The main goal of this two-phase clinical trial is to learn whether local heat therapy, using heat pads applied to the legs, can enhance skeletal muscle health, physical function, and blood sugar control in a manner comparable to exercise, specifically High-Intensity Interval Training (HIIT), in older individuals with prediabetes. The study aims to answer the following questions:

1. Does local heat therapy improve muscle architecture (e.g., muscle cross-sectional area, capillary density, mitochondrial content), glucose tolerance, and frailty indicators similarly to HIIT in older individuals with prediabetes?
2. Does local heat therapy as a pre-conditioning method enhance the skeletal muscle response to HIIT in older individuals with prediabetes?

To achieve the study objectives, researchers will first compare the outcomes of local heat therapy to: 1) HIIT and 2) heat pads set to maintain normal skeletal muscle temperature (control group). Then, researchers will compare the outcomes of the local heat therapy and control groups after a subsequent HIIT intervention. This will enable the researchers to assess the effectiveness of local heat therapy (compared to HIIT and preceding HIIT) to improve skeletal muscle health, physical function, blood sugar control.

Study Procedures:

All participants will visit the laboratory over three days at the start of the study for baseline assessments and sample collection.

Participants in the Control (CON) and Local Heat Therapy (LHT) groups will:

Phase 1:

• Use heat pads on both thighs at a pre-determined temperature for 90 minutes daily, 6 days a week (5 days at home and 1 day in the laboratory; 12 laboratory visits) for the first 12 weeks.
• Maintain a log of each heat pad session.
• Visit the laboratory over three days at the end of Phase 1 for follow-up assessments and sample collection.

Phase 2:

• Visit the laboratory three days per week for 12 weeks (a total of 36 visits) for exercise training.
• Visit the laboratory over three days at the end of Phase 2 for final assessments and sample collection.

Participants in the HIIT Group will:

Phase 1:

• Visit the laboratory three days per week for 12 weeks (a total of 36 visits) for exercise training.
• Visit the laboratory over three days at the end of Phase 1 for final assessments and sample collection.

Inclusion Criteria:

• Age ≥ 50 years
• Women who are postmenopausal, defined as no menstrual period for at least 12 consecutive months.
• Sedentary (structured exercise <30 minutes, 3x/week)
• Body weight is at least 110 lbs
• Meet criteria for prediabetes (fasting blood glucose 100-125 mg/dl, hemoglobin A1c 5.7-6.4%)
• Consume <8 (women) or <15 (men) alcohol-containing beverages per week
• Do not use nicotine or cannabis
• Not taking any medications that could interfere with responses to the interventions (e.g., corticosteroids, opiates, benzodiazepines, tricyclic antidepressants, beta blockers, sulfonylureas, insulin, metformin, anticoagulants, barbiturates, insulin sensitizers, fibrates, immunosuppressants). If you don't know, that's okay. We'll ask what medications you are on and check whether they fall into one of these categories.

Exclusion Criteria:

• History of peripheral neuropathies
• Currently taking prescription blood thinners
• Medical complications that could would contraindicate participation in the high intensity interval training (HIIT) intervention including: orthopedic complications that would limit your ability to perform cycling exercise, significant cardiovascular impairments (e.g., history of arrhythmias, severe uncontrolled hypertension, etc.), diagnosed metabolic disease (e.g., diabetes), renal disease, sickle cell anemia, or cancer in remission for <6 months.
• Known history of slow wound healing
• Lidocaine allergy
• Latex allergy
• Currently pregnant
• >1.5" subcutaneous fat over the thigh muscle
• Symptoms suggestive of cardiovascular, respiratory, metabolic, or renal diseases including discomfort, pressure, or pain in your chest, neck, jaw, arms, calves, or other areas potentially related to ischemia; shortness of breath at rest or with mild exertion; dizziness or fainting (syncope); difficulty breathing while lying flat (orthopnea) or sudden nighttime breathing difficulties (paroxysmal nocturnal dyspnea); palpitations or rapid heartbeat (tachycardia); pain or cramping in your legs during physical activity (intermittent claudication); a known heart murmur; swelling in your ankles (edema); unusual fatigue or shortness of breath during routine activities or at rest.

All raw data generated from this project will be stored on cloud-based servers at Texas Tech University. Cleaned data in an analysis-ready format will be stored in REDCap and periodically uploaded to repositories. Data of sufficient quality from human participants will be uploaded the Aging Research Biobank to allow others to validate replicate research findings.

In alignment with the Data Submission Worksheet for the Aging Research Biobank, the following will be submitted to accompany deidentified data derived from human participants:

• Full study protocol
• Names and descriptions of data sets
• Manual of operations
• Annotated data collection forms
• Data dictionary
• Documentation of calculated variables
• Summary of deidentification and crosslinking of study ID with new randomized ID
• Any changes made to the protocol over time
• Frozen datasets used for the primary publication, when applicable

Data associated with each publication will be made available when preprints are available and will continue to be available on the repositories and long as they are supported. Any data that are not yet available by the end of the award period will be made available at that time.

Requests for data must be submitted through the Aging Research Biobank (see https://agingresearchbiobank.nia.nih.gov/how-to-make-a-request/).

Blinded