Increased Physical Activity During Early Life Exacerbates High Fat Diet-Induced Bone Loss in Adult Mice

Abstract Objectives It has been recognized that mechanical stresses associated with physical activity (PA) have beneficial effects on increasing bone mineral density (BMD) and improving bone quality in humans and animal models. On the other hand, in rodents, high fat diet (HFD) and obesity increase bone marrow adiposity leading to increased production of pro-inflammatory cytokines that activate RANKL-induced bone resorption. In the current study, we investigated whether short-term increased PA via access to voluntary wheel running during early life has persistent effects on HFD-induced bone resorption. Methods Sixty (60) four-week-old male C57BL6/J mice were divided into two groups; without or with PA, access to voluntary running wheel (7 to 8 km per day) for 4 wks, with ad libitum access to control diet for all animals. After 4 wks with or without PA, mice were further subdivided into control diet or HFD groups for 8 wks, before all animals were switched back to control diet for an additional 4 wks. Mice from the HFD groups were significantly heavier, with more adiposity vs. control group at the 12 wk study time point, and returned to levels of mice with continues control diet at the 16 wk study time point. Results Using peripheral quantitative CT (pQCT) and micro-CT scan on tibias ex vivo, we determined that trabecular BMD and bone volume were significantly increased in animals after 4 wks of PA and control diet compared to sedentary animals without access to wheels. Eight weeks of HFD deteriorated bone development in mice, micro-CT showed 9% significant reduction on percentage of bone volume, and pQCT analysis showed 6% significant reduction of trabecular bone density of mice compared with those standard diet mice. Unexpectedly, early life PA exacerbated HFD-induced trabecular bone loss in adult mice. Early life PA accelerated HFD-induced osteoclastogenesis in adult mice. In accordance with these data, signal transduction studies revealed that HFD-induced Ezh2 and NFATc1, and IRF8 expression were amplified in non-adherent hematopoietic cells. Conclusions Increased PA in early life is capable of increasing bone mass; however, it alters the HFD-induced bone marrow hematopoietic cell differentiation program to exacerbate bone resorption if PA is halted. Funding Sources Supported in part by USDA-ARS Project 6026–51,000-010–05S.