Molecular Transducers of Physical Activity Consortium

Study Overview
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Brief Summary
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The goal of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) is to assess molecular changes that occur in response to physical activity (PA). To achieve this aim, a mechanistic randomized controlled trial (RCT) is conducted, in which adult study participants are randomized to endurance exercise (EE) training, resistance exercise (RE) training, or no exercise Control for a period of approximately 12 weeks. The overarching hypothesis is that there are discoverable molecular transducers that communicate and coordinate the effects of exercise on cells, tissues, and organs, which may initiate processes ultimately leading to the health benefits of exercise. Because this is a mechanistic trial, the main goal is not a health-related outcome. Rather, the goal is to generate a map of the molecular responses to exercise that will be used by the Consortium and by the scientific community at large to generate hypotheses for future investigations of the health benefits of PA.

Detailed Description
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Study assessments are completed before and after the intervention period (exercise or control), and at specific interim time points during the course of the intervention. Assessments include measurements of cardiorespiratory fitness, muscular strength, and body composition (including total body bone mineral content) determined by dual-energy x-ray absorptiometry (DXA). There is also collection of blood and muscle and adipose tissue biospecimens, monitoring of free-living PA level using wearable devices, and completion of participant reported outcomes and health status by interview and/or questionnaire. An additional group of highly active (HA) individuals currently active in either EE (HAEE) or RE (HARE) are recruited for a single acute exercise testing session of either endurance or resistance exercise and other study assessments. MoTrPAC participants are recruited, trained, and assessed via six adult Clinical Centers (CC), involving 10 clinical sites. As part of the MoTrPAC functions, participant data and biological samples are transferred from the clinical sites to the Consortium Coordinating Center (CCC) Data Management, Analysis and Quality Control Center (DMAQC)and to the Biological Sample Repository, and later analyzed by the Consortium Chemical Analysis Sites (CAS) and the Bioinformatics Center (BIC). Biological samples collected in this project undergo molecular phenotyping, including metabolomic, lipidomic, proteomic, epigenomic, transcriptomic, and genomic analyses. These assays are done at the MoTrPAC CAS. Overall coordination of the study and analyses occurs at 4 institutions which make up the CCC and the BIC.

Official Title
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Molecular Transducers of Physical Activity Consortium

Conditions
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Physical Activity

Intervention / Treatment
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* Other: Endurance Training
* Other: Restistance Training


