Aging is associated with a loss of body weight, often referred to as the anorexia of aging, which is accompanied by loss of muscle mass (sarcopenia) and bone loss (osteoporosis). The cytokine-like hormone leptin is secreted from peripheral fissues including fat and skeletal muscle, and leptin deficiency is associated with decreased bone mass as well as loss of muscle mass and strength. We have identified an animal model, the aged C57BL/6 mouse, that shares a number of key features in common with the aging human musculoskeletal system: an age-related decline in serum lepfin, decline in serum IGF-1, decreased muscle mass, and loss of bone density. We have also found that leptin treatment increases serum IGF-1 and muscle mass in aged mice. Our preliminary studies therefore suggest that the decline in musculoskeletal funcfion that occurs with aging is due in part to alterations in the lepfin-IGFI axis. We also show for the first time that musculoskeletal tissues from aged mice show increased expression of microRNAs (miRNAs) targefing leptin. The central hypothesis of our proposal is that leptin is a key factor linking nutrient intake with normal musculoskeletal funcfion, but leptin signaling in musculoskeletal tissues is altered with age, contributing direcfiy to age-related loss of muscle and bone.
Specific Aim 1 will identify cell- and tissue-specific alterations in leptin expression with age, and will define the role of circulating leptin in regulating age-associated changes in the local and systemic secretion of IGF-1.
Aim 2 will determine how aging and nutrient intake alter leptin sensitivity and the expression of functional leptin receptors in muscle and bone cells.
Aim 3 will identify fissue-specific microRNAs that are altered with age and leptin treatment, and functional in vitro studies will be used to define the role of these small molecules in the proliferation and differentiation of myogenic and osteogenic cells. The proposed studies will therefore define new therapeutic targets and diagnostic biomarkers related to sarcopenia and fall risk that can be developed to improve upon exisfing fracture treatment and prevention strategies.

Public Health Relevance

The research proposed in this application will investigate the basic mechanisms by which aging alters normal leptin signaling in muscle and bone, and as such will contribute directly to the development of new therapeutic strategies and diagnostic biomarkers related to fall risk and debilitating bone fractures.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG036675-03
Application #
8463097
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
3
Fiscal Year
2013
Total Cost
$199,098
Indirect Cost
$66,366
Name
Georgia Regents University
Department
Type
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
El Refaey, Mona; Zhong, Qing; Hill, William D et al. (2014) Aromatic amino acid activation of signaling pathways in bone marrow mesenchymal stem cells depends on oxygen tension. PLoS One 9:e91108
Herberg, Samuel; Kondrikova, Galina; Periyasamy-Thandavan, Sudharsan et al. (2014) Inkjet-based biopatterning of SDF-1? augments BMP-2-induced repair of critical size calvarial bone defects in mice. Bone 67:95-103
Pan, Guodong; Cao, Jay; Yang, Nianlan et al. (2014) Role of glucocorticoid-induced leucine zipper (GILZ) in bone acquisition. J Biol Chem 289:19373-82
Refaey, Mona El; Zhong, Qing; Ding, Ke-Hong et al. (2014) Impact of dietary aromatic amino acids on osteoclastic activity. Calcif Tissue Int 95:174-82
Herberg, Samuel; Shi, Xingming; Johnson, Maribeth H et al. (2013) Stromal cell-derived factor-1? mediates cell survival through enhancing autophagy in bone marrow-derived mesenchymal stem cells. PLoS One 8:e58207
Arounleut, Phonepasong; Bialek, Peter; Liang, Li-Fang et al. (2013) A myostatin inhibitor (propeptide-Fc) increases muscle mass and muscle fiber size in aged mice but does not increase bone density or bone strength. Exp Gerontol 48:898-904
Bollag, Wendy B; Isales, Carlos M (2013) GRowing an epidermal tumor. J Invest Dermatol 133:2659-62
Fulzele, Sadanand; Chothe, Paresh; Sangani, Rajnikumar et al. (2013) Sodium-dependent vitamin C transporter SVCT2: expression and function in bone marrow stromal cells and in osteogenesis. Stem Cell Res 10:36-47
Herberg, Samuel; Fulzele, Sadanand; Yang, Nianlan et al. (2013) Stromal cell-derived factor-1* potentiates bone morphogenetic protein-2-stimulated osteoinduction of genetically engineered bone marrow-derived mesenchymal stem cells in vitro. Tissue Eng Part A 19:1-13
Bowser, Matthew; Herberg, Samuel; Arounleut, Phonepasong et al. (2013) Effects of the activin A-myostatin-follistatin system on aging bone and muscle progenitor cells. Exp Gerontol 48:290-7

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