A major focus of our research has been to understand the molecular regulation of muscle stem cell (""""""""satellite cell"""""""" (SC)) function in homeostasis, regeneration, and aging of skeletal muscle. Our previous work has revealed a critical role of the Notch signaling pathway in the proliferative expansion of the pool of SC progeny after muscle injury, a necessary process for the effective regeneration of the tissue. We have also shown that it is a failure of this process, and a dysregulation of Notch signaling, in SCs from aged muscle that accounts at least in part for the decline in muscle regenerative potential with age. The focus of the studies of this proposal is to elucidate both the regulatory pathways that control Notch signaling and the downstream targets that mediated the effects of Notch signaling in activated SCs. In addition, we will explore the role of Notch signaling in the maintenance of SC quiescence, as suggested by several lines of evidence and our preliminary data. Using genetic tools to delete or enhance the Notch signaling pathway in the SC compartment, we will directly assess the role of Notch signaling in muscle regeneration and muscle aging, including the contribution of SCs to muscle maintenance during age-related muscle atrophy (""""""""sarcopenia""""""""). We will explore the role of the endogenous inhibitor of the Notch pathway, Numb, and the effects of individual Numb isoforms. Finally, we will examine the regulation of SC function by the """"""""longevity gene"""""""" and transcription factor FoxO3. Our preliminary data indicate that FoxO3 is a critical regulator of SC function, perhaps by directly controlling expression of components of the Notch pathway. Throughout these studies, we will seek to discover the underlying molecular mechanisms that regulate SC function in the adult and during aging. We will also take advantage of the fact that we can purify a large number of quiescent and activated SCs from adult and aged mice to perform genome wide analyses of the transcriptome and epigenome of these cells and to test for direct targets of RBP-J (as the key transcriptional regulator of the Notch pathway) and FoxO3 transcriptional regulation. Overall, our goal is to identify the complex regulatory network that influences SC function from quiescence, through activation, proliferative expansion and differentiation, and to understand the molecular basis of the decline in SC functionality with age. Within that context, we seek to identify mechanisms to restore aged SCs to their youthful state by modulating the reversible, epigenetic determinants of aged SC function.

Public Health Relevance

The mechanisms that control stem cell function are fundamental determinants of how tissues are maintained during normal activity, adapt in response to stress, and are repaired in response to injury. One of the hallmarks of aging is the decline in the ability of tissues to perform all of these functions. Therefore, understanding how stem cells change with age may provide insights into the basic mechanisms of aging. The studies of this proposal are designed to examine the molecular mechanisms that regulate muscle stem cell functions in adult mice and how those mechanisms change with age. We will focus on one particular biochemical pathway (the Notch signaling pathway) that we and others have studied in muscle stem cells. We will study what controls this pathway, and what cellular functions it influences when active. Finally, we will examine muscle in aged mice that have genetic alterations in the Notch pathway to determine if either enhancing or suppressing Notch signaling in muscle stem cells alters the aging of muscle. Ultimately, our goal is to identify ways to prevent the age-related decline in muscle function.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
5R37AG023806-10
Application #
8691631
Study Section
Cellular Mechanisms in Aging and Development Study Section (CMAD)
Program Officer
Williams, John
Project Start
2004-04-01
Project End
2015-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
10
Fiscal Year
2014
Total Cost
$277,835
Indirect Cost
$80,789
Name
Palo Alto Institute
Department
Type
DUNS #
624218814
City
Palo Alto
State
CA
Country
United States
Zip Code
94304
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Tang, Huibin; L Kennedy, Catherine; Lee, Myung et al. (2017) Smad3 initiates oxidative stress and proteolysis that underlies diaphragm dysfunction during mechanical ventilation. Sci Rep 7:14530
van Velthoven, Cindy T J; de Morree, Antoine; Egner, Ingrid M et al. (2017) Transcriptional Profiling of Quiescent Muscle Stem Cells In Vivo. Cell Rep 21:1994-2004
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Quarta, Marco; Cromie, Melinda; Chacon, Robert et al. (2017) Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss. Nat Commun 8:15613
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Luo, Dan; de Morree, Antoine; Boutet, Stephane et al. (2017) Deltex2 represses MyoD expression and inhibits myogenic differentiation by acting as a negative regulator of Jmjd1c. Proc Natl Acad Sci U S A 114:E3071-E3080
Du, Hongqing; Shih, Chung-Hsuan; Wosczyna, Michael N et al. (2017) Macrophage-released ADAMTS1 promotes muscle stem cell activation. Nat Commun 8:669
Mueller, Alisa A; van Velthoven, Cindy T; Fukumoto, Kathryn D et al. (2016) Intronic polyadenylation of PDGFR? in resident stem cells attenuates muscle fibrosis. Nature 540:276-279

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