title: Attenuated anabolic response to exercise in lamin A/C haploinsufficient mice.
abstract: The ability of exercise to decrease fat mass and increase bone mass occurs through mechanical biasing of mesenchymal stem cells away from adipogenesis and toward osteoblastogenesis. The mechanism explaining this effect remains poorly understood. Lamin A/C knockdown inhibits osteoblastogenesis while favors adipogenesis in vitro. In this study, we hypothesized that the presence of lamin A/C is required for the anabolic response of bone during exercise. Three-month-old female lamin A/C haploinsufficient (Lmna(+/-)) mice were exposed to strenuous maximal exercise protocol (2 sessions/week, 40 min/session) for 6 weeks. Wild type (WT) (exercise and sedentary) and sedentary Lmna(+/-) mice were used as controls. To determine changes in bone microarchitecture and cell numbers, distal femur was analyzed by microCT and histomorphometry respectively. Finally, levels of expression of nuclear β-catenin and sclerostin, two proteins involved in the anabolic response to exercise, were determined by immunofluorescence. Histomorphometry analysis showed a significant increase in bone volume fraction (BV/TV) in exercised vs. sedentary WT mice. In contrast, exercised Lmna(+/-) mice showed a significant reduction in microarchitecture as compared with sedentary Lmna(+/-) controls including trabecular and cortical thinning. In addition, we found a significant increase in bone cells number in exercised vs. sedentary WT mice whereas exercised Lmna(+/-) mice showed a significant reduction in osteoblasts and osteocytes number as compared with sedentary Lmna(+/-) controls. Finally, levels of activated β-catenin in osteoblasts and osteocytes were significantly decreased while sclerostin expression was increased in exercised Lmna(+/-) mice as compared with exercised WT controls. In summary, our data indicate that the presence of lamin A/C is required for the anabolic effect of exercise on bone thus suggesting a new important role of lamin A/C in bone biology.
authors.affiliation: Ageing Bone Research Program, Nepean Clinical School, University of Sydney, Penrith, NSW 2751, Australia. gustavo.duque@sydney.edu.au
authors.forename: Gustavo
authors.initials: G
authors.lastname: Duque
authors.forename: Wei
authors.initials: W
authors.lastname: Li
authors.forename: Li Sze
authors.initials: LS
authors.lastname: Yeo
authors.forename: Christopher
authors.initials: C
authors.lastname: Vidal
authors.forename: Diane
authors.initials: D
authors.lastname: Fatkin
mesh_terms: D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D002467:Cell Nucleus / Q000378:metabolism; D005260:Female; D005269:Femur / Q000378:metabolism / Q000648:ultrastructure; D057895:Haploinsufficiency; D034904:Lamin Type A / Q000235:genetics* / Q000378:metabolism*; D008660:Metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010805:Physical Conditioning, Animal / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D034904:Lamin Type A; D051176:beta Catenin; C440308:lamin C