L-BAIBA Synergizes with Sub-Optimal Mechanical Loading to Promote New Bone Formation.

The L-enantiomer of β-aminoisobutyric acid (BAIBA) is secreted by contracted muscle in mice, and exercise increases serum levels in humans. In mice, L-BAIBA reduces bone loss with unloading, but whether it can have a positive effect with loading is unknown. Since synergism can be more easily observed with sub-optimal amounts of factors/stimulation, we sought to determine whether L-BAIBA could potentiate the effects of sub-optimal loading to enhance bone formation. L-BAIBA was provided in drinking water to C57Bl/6 male mice subjected to either 7 N or 8.25 N of sub-optimal unilateral tibial loading for 2 weeks. The combination of 8.25 N and L-BAIBA significantly increased the periosteal mineral apposition rate and bone formation rate compared to loading alone or BAIBA alone. Though L-BAIBA alone had no effect on bone formation, grip strength was increased, suggesting a positive effect on muscle function. Gene expression analysis of the osteocyte-enriched bone showed that the combination of L-BAIBA and 8.25 N induced the expression of loading-responsive genes such as Wnt1 , Wnt10b , and the TGFb and BMP signaling pathways. One dramatic change was the downregulation of histone genes in response to sub-optimal loading and/or L-BAIBA. To determine early gene expression, the osteocyte fraction was harvested within 24 hours of loading. A dramatic effect was observed with L-BAIBA and 8.25 N loading as genes were enriched for pathways regulating the extracellular matrix ( Chad , Acan , Col9a2 ), ion channel activity ( Scn4b , Scn7a , Cacna1i ), and lipid metabolism ( Plin1 , Plin4 , Cidec ). Few changes in gene expression were observed with sub-optimal loading or L-BAIBA alone after 24 hours. These results suggest that these signaling pathways are responsible for the synergistic effects between L-BAIBA and sub-optimal loading. Showing that a small muscle factor can enhance the effects of sub-optimal loading of bone may be of relevance for individuals unable to benefit from optimal exercise. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.