Adult skeletal muscle robustly regenerates throughout adult life but fails to do so in old age. The reason for such a decline in the regenerative potential is not well understood and the relative roles of the changes in muscle cells versus the alterations in their aged environment have not been defined. Recently is has been shown that a young systemic milieu restores the activity of the regeneration-specific Notch pathway and enhances repair of old muscle, suggesting that largely intact regenerative potential of aged satellite cells is not properly triggered in the aged environment. Our most recent data suggest that it is not simply the lack of """"""""positive"""""""" systemic factors that causes impaired organ stem cell activation and tissue repair in the old, but that the aged systemic and muscle niches actually inhibit Notch activation and the regenerative potential of both old and young satellite cells. Namely, satellite cells isolated from old muscle or exposed to aged mouse serum in vitro are inhibited in their regenerative capacity and lack Notch activation. Moreover, our preliminary data identifies a molecular mechanism of this age-related inhibition by demonstrating that the reduced regenerative potential of satellite cells in the aged environments stems from excessive TGF-beta/pSmad signaling induced in these cells by their aged niches, which in turn is a result of the elevated levels of TGF- beta-family ligands in aged circulation and muscle tissue. Very importantly, our preliminary results suggest that both myogenic potential and Notch activation can be rejuvenated by attenuation of TGF-beta/pSmad signaling in satellite cells. These studies emphasize high therapeutic relevance of understanding the regulation of adult myogenesis by TGF-beta super-family and of designing the approaches for tunable calibration of TGF-beta/pSmad signaling in muscle stem cells. In order to decipher the age-related role of TGF-beta/pSmad signaling in muscle repair and to progress toward therapeutic applications, it is needed to determine 1) what are the """"""""youthful"""""""" positive versus """"""""aged"""""""" negative levels of TGF-beta-superfamily ligands in circulation and muscle tissue;2) at what age-related levels TGF-beta/pSmad signaling becomes excessive and """"""""negative"""""""" for satellite cell regenerative capacity and 3) how to design a tunable system for a precise """"""""youthful"""""""" recalibration of TGF-beta/pSmad signaling in satellite cells. These goals will be approached here in the proposed Specific Aims.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG027252-04
Application #
7846838
Study Section
Skeletal Muscle and Exercise Physiology Study Section (SMEP)
Program Officer
Williams, John
Project Start
2007-06-15
Project End
2012-05-31
Budget Start
2010-06-01
Budget End
2011-05-31
Support Year
4
Fiscal Year
2010
Total Cost
$297,667
Indirect Cost
Name
University of California Berkeley
Department
Biomedical Engineering
Type
Schools of Engineering
DUNS #
124726725
City
Berkeley
State
CA
Country
United States
Zip Code
94704
Li, Ju; Han, Suhyoun; Cousin, Wendy et al. (2015) Age-specific functional epigenetic changes in p21 and p16 in injury-activated satellite cells. Stem Cells 33:951-61
Elabd, Christian; Cousin, Wendy; Upadhyayula, Pavan et al. (2014) Oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration. Nat Commun 5:4082
Elabd, Christian; Cousin, Wendy; Chen, Robert Y et al. (2013) DNA methyltransferase-3-dependent nonrandom template segregation in differentiating embryonic stem cells. J Cell Biol 203:73-85
Chapman, Matthew R; Balakrishnan, Karthik R; Li, Ju et al. (2013) Sorting single satellite cells from individual myofibers reveals heterogeneity in cell-surface markers and myogenic capacity. Integr Biol (Camb) 5:692-702
Cousin, Wendy; Ho, Michelle Liane; Desai, Rajiv et al. (2013) Regenerative capacity of old muscle stem cells declines without significant accumulation of DNA damage. PLoS One 8:e63528
Pan, Deng; Zhu, Qingwei; Conboy, Michael J et al. (2012) SnoN activates p53 directly to regulate aging and tumorigenesis. Aging Cell 11:902-911
Paliwal, Preeti; Pishesha, Novalia; Wijaya, Denny et al. (2012) Age dependent increase in the levels of osteopontin inhibits skeletal muscle regeneration. Aging (Albany NY) 4:553-66
Paliwal, Preeti; Conboy, Irina M (2011) Inhibitors of tyrosine phosphatases and apoptosis reprogram lineage-marked differentiated muscle to myogenic progenitor cells. Chem Biol 18:1153-66
Conboy, Irina M; Yousef, Hanadie; Conboy, Michael J (2011) Embryonic anti-aging niche. Aging (Albany NY) 3:555-63
Jeong, Jaemin; Conboy, Irina M (2011) Phosphatidylserine directly and positively regulates fusion of myoblasts into myotubes. Biochem Biophys Res Commun 414:9-13

Showing the most recent 10 out of 17 publications