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

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

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.

• Other: Endurance Training
  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.
• Other: Restistance Training
  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.

• No Intervention: Sedentary control
  The control group does not engage in any acute exercise testing protocol.
• Active Comparator: Sedentary EE
  Participants randomized to ET first engage in a single acute exercise test of Endurance Exerciser (on a cycle ergometer) consistent with their random assignment.
  Intervention: Other: Endurance Training
• Active Comparator: Sedentary RE
  Participants randomized to RT first engage in a single acute exercise test of Resistance Exerciser, consistent with their random assignment.
  Intervention: Other: Restistance Training
• No Intervention: Highly Active EE
  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
  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.

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

• National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
• National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
• Stanford University
• Broad Institute
• Duke University
• Emory University
• Icahn School of Medicine at Mount Sinai
• Mayo Clinic
• Pacific Northwest National Laboratory
• University of Michigan
• Wake Forest University Health Sciences
• Wake Forest University
• University of Vermont
• National Institutes of Health (NIH)