Biology subjects

Santangelo, K. S.

Publications and source records attributed to Santangelo, K. S..

3 recordsLinked to original sources

bioRxiv2024

Impact of long-term rapamycin treatment on age-related osteoarthritis in common marmoset

PurposeGenetic deletion of mTOR has protected against post-traumatic osteoarthritis (OA) in male mice, however, effects of pharmacological mTOR-inhibition are equivocal and have not been tested in aging models nor in female subjects. Therefore, the goal of this study was to determine if mTOR-inhibition by rapamycin can modify OA pathology in aging non-human primates and female mice. MethodsCommon marmosets were administered oral rapamycin (1mg/kg/day) or vehicle starting near mid-life until death. Five-month-old, female C57BL/6J mice were treated with vehicle or rapamycin (IP, 2mg/kg, 3x/week) for 8-weeks following non-invasive ACL rupture. Knee OA pathology was assessed via microCT and histology. Phosphorylation of mTORC1 (p-RPS6S235/36) and mTORC2 (p-AktS473, p-NDRG1T638, p-PKCT348) substrates were evaluated via western blot in articular cartilage, meniscus, and/or infrapatellar fat pad. ATDC5 cells were cultured with rapamycin to determine time and dose effects on mTORC1/2 signaling. ResultsIn marmosets, rapamycin did not impact age-related radiographic OA severity or cartilage pathology but increased medial meniscus calcification and lowered lateral tibia subchondral thickness, particularly in females. In female mice, rapamycin worsened ACLR-induced meniscus calcification and cartilage pathology. In marmoset and mouse joint tissues, rapamycin inhibited mTORC1 and increased p-AktS473 but not p-NDRG1T638 or p-PKCT348. This mTOR signaling pattern was replicated in ATDC5 cells during exposure to low concentrations of rapamycin. ConclusionsRapamycin attenuated mTORC1 signaling with feedback activation of AktS473 in articular cartilage, meniscus, and/or infrapatellar fat pad and was accompanied by deleterious effects on meniscus calcification and/or cartilage pathology in female mice and common marmosets.

physiology↗

bioRxiv2021

Phytochemical Nrf2 activator attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a preclinical model of musculoskeletal aging

Musculoskeletal dysfunction is an age-related syndrome associated with impaired mitochondrial function and proteostasis. However, few interventions have tested targeting two drivers of musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a transcription factor that stimulates transcription of cytoprotective genes and improves mitochondrial function. We hypothesized daily treatment with a Nrf2 activator in Hartley guinea pigs, a model of age-related musculoskeletal dysfunction, attenuates the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis, preserving musculoskeletal function. We treated 2-month- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical Nrf2 activator PB125 (Nrf2a). Longitudinal assessments of voluntary mobility were measured using Any-Maze open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in permeabilized soleus muscles was measured using ex vivo high resolution respirometry. In both sexes, Nrf2a 1) increased electron transfer system capacity; 2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and 3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial, and cytosolic subfractions of the soleus. These improvements were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, these results demonstrate that treatment with an oral Nrf2 activator contributes to maintenance of skeletal muscle mitochondrial function and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these improvements are also accompanied by slowed progression of other aspects of musculoskeletal decline.

physiology↗

bioRxiv2021

Rapamycin induced hyperglycemia is associated with exacerbated age-related osteoarthritis

BackgroundThe objective of this study was to determine if mechanistic target of rapamycin (mTOR) inhibition with or without AMP-activated protein kinase (AMPK) activation can protect against primary, age-related OA. DesignDunkin-Hartley guinea pigs develop mild primary OA pathology by 5-months of age that progresses to moderate OA by 8-months of age. At 5-months, guinea pigs sacrificed as young control (n=3) or were fed either a control diet (n=8), a diet enriched with the mTOR-inhibitor rapamycin (Rap, 14ppm, n=8), or Rap with the AMPK-activator metformin (Rap+Met, 1000ppm, n=8) for 12 weeks. Knee joints were evaluated by OARSI scoring, micro-computed tomography, and immunohistochemistry. Glenohumeral articular cartilage was collected for western blotting. ResultsRap and Rap+Met treated guinea pigs displayed lower body weight than control. Rap and Rap+Met inhibited articular cartilage mTORC1 but not mTORC2 signaling. Rap+Met, but not Rap alone, stimulated AMPK. Despite lower body weight and articular cartilage mTORC1 inhibition, Rap and Rap+Met treated guinea pigs had greater OA severity in the medial tibial plateau due to articular cartilage structural damage and/or proteoglycan loss. Rap and Rap+Met increased plasma glucose compared to control. Plasma glucose concentration was positively correlated with proteoglycan loss, suggesting hyperglycemic stress may have contributed to worsened OA. ConclusionsThis is the first study to show that Rap induced increase in plasma glucose was associated with greater OA severity. Further, articular cartilage mTORC1 inhibition and bodyweight reduction by dietary Rap and Rap+Met did not protect against primary OA during the prevailing hyperglycemia.

physiology↗