Participation Criteria
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Eligibility Criteria
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ADULT PARTICIPANT INCLUSION CRITERIA - SEDENTARY PARTICIPANTS Willingness to provide informed consent to participate in the MoTrPAC Study Must be able to read and speak English well enough to provide informed consent and understand instructions Aged ≥18 y Body Mass Index (BMI) >19 to <35 kg/m2 Sedentary defined as self-reporting no more than 1 day per week, lasting no more than 60 minutes, of regular (structured) EE [e.g., brisk walking, jogging, running, cycling, elliptical, or swimming activity that results in feelings of increased heart rate, rapid breathing, and/or sweating] or RE (resulting in muscular fatigue) in the past year Persons bicycling as a mode of transportation to and from work >1 day/week etc. are not considered sedentary Leisure walkers are included unless they meet the heart rate, breathing, and sweating criteria noted above ADULT PARTICIPANT INCLUSION CRITERIA - HIGHLY ACTIVE PARTICIPANTS Willingness to provide informed consent to participate in the MoTrPAC Study Must be able to read and speak English well enough to provide informed consent and understand instructions Aged ≥18 y BMI >19 to <35 kg/m2 Comparator Participants HAEE: defined as >240 minutes/week of ET for >1 year; this can include running, walking (brisk, power), cycling, elliptical, etc. which (at a minimum) results in increased heart rate, rapid breathing and sweating Must include cycling at least 2 days/week HARE: defined as RT of ≥3 upper and ≥3 lower body muscle groups ≥2 times/week for >1 year; using a prescription sufficient to increase strength and muscle mass Elite or Competitive Athletes: can be included, if they meet HAEE or HARE inclusion criteria Potential participants are informed that use of performance enhancing drugs in the last 6 months is exclusionary In addition to meeting HAEE or HARE inclusion criteria, all HA participants must meet all other exclusion criteria defined in this protocol Individuals who meet inclusion criteria for both HAEE and HARE are exclude EXCLUSION CRITERIA ADULT PARTICIPANT EXCLUSION CRITERIA Exclusion criteria are confirmed by either self-report (i.e., medical and medication histories reviewed by a clinician), screening tests performed by the MoTrPAC study team at each clinical site, and/or clinician judgement as specified for each criterion. Diabetes (self-report and screening tests) Treatment with any hypoglycemic agents (self-report) or A1c >6.4 (screening test; may reassess once if 6.5-6.7) Fasting glucose >125 (screening test; may reassess once) Use of hypoglycemic drugs (e.g., metformin) for non-diabetic reasons (self-report) Abnormal bleeding or coagulopathy (self-report) History of a bleeding disorder or clotting abnormality Thyroid disease (screening test) Thyroid Stimulating Hormone (TSH) value outside of the normal range for the laboratory Individuals with hypothyroidism may be referred to their primary care provider (PCP) for evaluation and retested; any medication change must be stable for ≥3 months prior to retesting Individuals with hyperthyroidism are excluded, including those with normal TSH on pharmacologic treatment Pulmonary (self-report) Clinical diagnosis of Chronic Obstructive Pulmonary Disease (COPD) Metabolic bone disease (self-report) History of non-traumatic fracture from a standing height or less Current pharmacologic treatment for low bone mass or osteoporosis, other than calcium, vitamin D, or estrogen Estrogens, progestins (self-report) Supplemental, replacement or therapeutic use of estrogens or progestins within the last 6 months, other than birth control or to control menopausal symptoms Pregnancy (screening test) and pregnancy-related conditions (self-report) Pregnant - pregnancy test performed on day of DXA scan in women of child-bearing potential Post-partum during the last 12 months Lactating during the last 12 months Planning to become pregnant during the participation period Elevated blood pressure readings (screening test) Aged <60 years: Resting Systolic Blood Pressure (SBP) ≥140 mmHg or Resting Diastolic Blood Pressure (DBP) ≥90 mmHg Aged ≥60 years: Resting SBP ≥150 mmHg or Resting DBP ≥90 mmHg Reassessment of BP during screening will be allowed to ensure rested values are obtained Cardiovascular (self-report, screening test, and clinician judgement) Congestive heart failure, coronary artery disease, significant valvular disease, congenital heart disease, serious arrhythmia, stroke, or symptomatic peripheral artery disease (self-report, screening test) Specific criteria used to determine whether a volunteer can undergo the screening CPET follow the American Heart Association (AHA) Criteria [54] Inability to complete the CPET Abnormal blood lipid profile (screening test) Fasting triglycerides >500 mg/dL Low-density lipoprotein cholesterol (LDL-C) >190mg/dL Cancer (self-report) History of cancer treatment (other than non-melanoma skin cancer) and not cancer-free for at least 2 years Anti-hormonal therapy (e.g., for breast or prostate cancer) within the last 6 months Chronic infection (self-report) Infections requiring chronic antibiotic or anti-viral treatment Human Immunodeficiency Virus Individuals successfully treated for hepatitis C