Developing a Physiological Understanding of High Duration Activity

Study Overview
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Brief Summary
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When muscles are not contracting, the local energy demand by muscle and use of specific fuels used to produce energy by oxidative metabolism are minimal. The time people spend sitting inactive (sedentary time) typically comprises more than half of the day. This sedentary behavior is associated with elevated risk of diabetes, cardiovascular diseases, some cancers, and multiple conditions leading to poor aging. From a progressive series of experiments, the driving goal is to develop a physiological method for sustaining contractile activity via oxidative metabolism over more time than is possible by traditional exercise (hours, not minutes per day). Developing a physiological method suitable of prolonged muscular activity for ordinary people (who are often unfit) requires gaining fundamental insights about muscle biology and biomechanics. This also entails a careful appreciation of the ability to isolate specific muscles in the leg during controlled movements, such as the soleus muscle during isolated plantarflexion. This includes quantifying specific biological processes that are directly responsive to elevated skeletal muscle recruitment. The investigators will focus on movement that is safe and practical for ordinary people to do given their high amount of daily sitting time. This includes developing methods to optimally raise muscle contractile activity, in a way that is not limited by fatigue, and is feasible throughout as many minutes of the day as possible safely. This also requires development of methodologies to quantify specific muscular activity, rather than generalized body movement. There is a need to learn how much people can increase muscle metabolism by physical activity that is perceived to them as being light effort. It is important to learn if this impacts systemic metabolic processes under experimental conditions over a short term time span in order to avoid confounding influences of changes in body weight or other factors.

Detailed Description
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Physical activity/inactivity will be carefully measured with objective devices. Wearable devices most commonly include accelerometers capable of capturing various types of movement and body posture. The intensity of muscle activation (the soleus and other leg muscles) will be measured in some participants in the developmental studies with EMG, with the limb motion quantified with goniometry. Skeletal muscle and whole body metabolism will be evaluated, especially after isolated local contractile activity focusing on the slow oxidative soleus muscle. Blood chemistry will also be investigated in this comprehensive series of studies to understand how replacing sedentary time with low effort muscular activity can be enhanced. Glycemia will be evaluated in the postprandial period in the morning after an overnight fast when there can be standardized control of carbohydrate ingestion. This includes a standardized oral glucose tolerance test with careful experimental assessment of posture and muscular recruitment during the testing periods. One phase of this study is particularly interested in assessing the acute responses that occur immediately as a result of contractile activity, while also evaluating in another phase how this may be impacted by a change in the sedentary lifestyle. This includes assessing new approaches for improving metabolism throughout the day by reducing the amount of time sitting inactive (i.e. sedentary time). Importantly, because the potential immediate benefits of muscle contractile activity are directly dependent on the duration of activity, the investigators aim to develop in a series of experiments how much muscular activity time can be performed comfortably and safely by anybody instead of sitting inactive with low muscle metabolism regardless of age, fitness, body type, and other conditions commonly limiting effectiveness of traditional exercise prescriptions.

Official Title
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Adaptive Effects of Very Light Physical Activity on Metabolism

Conditions
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Lipid Metabolism Disorders, Inactivity, Physical, Metabolic Disorder, Glucose, Sedentary Lifestyle, Hyperinsulinemia, Glucose Tolerance Impaired, Low-density-lipoprotein-type, Aging Problems

Intervention / Treatment
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* Behavioral: Muscular Exercise


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age must be 18 years or older Able to fast overnight Can maintain diet, medications, and sleep habits between each of the testing visits. Lifestyle is consistent with participation in a study evaluating reductions of inactivity (defined by sitting at a low metabolic rate because of minimal muscular activity) Willing and able to wear small wearable activity monitors under their clothes as instructed. No plans to start a new diet or exercise program if enrolled in the present study. Exclusion Criteria: Practical barriers to completing the study, such as plans to move, or work, or family commitments. Plans to change lifestyle during the present study. Have physical, vocational, or reasons that prohibit ordinary sitting behaviors present in the modern world. Currently dieting to change body weight, or have eating disorder. Are pregnant or plan to become pregnant. Taking medications that affect bleeding (ie anticoagulants). Allergy to lidocaine excludes biopsy component of study.

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: Basic Science
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Muscular Exercise<br>Increased level of low effort muscular activity | Behavioral: Muscular Exercise<br>* Sedentary time (muscular inactivity when sitting) will be replaced with low effort muscular activity<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Oxygen cost of isolated muscle contractions | The energetics of isolated muscle contractions will be described relative to the distinct biomechanics of different types of muscular movement | Acute contractile activity (at least 3 minutes) | 
| Fatigue time during muscle group specific contractile activity | