Targeting a novel inter-tissue L-BAIBA/FGF23 axis to enhance adaptive musculoskeletal remodeling in aging

Aging causes deterioration of the musculoskeletal system via disruptions in critical paracrine and endocrine systems. Sarcopenia, the loss of muscle mass and function, and osteoporosis, the weakening of the bone, predispose the elderly to debilitating injuries, such as fracture, disability, and other adverse outcomes associated with morbidity and mortality. The societal costs of sarcopenia, osteoporosis, and their associated complications will rise dramatically as the aging population rapidly increases in size. Since 2011, when the first baby boomers reached retirement age, the age 65-and-older demographic has markedly grown. According to the US Census Bureau, in 2034, for the first time, adults over 65 years of age will outnumber children under 18, creating an essential need for improved clinical care. While the elderly retain some ability for bone and muscle improvement with exercise intervention, the anabolic response of musculoskeletal tissues is attenuated in the aged. Thus, new therapeutic strategies are required since the disease mechanisms involving tissue crosstalk are not understood. The osteocyte is an endocrine cell that responds to systemic and local cues to provide critical regulation of muscle. We validated that contracted muscle secretes L-β-aminoisobutyric acid (L-BAIBA), which protected against bone and muscle loss during hindlimb unloading. Our model suggests that L-BAIBA is in- creased with muscle contraction during exercise, and propose that L-BAIBA acts on the osteocyte which in turn produces fibroblast growth factor (FGF) 23 to target the kidney in order to maintain normal phosphate homeo- stasis. L-BAIBA acts through the Mas-Related G Protein receptor type D (Mrgprd) to directly increase Fgf23. This receptor is almost completely down regulated during aging, suggesting that this event causes an altered muscle-osteocyte homeostatic axis, leading to altered phosphate via lowered FGF23. Our central hypothesis is: L-BAIBA is a critical mediator of osteocyte FGF23 induction via Mrgprd-mediated β-catenin signaling, and the effects of aging on this system cause phosphate driven pathologies that compromise muscle function. We expect our studies using dovetailed, cutting-edge in vivo and in vitro techniques to provide novel insight into the trans- lational biology of muscle and bone function during aging. Our studies also feature a critical role for the kidney in exercise-induced musculoskeletal adaptation via excretion and balance of excess phosphate generated during exercise or aging. If successful, our studies would support that L-BAIBA protects muscle via controlling osteocyte FGF23. These findings would suggest that interventions that target molecular regulation of phosphate balance, including inducing levels of L-BAIBA might have protective effects during aging onset, a syndrome of progressive Mrgprd down regulation, to increase FGF23 and thus improve muscle function and patient outcomes. Project Number: 1RF1AG088242-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Institute on Aging (NIA) | Principal Investigator: KENNETH WHITE (+1 co-PI) | Institution: INDIANA UNIVERSITY INDIANAPOLIS, INDIANAPOLIS, IN | Award Amount: $3,126,515 | Activity Code: RF1 | Study Section: Skeletal Biology Structure and Regeneration Study Section[SBSR] View on NIH RePORTER: https://reporter.nih.gov/project-details/11132316