and virologically negative for at least 6 months are not excluded Liver enzyme tests (Alanine transaminase, Aspartate transaminase) (screening test) >2 times the laboratory upper limit of normal Reassessment during screening may be allowed under some conditions (e.g., recent use of acetaminophen) Individuals may be referred to their PCP for evaluation; any medication change must be stable for ≥3 months prior to retesting Chronic renal insufficiency (screening test) Estimated glomerular filtration rate <60 mL/min/1.73 m2 from serum creatinine (mg/dL) by the Chronic Kidney Disease Epidemiology Collaboration equation Reassessment may be allowed under some conditions (e.g., questionable hydration status or other acute renal insult) Hematocrit (screening test) Hematocrit >3 points outside of the local normal laboratory ranges for women and men Reassessment may be allowed under certain conditions Individuals may be referred to their PCP for evaluation; any medication change must be stable for ≥3 months prior to retesting Individuals with known thalassemia trait may be included (despite having >3 points outside of the local normal laboratory ranges), upon approval from their PCP or a hematologist Blood donation (self-report) Whole blood donation in the last 3 months or plans for blood donation during the entire protocol period Platelet or plasma donation in the last week or plans for platelet or plasma donation during the entire protocol period Autoimmune disorders (self-report) Individuals receiving any active treatment (including monoclonal antibodies) within the last 6 months Alcohol consumption (self-report) More than 7 drinks per week for women More than 14 drinks per week for men History of binge drinking (≥5 drinks for males or ≥4 drinks for females in a 2-hour period more than once per month) Tobacco (self-report) Self-reported use ≥3 days/week of tobacco or e-cigarette/e-nicotine products Marijuana (self-report) Self-reported use ≥3 days/week in any form Shift workers (self-report) Night shift work in the last 6 months Planning night shift work during the study period Cognitive status (screening) Unable to give consent to participate in and safely complete the protocol, as based on the judgement of the local investigator Psychiatric illness (self-report and screening test) Hospitalization for any psychiatric condition within one year (self-report) Center for Epidemiological Studies-Depression Scale (CESD) score ≥16 [55] (screening test) Weight change (self-report) Weight change (intentional or not) over the last 6 months of >5% of body weight Plan to lose or gain weight during the study Lidocaine or other local anesthetic (self-report) Known allergy to lidocaine or other local anesthetic Other (clinician judgement) Any other cardiovascular, pulmonary, orthopedic, neurologic, psychiatric or other conditions that, in the opinion of the local clinician, would preclude participation and successful completion of the protocol Any other illnesses that, in the opinion of the local clinician, would negatively impact or mitigate participation in and completion of the protocol EXCLUSIONS FOR MEDICATION USE Use of any new drug in the last 3 months Dose change for any drug in the last within 3 months Cardiovascular Beta blockers and centrally acting anti-hypertensive drugs (clonidine, guanfacine and alpha-methyl-dopa) Anticoagulants (coumadin or Direct Oral Anticoagulants) Antiarrhythmic drugs: amiodarone, dronaderone, profafenone, disopyrimide, quinidine Antiplatelet drugs (other than aspirin ≥100 mg/day): dipyridamole, clopidogrel, ticagrelor Lipid-lowering medications Participants who volunteer to stop lipid-lowering medications for the duration of the study are allowed; inclusion requires lipid-lowering medication to be stopped for 3 months and participant re-evaluated for LDL-C eligibility Psychiatric drugs Chronic use of medium or long-acting sedatives and hypnotics (short-acting non-benzodiazepine sedative-hypnotics are allowed) All benzodiazepines Tricyclic antidepressants at a dose ≥75 mg total dose per day Two or more drugs for depression Mood stabilizers Antiepileptic drugs Stimulants, Attention-Deficit/Hyperactivity Disorder (ADHD) drugs Muscle relaxants Methacarbamol; cyclobenzaprine; tizanidine; baclofen Pulmonary, inflammation Chronic oral steroids Burst/taper oral steroids more than once in the last 12 months B2-agonists allowed if on stable dose at least 3 months Genitourinary Finasteride or dutasteride Daily phosphodiesterase type 5 inhibitor use Hormonal Testosterone, dehydroepiandrosterone, anabolic steroids Anti-estrogens, anti-androgens Growth hormone, insulin like growth factor-I, growth hormone releasing hormone Any drugs used to treat diabetes mellitus or to lower blood glucose Metformin for any indication Any drugs used specifically to induce weight loss Any drugs used specifically to induce muscle growth/hypertrophy or augment exercise-induced muscle hypertrophy Pain/inflammation Narcotics and narcotic receptor agonists Regular use of non-steroidal anti-inflammatory drugs (NSAIDs) or acetaminophen ≥3 days per week Other Anti-malarials Low-potency topical steroids if ≥10% of surface area using rule of 9s Any other medications that, in the opinion of local clinicians, would negatively impact or mitigate full participation and completion

