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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, 40min/session) for 6weeks. 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. [Copyright &y& Elsevier]