Precision High-Intensity Training Through Epigenetics (PHITE)
Condition: Healthy
Study type: Interventional

Summary: 
      The PHITE collaborative team, consisting of Tim Broderick, MD (Overall PI), Wright State
      University (WSU); Marcas Bamman, PhD (Site PI), The University of Alabama at Birmingham
      (UAB); and Ron Evans, PhD and Joe Ecker, PhD, Salk Institute for Biological Studies, are
      working with funding from the US Department of Defense (DoD), Office of Naval Research (ONR),
      to explore the link between physical training and epigenetics. This is a key interest area
      for the DoD ONR because it provides high-impact optimization of force readiness in
      warfighters with diverse backgrounds.

      The term epigenetics refers to heritable changes in gene expression (active versus inactive
      genes) that does not involve changes to the underlying DNA sequence; a change in phenotype
      (the set of observable characteristics of an individual resulting from the interaction of its
      genotype with the environment) without a change in genotype (the genetic constitution of an
      individual organism) . This in turn affects how cells read the genes. Epigenetic change is a
      regular and natural occurrence but can also be influenced by several factors including age,
      the environment/lifestyle, and disease state. Epigenetic modifications can manifest as
      commonly as the manner in which cells terminally differentiate to end up as skin cells, liver
      cells, brain cells, etc. New and ongoing research is continuously uncovering the role of
      epigenetics in a variety of human conditions. This study is designed to assess whether
      epigenetics is a primary mechanism modulating how individuals adapt to specific exercise
      training prescriptions designed to produce a warfighter phenotype.

      The PHITE team is organized around a shared test population of human subjects for which UAB
      will oversee recruitment, training, testing, and sampling. Healthy but untrained volunteers,
      both men and women, 18-27 y of age-phenotypical of the US warfighter-will participate in a
      12-wk, two-arm, single-blind, randomized, exercise dose-response trial comparing two
      intensities of combined training: Moderate-Intensity vs. High-Intensity. Biospecimens are
      collected before and after an acute exercise bout in the pre-training state, and again after
      12 weeks of 3 d/wk combined exercise training. Numerous phenotyping assessments are collected
      before after the 12-week intervention period to associate exercise training outcomes with
      molecular changes in the skeletal muscle and blood biospecimens.
    

Detailed description: 
      Overview:

      The US military relies on physical training to increase and maintain force readiness. In this
      study, we hypothesize that epigenetic modification is a primary mechanism by which specific
      physical exercise training prescriptions transduce warfighter genotype into warfighting
      phenotype. Our aim with this program is 3- fold. We will (1) identify training methodologies
      that modify epigenetic responses; (2) characterize epigenetic regulation of physiological
      processes, pathways and mechanisms associated with moderate and high-intensity physical
      training, and (3) produce real-time biomarkers of cardiorespiratory and neuromuscular
      performance that predict physical training outcomes. We will satisfy these goals through the
      following six research projects:

      I. Phenotyping the Exercise Dose-Response

        1. Determine the effect of exercise Intensity on neuromuscular and cardiorespiratory
           performance

        2. Assess the impact of baseline, pre-training phenotype on acute responsiveness and
           adaptability to different intensity exercise regimens

        3. Determine the effect of exercise intensity on mechanisms regulating muscle protein
           metabolism, myofiber hypertrophy, and muscle oxidative capacity

      II. Real-time Genetic and Epigenetic Biomarkers of Performance

        1. Identify muscle miRNA that are differentially expressed in response to varying exercise
           intensities

        2. Identify circulating muscle-derived miRNA that are differentially expressed in response
           to varying exercise intensities

        3. Genotype individual athletic potential for biomarker optimization

      IV. Epigenomic Signatures of Human Performance

        1. Identify and correlate exercise induced methylation changes in blood and muscle

        2. Functionally link changes in gene expression signatures and physiologic outcomes

        3. Define nuclear receptor induced epigenetic signatures in metabolically active tissues

      V. Exercise Induced Histone Modifications and Chromatin Remodeling

        1. Profile histone modification and histone subunit usage signatures

        2. Assess chromatin as a signal integration platform for long-term stability

      VI. Integrative Epigenomics

        1. Categorize baseline performance and group subjects

        2. Characterize epigenetic changes in response to varied exercise intensities

        3. Develop forecasting models from miRNA biomarkers of performance

        4. Develop epigenetic regulatory network models using Deep Belief Networks

           UAB will enroll healthy, untrained men and women who resemble the US soldier. They
           participate in an exercise dose response training trial that lasts approximately 12
           weeks.

