Osteoporosis and sarcopenia are major clinical problems in the aging population and in many patients these two conditions occur concurrently. This combination results in instability, susceptibility to falls and consequently to fracture, morbidity, and premature death. It is unclear whether one condition precedes the other or if the conditions are linked. The traditional view of skeletal muscle and bone interaction is that skeleta muscle loads bone and bone provides an attachment site for muscle. The mechanical perspective implies that as muscle function declines, this would result in decreased loading of the skeleton and therefore would result in a decrease in bone mass. However, muscle atrophy alone cannot fully explain the totality of osteoporosis and, reciprocally, aging associated decreases in bone mass do not fully explain sarcopenia. Our preliminary data suggest that soluble factors may play a role in crosstalk between bone and muscle. The hypothesis for the Program Project is that there is an endocrine loop between muscle and bone through the production of systemic factors by each tissue that are critical regulatory factors for function in the other tissue. The osteocyte response to mechanical loading by the action of muscles is modified by these muscle secreted factors. In turn, the osteocyte regulates both osteoblast and muscle cell function through modulators of the Wnt/beta-catenin pathway. A series of experiments to examine the role of the osteocyte in muscle-bone crosstalk and what happens with aging are proposed.
The specific aims are 1). Determine the effects of muscle on osteoblast/osteocyte function with aging, 2). Determine the effects of osteocytes on muscle mass and function with aging, 3). Examine osteocyte regulation of osteoblast function with aging and how this is regulated or influenced by muscle-bone crosstalk, and 4). Determine the effects of mechanical loading on osteocyte regulation of muscle mass and function with aging. This program project is innovative in concept, preliminary data, approach, tools, interdisciplinarity, and cadre of investigators. The results of these experiments should lead to novel therapeutics for the prevention and treatment of both osteoporosis and sarcopenia.
The traditional view of the muscle-bone relationship is that muscle functions to apply load to the skeleton and bone provides an attachment site for skeletal muscle. Our data suggests that soluble factors from bone cells including osteocytes within their lacunocanalicular network can target muscle. Basic understanding of how bone cells respond to mechanical load and the cross-talk with associated muscles will help to define therapeutic strategies for combating changes in skeletal microarchitecture and muscle weakness. REVIEW OF INDIVIDUAL COMPONENTS OF THE PROGRAM PROJECT CORE A: ADMINISTRATIVE CORE;LYNDA F. BONEWALD, CORE LEADER (CL) DESCRIPTION (provided by applicant): The main objective of the Administrative Core is to provide leadership, coordination of effort, statistical advice, managerial support, and facilitatio for the overall operation of the program project grant. The program project grant will be under the directorship of Dr. Lynda F. Bonewald and Co-Director, Dr. Mark Johnson. Dr. Bonewald has been the director of a very successful program project entitled Osteocyte Function and Response to Mechanical Loading for 11 years and therefore has the skills and experience to insure the success of this application. The specific aims of this core are: 1).To provide leadership, management, and statistical skills necessary to coordinate and to experimentally design the activities of the program. 2). To coordinate and schedule the activities of the Internal and External Advisory Boards, the PIs meetings, and any support consultants. 3). To coordinate scientific presentations locally and at national and international meetings. 4). To provide for the development and education of students and postdoctoral fellows involved in the program including seminars and data meetings. 5). To provide staff support in the form of budgetary support and review, preparation of grant reports, written communications, manuscripts, and other supportive activities. The program project will contain four subprojects, an administrative core and two support cores, the Muscle/Bone Phenotyping Core and the Transgenic and Mechanical Loading Core. The Director, Co-Director, Principal Investigators and Core Directors will meet with the Internal Advisory Council at least twice a year and with the External Advisory Board once a year. This core will insure the success of each subproject and core.
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|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|
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|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|
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