Aging sarcopenia is a multifaceted health problem that is further complicated since sarcopenia and osteoporosis are normally related or simultaneous conditions. The current interpretation is that sarcopenia contributes to osteoporosis because muscles, through the loading forces of contraction and stretch, are anabolic stimulators of bones. This view essentially negates the potential for signaling from bone to muscle. Nevertheless, highly innovative, emerging new research has led to the discovery of endocrine functions of bone that could potentially influence muscle through yet unknown mechanisms. The major goal of Subproject 2 is to understand the communication from the osteocyte to muscle, and how aging affects such communication. Our preliminary studies strongly support our concept that bone signals to muscle by modulating muscle myogenic differentiation. Intracellular calcium homeostasis and contractile function. Furthermore, our data now suggests that this bone-muscle signaling Is mediated by the Wnt/b-catenin pathway, and of utmost importance, that this signaling Is compromised during aging. Therefore, we hypothesize that osteocytes signal to muscles via factors that modulate the Wnt/b-catenin pathway and are important for myogenic differentiation, Ca2-*- homeostasis, and contractile function. During aging the signaling from osteocytes to muscles is compromised, thereby contributing to the aging-related decline in muscle function. We will test this hypothesis by tiie following specific aims:
Specific Aim 1 : To determine the molecular mechanisms by which osteocytes modulate muscle myogenic differentiation, and Ca2-i- homeostasis as a function of age.
Specific Aim 2 : To determine how osteocyte factors modulate muscle contractility as a function of age. These studies are the first to propose to systematically investigate the contribution of the Wnt/beta-catenin signaling pathway to the aging decline in muscle function by studying the bone-muscle crosstalk at the cellular and molecular levels. Such knowledge will assist with the identification of new targets for development of therapeutic interventions for sarcopenia and osteoporosis.

Public Health Relevance

Aging sarcopenia (muscle atrophy and weakness) is a serious health problem that afflicts more than 40 million Americans. Sarcopenia is further complicated since sarcopenia and osteoporosis are normally simultaneous conditions. Our studies offer a new interpretation for the effects of bones on muscles and such knowledge will assist with the discovery of new therapeutic interventions for sarcopenia and osteoporosis.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Program Projects (P01)
Project #
5P01AG039355-03
Application #
8663806
Study Section
Special Emphasis Panel (ZAG1-ZIJ-9)
Project Start
Project End
Budget Start
2014-05-01
Budget End
2015-04-30
Support Year
3
Fiscal Year
2014
Total Cost
$282,359
Indirect Cost
$94,120
Name
University of Missouri Kansas City
Department
Type
DUNS #
010989619
City
Kansas City
State
MO
Country
United States
Zip Code
64110
Thiagarajan, Ganesh; Lu, Yunkai; Dallas, Mark et al. (2014) Experimental and finite element analysis of dynamic loading of the mouse forearm. J Orthop Res 32:1580-8
Huang, Jian; Hsu, Yi-Hsiang; Mo, Chenglin et al. (2014) METTL21C is a potential pleiotropic gene for osteoporosis and sarcopenia acting through the modulation of the NF-?B signaling pathway. J Bone Miner Res 29:1531-40
Javaheri, Behzad; Stern, Amber Rath; Lara, Nuria et al. (2014) Deletion of a single *-catenin allele in osteocytes abolishes the bone anabolic response to loading. J Bone Miner Res 29:705-15
Pan, Zui; Brotto, Marco; Ma, Jianjie (2014) Store-operated Ca2+ entry in muscle physiology and diseases. BMB Rep 47:69-79
Dallas, Sarah L; Prideaux, Matthew; Bonewald, Lynda F (2013) The Osteocyte: An Endocrine Cell and More. Endocr Rev :