β-aminoisobutyric Acid, l-BAIBA, Is a Muscle-Derived Osteocyte Survival Factor

Exercise has beneficial effects on metabolism and on tissues. The exercise-induced muscle factor β-aminoisobutyric acid (BAIBA) plays a critical role in the browning of white fat and in insulin resistance. Here we show another function for BAIBA, that of a bone-protective factor that prevents osteocyte cell death induced by reactive oxygen species (ROS). l-BAIBA was as or more protective than estrogen or N-acetyl cysteine, signaling through the Mas-Related G Protein-Coupled Receptor Type D (MRGPRD) to prevent the breakdown of mitochondria due to ROS. BAIBA supplied in drinking water prevented bone loss and loss of muscle function in the murine hindlimb unloading model, a model of osteocyte apoptosis. The protective effect of BAIBA was lost with age, not due to loss of the muscle capacity to produce BAIBA but likely to reduced Mrgprd expression with aging. This has implications for understanding the attenuated effect of exercise on bone with aging. [Display omitted] •The muscle metabolite l-BAIBA protects osteocytes from ROS-induced cell death•l-BAIBA prevents mitochondrial breakdown in osteocytes•The effects of l-BAIBA are mediated via MRGPRD that decreases with aging•In vivo, l-BAIBA reduces bone and muscle loss resulting from immobilization Kitase et al. show that the muscle-derived factor l-BAIBA signals through the MRGPRD to prevent osteocyte cell death induced by reactive oxygen species, a function lost with aging.