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 #
5P01AG036675-02
Application #
8377778
Study Section
Special Emphasis Panel (ZAG1-ZIJ-8)
Project Start
Project End
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$211,623
Indirect Cost
$70,384
Name
Georgia Regents University
Department
Type
DUNS #
966668691
City
Augusta
State
GA
Country
United States
Zip Code
30912
Kolhe, Ravindra; Mondal, Ashis K; Pundkar, Chetan et al. (2018) Modulation of miRNAs by Vitamin C in Human Bone Marrow Stromal Cells. Nutrients 10:
Yu, Kanglun; Sellman, David P; Bahraini, Anoosh et al. (2018) Mechanical loading disrupts osteocyte plasma membranes which initiates mechanosensation events in bone. J Orthop Res 36:653-662
Kesterke, Matthew J; Judd, Margaret A; Mooney, Mark P et al. (2018) Maternal environment and craniofacial growth: geometric morphometric analysis of mandibular shape changes with in utero thyroxine overexposure in mice. J Anat 233:46-54
Howie, R Nicole; Herberg, Samuel; Durham, Emily et al. (2018) Selective serotonin re-uptake inhibitor sertraline inhibits bone healing in a calvarial defect model. Int J Oral Sci 10:25
Elsayed, Ranya; Abraham, Pheba; Awad, Mohamed E et al. (2018) Removal of matrix-bound zoledronate prevents post-extraction osteonecrosis of the jaw by rescuing osteoclast function. Bone 110:141-149
Murphy, Cameron; Withrow, Joseph; Hunter, Monte et al. (2018) Emerging role of extracellular vesicles in musculoskeletal diseases. Mol Aspects Med 60:123-128
Roser-Page, Susanne; Vikulina, Tatyana; Yu, Kanglun et al. (2018) Neutralization of CD40 ligand costimulation promotes bone formation and accretion of vertebral bone mass in mice. Rheumatology (Oxford) 57:1105-1114
Bollag, Wendy B; Choudhary, Vivek; Zhong, Qing et al. (2018) Deletion of protein kinase D1 in osteoprogenitor cells results in decreased osteogenesis in vitro and reduced bone mineral density in vivo. Mol Cell Endocrinol 461:22-31
Kim, Beom-Jun; Lee, Seung Hun; Kwak, Mi Kyung et al. (2018) Inverse relationship between serum hsCRP concentration and hand grip strength in older adults: a nationwide population-based study. Aging (Albany NY) 10:2051-2061
Kim, B-J; Lee, S H; Isales, C M et al. (2018) The positive association of total protein intake with femoral neck strength (KNHANES IV). Osteoporos Int 29:1397-1405

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