RF1AG088242

TARGETING A NOVEL INTER-TISSUE L-BAIBA/FGF23 AXIS TO ENHANCE ADAPTIVE MUSCULOSKELETAL REMODELING IN AGING - ABSTRACT: 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.

Trustees Of Indiana University

TO ENCOURAGE BIOMEDICAL, SOCIAL, AND BEHAVIORAL RESEARCH AND RESEARCH TRAINING DIRECTED TOWARD GREATER UNDERSTANDING OF THE AGING PROCESS AND THE DISEASES, SPECIAL PROBLEMS, AND NEEDS OF PEOPLE AS THEY AGE. THE NATIONAL INSTITUTE ON AGING HAS ESTABLISHED PROGRAMS TO PURSUE THESE GOALS. THE DIVISION OF AGING BIOLOGY EMPHASIZES UNDERSTANDING THE BASIC BIOLOGICAL PROCESSES OF AGING. THE DIVISION OF GERIATRICS AND CLINICAL GERONTOLOGY SUPPORTS RESEARCH TO IMPROVE THE ABILITIES OF HEALTH CARE PRACTITIONERS TO RESPOND TO THE DISEASES AND OTHER CLINICAL PROBLEMS OF OLDER PEOPLE. THE DIVISION OF BEHAVIORAL AND SOCIAL RESEARCH SUPPORTS RESEARCH THAT WILL LEAD TO GREATER UNDERSTANDING OF THE SOCIAL, CULTURAL, ECONOMIC AND PSYCHOLOGICAL FACTORS THAT AFFECT BOTH THE PROCESS OF GROWING OLD AND THE PLACE OF OLDER PEOPLE IN SOCIETY. THE DIVISION OF NEUROSCIENCE FOSTERS RESEARCH CONCERNED WITH THE AGE-RELATED CHANGES IN THE NERVOUS SYSTEM AS WELL AS THE RELATED SENSORY, PERCEPTUAL, AND COGNITIVE PROCESSES ASSOCIATED WITH AGING AND HAS A SPECIAL EMPHASIS ON ALZHEIMER'S DISEASE. SMALL BUSINESS INNOVATION RESEARCH (SBIR) PROGRAM: TO EXPAND AND IMPROVE THE SBIR PROGRAM, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, TO INCREASE SMALL BUSINESS PARTICIPATION IN FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION. SMALL BUSINESS TECHNOLOGY TRANSFER (STTR) PROGRAM: TO STIMULATE AND FOSTER SCIENTIFIC AND TECHNOLOGICAL INNOVATION THROUGH COOPERATIVE RESEARCH DEVELOPMENT CARRIED OUT BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO FOSTER TECHNOLOGY TRANSFER BETWEEN SMALL BUSINESS CONCERNS AND RESEARCH INSTITUTIONS, TO INCREASE PRIVATE SECTOR COMMERCIALIZATION OF INNOVATIONS DERIVED FROM FEDERAL RESEARCH AND DEVELOPMENT, AND TO FOSTER AND ENCOURAGE PARTICIPATION OF SOCIALLY AND ECONOMICALLY DISADVANTAGED SMALL BUSINESS CONCERNS AND WOMEN-OWNED SMALL BUSINESS CONCERNS IN TECHNOLOGICAL INNOVATION.

93.866 - Aging Research

National Institute on Aging (NIA) [HHS - NIH]

Indianapolis, Indiana 46202 United States

Single Zip Code

NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed) (PA-20-185)