Short-term increased physical activity during early life affects high-fat diet-induced bone loss in young adult mice

Authors: CHEN, JIN-RAN - Arkansas Children'S Nutrition Research Center (ACNC); LAZARENKO, OXANA - Arkansas Children'S Nutrition Research Center (ACNC); CARVALHO, EUGENIA - Arkansas Children'S Nutrition Research Center (ACNC); BLACKBURN, MICHAEL - Arkansas Children'S Nutrition Research Center (ACNC); SHANKAR, KARTIK - University Arkansas For Medical Sciences (UAMS); WANKHADE, UMESH - Arkansas Children'S Nutrition Research Center (ACNC); BORSHEIM, ELISABET - Arkansas Children'S Nutrition Research Center (ACNC)

Submitted to: JBMR Plus
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 4/21/2021
Publication Date: 5/14/2021
Citation: Chen, J., Lazarenko, O.P., Carvalho, E., Blackburn, M.L., Shankar, K., Wankhade, U.D., Borsheim, E. 2021. Short-term increased physical activity during early life affects high-fat diet-induced bone loss in young adult mice. JBMR Plus. https://doi.org/10.1002/jbm4.10508.
DOI: https://doi.org/10.1002/jbm4.10508

Interpretive Summary: Increased physical activity (PA) has beneficial effects on increasing bone mineral density (BMD) and improving bone quality. On the other hand, chronic high fat diet (HFD) intake and obesity tend to have negative effects on bone. We investigated if short-term increased PA during early life has persistent and protective effects on ameliorating HFD-induced negative effects on bone in mice. Sixty (60) four-week-old male C57BL6/J mice were divided into two groups post-weaning: without or with PA [access to voluntary running wheel (7 to 8 km per day)] for 4 wks. After 4 wks with or without PA, mice were further subdivided into control diet or HFD groups for 8 wks, and then all animals were switched back to control diet for an additional 4 wks. As expected, mice from the HFD groups were significantly heavier and obese; however, after 4 wks of a switch back to control diet their body weights returned to normal levels. Using instruments called micro-CT and peripheral quantitative CT (pQCT) to measure bone outcomes in tibia and spine, we determined that bone mass was significantly increased with PA in control diet animals compared to sedentary animals without access to wheels, confirming a positive effect of exercise on bone health. Such effects of PA on bone were sustained even after ceasing PA in adult mice. Eight weeks of HFD deteriorated bone development in mice. Unexpectedly, early life PA did not prevent persistent effects of HFD on deteriorating bone quality, and in fact exacerbated HFD-induced increased bone resorption. In conclusion, increased PA in early life is capable of increasing bone mass; however, it alters the HFD-induced bone development program to exacerbate obesity-associated bone issues in mice. The studies support the idea that early-life exercise is healthy for bone and has positive effects long-term, but diet and obesity status strongly influence the net effect of physical activity on bone.

Technical Abstract: Mechanical stresses associated with physical activity (PA) have beneficial effects on increasing bone mineral density (BMD) and improving bone quality. On the other hand, high fat diet (HFD) and obesity tend to have negative effects on bone, by increasing bone marrow adiposity leading to increased excretion of pro-inflammatory cytokines, which 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 and protective effects on HFD-induced bone resorption. Sixty (60) four-week-old male C57BL6/J mice were divided into two groups post-weaning: without or with PA [access to voluntary running wheel (7 to 8 km per day)] for 4 wks. After 4 wks with or without PA, mice were further subdivided into control diet or HFD groups for 8 wks, and then all animals were switched back to control diet for an additional 4 wks. Mice from the HFD groups were significantly heavier and obese; however, after 4 wks of additional control diet their body weights returned to levels of mice on continuous control diet. Using micro-CT and confirmed by peripheral quantitative CT (pQCT) scan on tibia and spine ex vivo, we determined that bone volume and trabecular BMD were significantly increased with PA in control diet animals compared to sedentary animals without access to wheels, and such anabolic effects of PA on bone were sustained after ceasing PA in adult mice. Eight weeks of HFD deteriorated bone development in mice. Unexpectedly, early life PA did not prevent persistent effects of HFD on deteriorating bone quality, and in fact exacerbated HFD-induced inflammation, osteoclastogenesis and trabecular bone loss in adult mice. In accordance with these data, signal transduction studies revealed that HFD-induced Ezh2, DNMT3a and NFATc1 expression were amplified in non-adherent hematopoietic cells. In conclusion, short-term 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 increased bone resorption if PA is halted.