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

Abstract

SUMMARY 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.

Irisin Mediates Effects on Bone and Fat via αV Integrin Receptors

“…The cell images were taken using Nikon Eclipse TE300 inverted fluorescence microscope with a Photometrics Coolsnap EZ cooled CCD camera and analyzed using ImageJ. Percentage of cell death was calculated as EthD-1 positive cells divided by the total number of cells stained with 5µg/mL Hoechst 33342 (ThermoFisher Scientific, H3570) as a nuclear counterstain (Kitase et al, 2018). …”

“…For anti-apoptosis assay, Percentage of cell death was calculated as EthD-1 positive cells divided by the total number of cells stained with 5µg/mL Hoechst 33342 (ThermoFisher Scientific, H3570) as a nuclear counterstain (Kitase et al, 2018). …”

“…Osteocytes are lost with aging and their death is thought to be an important component in the pathogenesis of age-related osteoporosis. Treatment with hydrogen peroxide has been previously used in these osteocyte-like cells as an assay for apoptotic death (Kitase et al, 2018). Therefore, MLO-Y4 cells were treated with irisin in the presence of hydrogen peroxide at amounts sufficient to induce apoptosis (Figure 1A).…”

Myokines in skeletal muscle physiology and metabolism: Recent advances and future perspectives

“…7,25,65 BAIBA consists of two enantiomers, L-BAIBA and D-BAIBA. 7,25,65 The increase in PGC-1α observed during physical exercise results in a concomitant increase in BAIBA serum levels. 66 D-BAIBA is produced in cytosol as an intermediate product of thymine degradation, and its degradation also occurs in mitochondria through the action of an enzyme found in liver and kidneys, alanine:glyoxylate aminotransferase 2 (AGXT2).…”

“…The production and degradation of L-BAIBA is catalysed by 4-aminobutyrate aminotransaminase (ABAT), a mitochondrial enzyme which is expressed mainly in the brain, kidney, liver and muscles. 7,25,65 The identification of BAIBA as a PGC-1α-mediated and exercise-induced signal has significant implications for our understanding of muscle biology and its protective role against the development of metabolic diseases. 66 L-BAIBA (hereafter referred to as BAIBA) being the biologically active form, is produced by contracting muscle regardless of fibre type, gender and age.…”