           There are 2 randomly assigned exercise prescriptions: MOD - 3 days per week on treadmill
           or stationery cycle ergometer, combined with 2 days per week of resistance training; HI
           - 3 days per week high intensity interval training similar to military high intensity
           tactical training, combined with high intensity resistance training 2 days per week.

           Physical performance is evaluated pre-training, mid-training and post-training.
           Additionally, body composition is evaluated pre-training and post-training. Muscle
           biopsies and blood draws are performed at pre-training and post-training acute exercise
           response bouts, and samples are sent to additional study sites for specific evaluations.

           Recruitment:

           Participants are recruited through IRB approved advertisements.

           Informed Consent:

           Once an individual is identified; meets the inclusion/exclusion criteria (pre-screen);
           and expresses interest in the study, a member of the research team provides the
           individual with a consent form to review. A member of the team follows up with the
           individual to further explain the study and provide an opportunity for the prospective
           participant to ask any questions. If the person decides to participate, he/she is
           scheduled for the initial visit. He/she is encouraged to ask any further questions prior
           to giving written informed consent.

           Participant Procedures:

           MOD exercise regimen - 3 days per week of endurance exercise at 70% heart rate reserve
           for 30 mins on a stationary cycle or treadmill, combined with resistance exercise on 2
           of the 3 days. The resistance training prescription involves 3 sets x 10-14 repetitions
           for each movement, with 1 minute rest between set. The movements include leg press or
           squat, knee extension, chest press, overhead press, seated row, wide grip pull down, ab
           crunch, heel raise, triceps push down, bicep curls. Resistance loads are progressed when
           14 repetitions are achieved for 2 of 3 sets. Heart rate is monitored throughout each
           session.

           HI Exercise regimen - 3 days per week of maximum intensity interval exercise, combined
           with resistance exercise on 2 of the 3 days. Instead of moderate intensity endurance
           exercise, participants in this group perform 10 high-intensity intervals (30 sec of
           work, 30 sec of rest) including box jumps, burpees, split squat jumps, kettle bell
           swings, cycling sprints, battle ropes, wall ball, dips, etc. The resistance training
           prescription involves 3 sets x 8-10 repetitions for the same movements as MOD, but with
           supersets of two movements. Resistance loads are progressed when 10 repetitions are
           achieved for 2 of 3 sets. Rest periods are 30-45 seconds between supersets. Heart rate
           is monitored throughout each session.

           DXA Scan -The dual energy x-ray absorptiometry (DXA) procedure for determination of body
           composition (muscle, fat, bone) involves minor x-ray exposure. DXA will be performed at
           weeks 0, and 12. The effective dose exposure is comparable to 4 hours of sun exposure

           Urine Pregnancy Test - All females who have had at least one menstrual cycle have a
           urine pregnancy test at initial assessment and prior to each DEXA scan. All females who
           have had at least one menstrual cycle are asked questions pertaining to their menstrual
           cycle. Because hormone levels may have significant impact on biospecimen analysis, the
           acute exercise bout with muscle and blood collections after the intervention period will
           be timed to occur in the same phase of the menstrual cycle as the pre-training acute
           response exercise bout.

           Muscle Sampling - A total of 7 muscle samples are collected by percutaneous needle
           muscle biopsy from the vastus lateralis using established procedures:

           3 collected before and after the first acute response exercise bout in the pre-training
           state (pre-exercise, 3 h post-exercise, 24 h post-exercise); 3 collected before and
           after the acute response exercise bout in the post-training state (pre-exercise, 3 h
           post-exercise, 24 h post-exercise);

           1 collected at a follow up visit 4 weeks after the conclusion of the intervention
           period.

