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- Title
Rapamycin Affects Palmitate-Induced Lipotoxicity in Osteoblasts by Modulating Apoptosis and Autophagy.
- Authors
Saedi, Ahmed Al; Goodman, Craig A.; Myers, Damian E.; Hayes, Alan; Duque, Gustavo; Al Saedi, Ahmed; A Goodman, Craig; E Myers, Damian
- Abstract
Bone marrow fat infiltration is one of the hallmarks of aging and osteoporotic bones. Marrow adipocytes produce substantial amounts of palmitic acid (PA). PA is toxic to bone-forming osteoblasts in vitro, affecting their differentiation, function, and survival. Since rapamycin (RAP)-induced inhibition of target of rapamycin complex 1 (mTORC1) activates autophagy and prevents apoptosis, we hypothesized that RAP may preserve osteoblast viability and reduce PA-induced lipotoxicity. Normal human osteoblasts were incubated with RAP in the presence of a lipotoxic concentration of PA or vehicle for 24 and 48 hours. Expression of LC3 protein levels and the phosphorylation of the direct mTORC1 target p70S6K1-T389 were quantified by Western blot. Lysosomes and autophagosomes were studied using confocal fluorescence imaging, lysotracker, and live-cell imaging. RAP reduced PA-induced apoptosis. In addition, PA-induced autophagosome formation increased substantially over the time-course, an effect that was significantly regulated by the presence of RAP in the media. In addition, LC3I/II ratios were higher in PA-induced cells with RAP whereas p70S6K1-T389 were lower in PA and RAP together. In summary, this study highlights the role of the RAP-sensitive mTORC1 pathway in normal human osteoblasts under lipotoxic conditions. RAP-associated therapies could, potentially, be targeted for specific roles in osteoporosis and aging bone.
- Subjects
OSTEOBLASTS; RAPAMYCIN; PALMITIC acid; APOPTOSIS; BONE marrow
- Publication
Journals of Gerontology Series A: Biological Sciences & Medical Sciences, 2020, Vol 75, Issue 1, p58
- ISSN
1079-5006
- Publication type
journal article
- DOI
10.1093/gerona/glz149