Project Grant R01AG084597

GLYCEMIC CONTROL AND FRAILTY RISK IN OLDER PEOPLE AT RISK FOR TYPE 2 DIABETES: IMPACT OF LOCAL HEAT THERAPY - PROJECT SUMMARY/ABSTRACT FRAILTY-RELATED MEDICAL EXPENSES COST APPROXIMATELY $18 BILLION ANNUALLY IN THE USA. PROGRESSIVE LOSSES IN SKELETAL MUSCLE (SKM) MASS AND FUNCTION, OFTEN OBSERVED WITH AGING AND TYPE 2 DIABETES (T2D), CONTRIBUTE TO PHENOTYPIC FRAILTY CHARACTERIZED BY SLOW GAIT SPEED, WEAKNESS, WEIGHT LOSS, FATIGUE, AND LOW PHYSICAL ACTIVITY. T2D INCREASES FRAILTY RISK BY NEARLY 50% AND RISK FOR BOTH CONDITIONS INCREASES WITH AGE; THEREFORE, PREVENTING PROGRESSION TO T2D IN OLDER ADULTS WITH PREDIABETES IS CRITICAL. ADDITIONALLY, SKM IS THE LARGEST GLUCOSE DISPOSAL SITE IN THE BODY AND INSULIN RESPONSIVENESS, A COMPONENT OF GLYCEMIC CONTROL, IS ESSENTIAL TO MAINTAIN FUNCTIONAL SKM MASS. THUS, IMPAIRED GLYCEMIC CONTROL, A PATHOPHYSIOLOGICAL CHANGE UNDERLYING THE DEVELOPMENT OF T2D AND OBSERVED IN PREDIABETES, INCREASES FRAILTY RISK. CONVERSELY, IMPROVING CAPILLARIZATION AND MITOCHONDRIAL FUNCTION SUPPORT INCREASED SKM MASS AND GLYCEMIC CONTROL, THEREBY DECREASING T2D AND FRAILTY RISK. TOGETHER, THESE SKM ARCHITECTURAL VARIABLES (E.G., CROSS-SECTIONAL AREA [CSA], CAPILLARIZATION, MITOCHONDRIA) ARE ATTRACTIVE TARGETS FOR INTERVENTIONS SUCH AS EXERCISE IN PREDIABETIC OLDER PEOPLE. HIGH-INTENSITY INTERVAL TRAINING (HIIT) HAS BEEN USED EFFECTIVELY IN OLDER ADULTS WITH SKM BENEFITS SIMILAR TO THOSE FROM AEROBIC AND RESISTANCE TRAINING, AND IS MORE TIME-EFFICIENT. HOWEVER, PREDIABETIC OLDER PEOPLE MAY BE EXERCISE-INTOLERANT OR -RESISTANT, UNDERSCORING THE NEED FOR ALTERNATIVE THERAPIES IN PLACE OF (OR IN ADDITION TO) EXERCISE. EMERGING EVIDENCE SUPPORTS REPEATED HEAT THERAPY AS AN ALTERNATIVE METHOD TO IMPROVE GLYCEMIC CONTROL AND SKM ARCHITECTURE, AND SUCH ADAPTATIONS MAY ALSO IMPROVE MUSCLE GROWTH RESPONSES TO SUBSEQUENT EXERCISE. HEAT-SENSITIVE TRANSIENT RECEPTOR POTENTIAL VANILLOID RECEPTOR 1 (TRPV1), A HIGHLY CA2+-PERMEABLE ION CHANNEL, IS A PROMISING MECHANISTIC CANDIDATE UNDERLYING SKM ADAPTATIONS TO REPEATED HEAT STRESS. WHILE WHOLE-BODY HEAT THERAPY IS WIDELY STUDIED, LOCAL HEAT THERAPY (E.G., HEAT PAD) IS MORE PRACTICAL AND LIKELY PROVIDES SIMILAR HEALTH BENEFITS. WHETHER LOCAL HEAT THERAPY WOULD HAVE SIMILAR BENEFITS TO HIIT OR WHETHER HEAT PRE-CONDITIONING WOULD IMPROVE ADAPTATIONS TO SUBSEQUENT HIIT IN PREDIABETIC OLDER ADULTS IS UNKNOWN. THEREFORE, THE OVERALL HYPOTHESIS OF THIS ESI R01 APPLICATION IS THAT LOCAL HEAT THERAPY IMPROVES SKM ARCHITECTURE, GLYCEMIC CONTROL, AND SUBSEQUENT EXERCISE ADAPTATIONS, AND DECREASES FRAILTY RISK IN PREDIABETIC OLDER ADULTS, WITH TRPV1 AS AN UNDERLYING MECHANISM. THE PROJECT'S SPECIFIC AIMS WILL TEST WHETHER: 1) LOCAL HEAT THERAPY IMPROVES SKM ARCHITECTURE, GLUCOSE TOLERANCE, AND FRAILTY INDICATORS SIMILAR TO HIIT IN OLDER PREDIABETIC PEOPLE; 2) LOCAL HEAT THERAPY PRE-CONDITIONING IMPROVES THE SKM RESPONSE TO HIIT IN OLDER PREDIABETIC PEOPLE; AND 3) TRPV1 MECHANISTICALLY UNDERLIES SKM ADAPTATIONS TO HEAT THERAPY. THE FINDINGS OF THIS STUDY WILL PROVIDE EVIDENCE SUPPORTING A DIRECTLY TRANSLATABLE LOCAL HEAT THERAPY INTERVENTION FOR OLDER ADULTS AT RISK FOR T2D. IN LINE WITH THE KATZ MECHANISM, THE PROPOSED WORK LEVERAGES THE EXPERTISE OF THE PIS AND REPRESENTS A SHIFT IN RESEARCH FOCUS. WE PROPOSE TO TEST A HIGHLY PRACTICAL AND PROMISING INTERVENTION TO COMBAT METABOLIC COMPLICATIONS IN AGING, A CRUCIAL AREA OF STUDY WITH THE CURRENT AGING POPULATION.