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: The randomized trial is conducted in accordance with an intent-to-treat (ITT) design.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| No Intervention: Sedentary control<br>The control group does not engage in any acute exercise testing protocol. | |
| Active Comparator: Sedentary EE<br>Participants randomized to ET first engage in a single acute exercise test of Endurance Exerciser (on a cycle ergometer) consistent with their random assignment. | Other: Endurance Training<br>* Participants randomized to ET engage in four center-based ET sessions each week for 12 weeks; each session lasting roughly 1-hour with a 40-45 minute stimulus phase and the remaining time being used to warm up and cool down. Each week, two of the sessions occur on a cycle ergometer and two involve treadmill exercise (4 total sessions per week). During all sessions, the participant's heart rate is monitored to ensure they maintain exercise intensity at 70% of heart rate reserve (± 5%). Periodically during training sessions perceptual data from participants are recorded, which is used to track the subjective experience of participants and in interpreting adherence data.<br>|
| Active Comparator: Sedentary RE<br>Participants randomized to RT first engage in a single acute exercise test of Resistance Exerciser, consistent with their random assignment. | Other: Restistance Training<br>* Participants randomized to RT engage in four center-based RT sessions each week for 12 weeks; each session lasting roughly 1-hour with a 40-45 minute stimulus phase and the remaining time being used to warm up and cool down. The prescription is a 2-day split, meaning approximately half of the major muscle groups are exercised each session and each muscle group is exercised twice per week. Two sessions per week include seven exercises that focus on the hips/thighs, back and biceps, and the other two sessions per week include seven exercises that focus on the chest, shoulders, triceps, calves and abdominal muscles. The first set per muscle group is a warm-up performed at 50-70% of prescribed loads that are based on 10-repetition maximum (RM). Three sets per exercise are then performed at 10RM intensity. Load increases when a participant is able to perform 12 repetitions for 2 of 3 sets of an exercise. During all sessions, heart rate is monitored and perceived exertion is recorded.<br>|
| No Intervention: Highly Active EE<br>A comparison group of highly active EE participants are recruited and engage only in the initial round of acute exercise testing. Highly Active Endurance Exerciser (HAEE) participants are tested on a cycle ergometer. | |
| No Intervention: Highly Active RE<br>A comparison group of highly active RE participants are recruited and engage only in the initial round of acute exercise testing. Highly Active Resistance Exerciser (HARE) participants are tested via a bout of resistance exercise. | |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transcriptome in muscle | Changes in mRNA-based expression within skeletal muscle tissue | Baseline; Week 12 | 
| Metabolome in muscle | Changes in metabolites within skeletal muscle tissue | Baseline; Week 12 | 
| Lipidome in muscle | Changes in lipids within skeletal muscle tissue | Baseline; Week 12 | 
| Proteome in muscle | Changes in proteins within skeletal muscle tissue | Baseline; Week 12 | 
| Epigenome in muscle | Epigenomic changes within skeletal muscle tissue | Baseline; Week 12 | 
| Genomic influence in muscle | Influence of genomic allelic variants on the levels of molecular feature patterns within skeletal muscle tissue | Baseline; Week 12 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Transcriptome in fat | Changes in mRNA-based expression within sub-cutaneous fat | Baseline; Week 12 | 
| Metabolome in fat | Changes in metabolites within sub-cutaneous fat | Baseline; Week 12 | 
| Lipidome in fat | Changes in lipids within sub-cutaneous fat | Baseline; Week 12 | 
| Proteome in fat | Changes in proteins within sub-cutaneous fat | Baseline; Week 12 | 
| Epigenome in fat | Epigenomic changes within sub-cutaneous fat | Baseline; Week 12 | 
| Genomic influence in fat | Influence of genomic allelic variants on the levels of molecular feature patterns within sub-cutaneous fat | Baseline; Week 12 | 
| Transcriptome in plasma | Changes in mRNA-based expression within blood plasma | Baseline; Week 12 | 
| Metabolome in plasma | Changes in metabolites within blood plasma | Baseline; Week 12 | 
| Lipidome in plasma | Changes in lipids within blood plasma | Baseline; Week 12 | 
| Proteome in plasma | Changes in proteins within blood plasma | Baseline; Week 12 | 
| Epigenome in plasma | Epigenomic changes within blood plasma | Baseline; Week 12 | 
| Genomic influence in plasma | Influence of genomic allelic variants on the levels of molecular feature patterns within blood plasma | Baseline; Week 12 |