LncRNA NEAT1 controls the lineage fates of BMSCs during skeletal aging by impairing mitochondrial function and pluripotency maintenance

Aged bone marrow mesenchymal stem cells (BMSCs) exhibit aberrant self-renewal and lineage specification, which contribute to imbalanced bone-fat and progressive bone loss. In addition to known master regulators of lineage commitment, it is crucial to identify pivotal switches governing the specific differentiation fate of aged BMSCs. Here, we profiled differences in epigenetic regulation between adipogenesis and osteogenesis and identified super-enhancer associated lncRNA nuclear-enriched abundant transcript 1 (NEAT1) as a key bone-fat switch in aged BMSCs. We validated that NEAT1 with high enhancer activity was transcriptionally activated by ATF2 and directed aged BMSCs to a greater propensity to differentiate toward adipocytes than osteoblasts by mediating mitochondrial function. Furthermore, we confirmed NEAT1 as a protein-binding scaffold in which phosphorylation modification of SOX2 Ser249/250 by CDK2 impaired SOX2/OCT4 complex stability and dysregulated downstream transcription networks of pluripotency maintenance. In addition, by sponging miR-27b-3p, NEAT1 upregulated BNIP3L, BMP2K, and PPARG expression to shape mitochondrial function and osteogenic/adipogenic differentiation commitment, respectively. In extracellular communication, NEAT1 promoted CSF1 secretion from aged BMSCs and then strengthened osteoclastic differentiation by extracellular vesicle delivery. Notably, Neat1 small interfering RNA delivery induced increased bone mass in aged mice and decreased fat accumulation in the bone marrow. These findings suggest that NEAT1 regulates the lineage fates of BMSCs by orchestrating mitochondrial function and pluripotency maintenance, and might be a potential therapeutic target for skeletal aging.

ACCELERATED CHILDHOOD SKELETAL AGING IS PROTECTIVE OF DEVELOPMENT OF SARCOPENIA IN LATER LIFE

Sarcopenia is an age-related loss of muscle mass and strength that has a multitude of adverse sequelae. Similar to other aging-related phenomenon, sarcopenia is likely the product of inputs that begin in utero and continue throughout the lifespan. We hypothesized that patterns of childhood skeletal growth predict sarcopenia status later in life. Data are from N=202 lifelong participants of the Fels Longitudinal Study (median lifetime visits=33). At the sarcopenia measure visit, participants were aged 65.8 + 10.3 years, 54% female, with body mass index of 27.5 + 4.9. Sarcopenia was defined using published sex-specific cutpoints from dual energy x-ray absorptiometry quantified appendicular lean mass/height2. Childhood skeletal age was calculated from serial hand-wrist radiographs (FELS method). Residual skeletal aging (RSA) was calculated as skeletal age minus predicted chronological age at peak height growth velocity during adolescence. RSA variance was similar in both sexes, with a range of -2 (delayed skeletal aging) to +2 years (accelerated skeletal aging). In older age, 6% of males and 22% of females exhibited sarcopenia. In multivariate logistic regression models controlling for age, self-reported physical activity, and grip strength (all measured at sarcopenia visit), accelerated RSA was protective of sarcopenia (Adjusted OR=0.58; 95% CI: 0.35-0.94). This is the first study to link childhood skeletal maturation to sarcopenia later in life. Biological pathways that explain this association likely include physiological, environmental, and genetic factors that facilitate communication between bone and muscle, and span the life course. Determining their influence is the next important step in this work.