenia) is characterized by a decline in mass, strength, endurance and repair capacity, and by fat accumulation between and within myofibers. Myofiber repair is enabled by satellite cells, myogenic stem cells situated underneath the myofiber basal lamina. Subtle muscle injuries that occur during routine muscle activity raise a continuous demand for functional myofiber repair throughout life. However, satellite cell performance declines in old age and this decline can be a contributory factor to sarcopenia. While satellite cells have classically been thought to function as tissue-specific myogenic progenitors, we have shown that they can also enter a mesenchymal alternative path, which culminates in terminal adipogenic differentiation. Such an alternative lineage commitment may contribute to impaired myogeneity and increased muscle adipostiy in old age. Gaining insight into mechanisms involved in impairing satellite cell self-renewal and myogeneity, and in promoting their mesenchymal plasticity, will contribute to the design of therapies to improve the number and function of myogenic progenitors in aging muscle. Accordingly, the aims of this proposal are: 1) Investigate the potential of satellite cells to contribute myogenic progeny and undergo self-renewal throughout life. 2) Determine the role of the myogenic transcription factors Myf5 and MyoD, and the muscle integrin alpha7, in the balance between myogenic versus mesenchymal alternative fate of satellite cells. 3) Investigate the effect of metalloproteinase and disintegrin activities on mesenchymal fate and self-renewal of satellite cells. Wildtype and genetically modified mice, of age groups ranging from juvenile to senile, will be investigated. Satellite cell performance will be examined in isolated myofibers and clones, using protein and RNA expression methodologies. Additionally, the functional role of relevant genes will be determined by transducing satellite cells with viral-based expression vectors. The proposed studies will contribute new insight into the status of satellite cells in adult and aging muscles, and will, therefore, provide important information for muscle rehabilitation strategies during disease and aging. Skeletal muscle repair is enabled by myogenic progenitors named satellite cells. Age-associated decline in the performance of these cells can be a contributory factor to the deterioration of skeletal muscle in old age (sarcopenia). The proposed studies will contribute new insight into the regulation of satellite cell function throughout the lifespan and will, therefore, provide important information for muscle rehabilitation strategies during disease and aging.

National Institute of Health (NIH)
National Institute on Aging (NIA)
Research Project (R01)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-MOSS-L (07))
Program Officer
Williams, John
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Washington
Anatomy/Cell Biology
Schools of Medicine
United States
Zip Code
Phelps, Michael; Stuelsatz, Pascal; Yablonka-Reuveni, Zipora (2016) Expression profile and overexpression outcome indicate a role for ?Klotho in skeletal muscle fibro/adipogenesis. FEBS J 283:1653-68
Stuelsatz, Pascal; Shearer, Andrew; Li, Yunfei et al. (2015) Extraocular muscle satellite cells are high performance myo-engines retaining efficient regenerative capacity in dystrophin deficiency. Dev Biol 397:31-44
Carvajal Monroy, Paola L; Yablonka-Reuveni, Zipora; Grefte, Sander et al. (2015) Isolation and Characterization of Satellite Cells from Rat Head Branchiomeric Muscles. J Vis Exp :e52802
Stuelsatz, Pascal; Shearer, Andrew; Yablonka-Reuveni, Zipora (2014) Ancestral Myf5 gene activity in periocular connective tissue identifies a subset of fibro/adipogenic progenitors but does not connote a myogenic origin. Dev Biol 385:366-79
Keire, Paul; Shearer, Andrew; Shefer, Gabi et al. (2013) Isolation and culture of skeletal muscle myofibers as a means to analyze satellite cells. Methods Mol Biol 946:431-68
Shefer, Gabi; Rauner, Gat; Stuelsatz, Pascal et al. (2013) Moderate-intensity treadmill running promotes expansion of the satellite cell pool in young and old mice. FEBS J 280:4063-73
Phelps, Michael; Pettan-Brewer, Christina; Ladiges, Warren et al. (2013) Decline in muscle strength and running endurance in klotho deficient C57BL/6 mice. Biogerontology 14:729-39
Yoshida, Tadashi; Galvez, Sarah; Tiwari, Sumit et al. (2013) Angiotensin II inhibits satellite cell proliferation and prevents skeletal muscle regeneration. J Biol Chem 288:23823-32
Danoviz, Maria Elena; Yablonka-Reuveni, Zipora (2012) Skeletal muscle satellite cells: background and methods for isolation and analysis in a primary culture system. Methods Mol Biol 798:21-52
Stuelsatz, Pascal; Keire, Paul; Almuly, Ricardo et al. (2012) A contemporary atlas of the mouse diaphragm: myogenicity, vascularity, and the Pax3 connection. J Histochem Cytochem 60:638-57

Showing the most recent 10 out of 33 publications