Aging sarcopenia is a multifaceted health problem tiiat 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 conti^ction 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 infiuence muscle through yet unknown mechanisms. The major goal of Subproject 2 is to understand the communication from tiie 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. Furthemiore, 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 detennine 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.
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.
|Johnson, Mark L (2016) How rare bone diseases have informed our knowledge of complex diseases. Bonekey Rep 5:839|
|Zhu, Meiling; Sun, Ben-Hua; Saar, Katarzyna et al. (2016) Deletion of Rac in Mature Osteoclasts Causes Osteopetrosis, an Age-Dependent Change in Osteoclast Number, and a Reduced Number of Osteoblasts In Vivo. J Bone Miner Res 31:864-73|
|Gorski, Jeff P; Huffman, Nichole T; Vallejo, Julian et al. (2016) Deletion of Mbtps1 (Pcsk8, S1p, Ski-1) Gene in Osteocytes Stimulates Soleus Muscle Regeneration and Increased Size and Contractile Force with Age. J Biol Chem 291:4308-22|
|Duan, Peipei; Bonewald, L F (2016) The role of the wnt/Î²-catenin signaling pathway in formation and maintenance of bone and teeth. Int J Biochem Cell Biol 77:23-9|
|Maurel, Delphine B; Duan, Peipei; Farr, Joshua et al. (2016) Beta-Catenin Haplo Insufficient Male Mice Do Not Lose Bone in Response to Hindlimb Unloading. PLoS One 11:e0158381|
|Brotto, Marco; Bonewald, Lynda (2015) Bone and muscle: Interactions beyond mechanical. Bone 80:109-14|
|Prideaux, Matthew; Dallas, Sarah L; Zhao, Ning et al. (2015) Parathyroid Hormone Induces Bone Cell Motility and Loss of Mature Osteocyte Phenotype through L-Calcium Channel Dependent and Independent Mechanisms. PLoS One 10:e0125731|
|Lara-Castillo, N; Kim-Weroha, N A; Kamel, M A et al. (2015) In vivo mechanical loading rapidly activates Î²-catenin signaling in osteocytes through a prostaglandin mediated mechanism. Bone 76:58-66|
|Johnson, Mark L (2015) Unlocking the sost gene. J Bone Miner Res 30:397-9|
|Mo, Chenglin; Zhao, Ruonan; Vallejo, Julian et al. (2015) Prostaglandin E2 promotes proliferation of skeletal muscle myoblasts via EP4 receptor activation. Cell Cycle 14:1507-16|
Showing the most recent 10 out of 27 publications