           Blood Sampling - A total of 9 blood samples are collected by venipuncture using
           established procedures:

           4 collected before and after the first acute response exercise bout in the pre-training
           state (pre-exercise, 15 min post-exercise, 3 h post-exercise, 24 h post-exercise); 3
           collected before and after the acute response exercise bout in the post-training state
           (pre-exercise, 15 min post-exercise, 3 h post-exercise, 24 h post-exercise);

           1 collected at a follow up visit 4 weeks after the conclusion of the intervention
           period.

           Exercise Performance Evaluations - 1-repetition maximum (1RM) strength on upper and
           lower body movements, peak aerobic capacity (VO2peak) on a cycle ergometer, Wingate
           anaerobic power test, peak muscle power of the knee extensors using a
           computer-controlled dynamometer, and vertical jump test are conducted before and after
           the intervention period. Some performance tests are also conducted mid-intervention
           (approximately week 6).

           Dietary Intake - Dietary intake will be monitored using a validated 24 hour recall at
           weeks 0 and 12.

           Quality Assurance:

           Exercise Sessions: Subjects will be carefully instructed in proper methods and are
           monitored continuously. All exercise sessions are performed under full supervision by
           experienced, certified staff [Certified Strength and Conditioning Specialist (National
           Strength and Conditioning Association) and/or Certified Exercise Specialist (American
           College of Sports Medicine)].

           Biospecimens Collection: All muscle biopsies and blood draws are performed by trained,
           professional clinician's and research staff who are experienced and locally certified.

           DXA scans: All DXA scans are performed by trained technicians at UAB.

           Genetic Testing: Genetic testing of samples will be linked to a unique participant ID
           that will not identify a participant in any way. Linkages to personal health information
           are kept secure at the clinical site (UAB).

           The research will be conducted by well trained and experienced personnel who will be
           identified to the IRB prior to working on this study.

           PI will be ultimately responsible for data and safety monitoring: (i) Keeping all study
           documents updated and available for inspection by the sponsor, UAB IRB, and other
           authorized reviewers; (ii) Ensuring that appropriate mechanisms to protect the safety of
           study participants are being followed; (iii) Ensuring adherence to protocol
           requirements; and (iv) Ensuring that data are accurate, complete, and secure. All
           documents pertaining to the conduct of the study will be kept on file by the PIs.

           Even though this trial does not meet the requirements for a Data and Safety Monitoring
           Board, we will follow a proactive, Data and Safety Monitoring Plan as described below.

             1. Weekly reviews at investigators/staff team meetings of recruitment progress notes,
                updates/reports from the exercise facility, laboratories, and data management
                staff, and newly available data.

             2. PIs' quarterly review of safety and interim data analysis.

             3. Annual review performed by the UAB IRB.

             4. Semi-annual patient safety review by the study team.

           All non-serious AEs will be documented, and a summary delivered to the UAB IRB at
           pre-determined intervals (at least annually). Any SAEs will be reported to the UAB IRB
           within 3 days of their discovery. Aggregate reports of AEs/SAEs will be delivered to the
           sponsor as mandated. If an AE (serious or non-serious) occurs, the PI will be
           immediately notified. Depending on the event, follow up may require additional tests or
           medical procedures as indicated, and/or referral to a specialist. The study physicians
           will make such decisions. Depending on the type of AE/SAE, the PIs may opt to
           discontinue the subject from the study. The PIs will be ultimately responsible for
           evaluating each AE for relationship to the protocol, seriousness and expectedness, any
           impact on the risk-to-benefit ratio, and whether modifications are needed to the
           informed consent document and/or protocol. The PIs will also have the responsibility of
           determining whether the protocol must be suspended until satisfactory modifications are
           made; however, ultimate authority in such cases will rest with the UAB IRB.
    

Intervention name(s): Moderate Intensity; High Intensity
Intervention type(s): Behavioral; Behavioral
Intervention description(s): Exercise prescription intensity is moderate; Exercise prescription intensity is high
Other intervention name(s): MOD; HI
Allocation: Randomized
Intervention model: Parallel Assignment
Intervention model description: Randomized to moderate intensity vs. high-intensity exercise training prescription.
Masking: Double (Investigator, Outcomes Assessor)
Primary purpose: Basic Science
Keywords: epigenetics; exercise dose-response; inter-individual response heterogeneity; exercise training adaptations