With aging, the skeleton decreases In mass and Increases In fragility and susceptibility to fracture and it is not clear why exercise becomes less effective with aging. The osteocyte is not only a mechanosensory cell that responds to mechanical load, but also a source of factors that regulate osteoclasts and osteoblasts and act as endocrine cells to regulate other organs. Like osteocytes, muscle is also a source of signaling factors, tenned 'myokines'. Therefore, we hypothesize that active muscle not only loads the bone, but also sends soluble signals that have beneficial synergistic effects on bone cells, especially osteocytes. Our exciting data show that conditioned media (CM) from differentiated C2C12 myotubes protects osteocytes from the apoptotic effects of glucocorticoid. Interestingly, CM from differentiated myotubes had a more potent anti- apoptotic effect than CM from undifferentiated myoblasts. We have also found that myotube CM enhances osteocyte responses to shear stress, including prostaglandin production, t>-catenin translocation to the nucleus, and Akt phosphorylation. These results were confirmed using CM from isolated whole muscle explants of soleus and extensor digitomm longus muscle from 5 month old mice, which had similar protective anti-apoptotic effects on osteocytes. In striking contrast, muscle explant CM from aged 22 month old mice actually induced osteocyte cell death. Our overall hypothesis is that muscle can signal bone cells independent of the effect of loading on the skeleton and during aging, positive muscle signaling declines or converts to negative signals contributing to the aging-related decline in bone cell function. The following specific aims are proposed: To determine the effects of muscle soluble Actors on osteocyte viability and function and to determine how aging affects the ability of muscle cells to regulate osteocyte function. The completion of these specific aims will significantly advance the field of musculoskeletal biology. Identification of osteocyte viability factors produced by young muscle and of osteocyte apoptotic factors produced by aged muscle is novel and paradigm shifting. Characterizing these muscle signaling factors and their effects on bone cells should lead to novel therapeutics for treatment of both bone and muscle loss with age.

Public Health Relevance

Osteoporosis and aging sarcopenia, usually occur concurrently with age and is a major public health problem in the United States. Our goal is to Identify molecular mechanisms that contribute to loss of bone mass with aging, which will allow the development of effective treatments and the improvement in quality of life for the aging population.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG039355-02
Application #
8460477
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9)
Project Start
Project End
Budget Start
2013-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2013
Total Cost
$302,845
Indirect Cost
$100,948
Name
University of Missouri Kansas City
Department
Type
DUNS #
010989619
City
Kansas City
State
MO
Country
United States
Zip Code
64110
Bonewald, Lynda (2018) Use it or lose it to age: A review of bone and muscle communication. Bone 120:212-218
Kitase, Yukiko; Vallejo, Julian A; Gutheil, William et al. (2018) ?-aminoisobutyric Acid, l-BAIBA, Is a Muscle-Derived Osteocyte Survival Factor. Cell Rep 22:1531-1544
Pin, Fabrizio; Barreto, Rafael; Kitase, Yukiko et al. (2018) Growth of ovarian cancer xenografts causes loss of muscle and bone mass: a new model for the study of cancer cachexia. J Cachexia Sarcopenia Muscle 9:685-700
Morris, Josephine L; Cross, Stephen J; Lu, Yinhui et al. (2018) Live imaging of collagen deposition during skin development and repair in a collagen I - GFP fusion transgenic zebrafish line. Dev Biol 441:4-11
Tiede-Lewis, LeAnn M; Xie, Yixia; Hulbert, Molly A et al. (2017) Degeneration of the osteocyte network in the C57BL/6 mouse model of aging. Aging (Albany NY) 9:2190-2208
Wang, Zhiying; Bian, Liangqiao; Mo, Chenglin et al. (2017) Targeted quantification of lipid mediators in skeletal muscles using restricted access media-based trap-and-elute liquid chromatography-mass spectrometry. Anal Chim Acta 984:151-161
Jähn, Katharina; Kelkar, Shilpa; Zhao, Hong et al. (2017) Osteocytes Acidify Their Microenvironment in Response to PTHrP In Vitro and in Lactating Mice In Vivo. J Bone Miner Res 32:1761-1772
Huang, Jian; Romero-Suarez, Sandra; Lara, Nuria et al. (2017) Crosstalk between MLO-Y4 osteocytes and C2C12 muscle cells is mediated by the Wnt/?-catenin pathway. JBMR Plus 1:86-100
Bonewald, Lynda F (2017) The Role of the Osteocyte in Bone and Nonbone Disease. Endocrinol Metab Clin North Am 46:1-18
Vemula, Harika; Kitase, Yukiko; Ayon, Navid J et al. (2017) Gaussian and linear deconvolution of LC-MS/MS chromatograms of the eight aminobutyric acid isomers. Anal Biochem 516:75-85

Showing the most recent 10 out of 39 publications