Osteocyte energy metabolism in aging

PROJECT SUMMARY Aging is associated with negative effects on the skeletal system, leading to impaired bone health, increased frailty, and risk of musculoskeletal disorders. However, our current understanding of the mechanisms by which aging affects skeletal health is limited. Osteocytes are the most numerous and long-lived cells in bone and play key roles in maintaining bone mass by responding to anabolic signals such as mechanical loading. This response to loading is impaired in aged bone, by unknown mechanisms, leading to derangements in bone homeostasis. Energy metabolism is disrupted in many cells and tissues with aging, however regulation of energy metabolism in osteocytes and how this is affected during aging and by mechanical loading remains undefined. Our preliminary findings have identified that anabolic mechanical loading regulates energy metabolism in osteocytes in vitro and in vivo. Specifically, fatty acid β-oxidation is upregulated in response to strain, as are the key promoters of β-oxidation, peroxisome proliferator-activated receptor delta (Pparδ) and carnitine palmitoyltransferase 1 (Cpt1). Deletion of Pparδ in osteocytes in vivo inhibited β-oxidation and decreased bone mass in female mice but not males. Furthermore, β-oxidation is decreased in aged mouse bone compared to young animals, and pharmacological activation of PPARδ in aging mice improves bone health. These findings suggest important functions of osteocyte energy metabolism, and β-oxidation in particular, in the effects of aging and mechanical loading on bone. In this proposal, we will determine the role of osteocyte β-oxidation in the response to mechanical stimulation and the maintenance of bone health with aging. For these studies, we have generated mice with targeted deletion of Pparδ in osteocytes and will use these mice and ex vivo isolated osteocytes from young and aged mice to determine the function of β-oxidation in osteocytes. In Aim 1, we will determine the role of osteocyte β-oxidation in regulating bone health in young and aged mice. In Aim 2, we will determine how aging affects the metabolic response of osteocytes to mechanical loading and the role of PPARδ-driven β-oxidation in this process. In Aim 3, we will examine whether activation of PPARδ to increase β-oxidation in osteocytes can improve bone health in aged mice. The findings from the proposed studies will markedly increase the knowledge of osteocyte energy metabolism and define the role of PPARδ-driven β-oxidation in osteocytes and its function during aging and under mechanical loading.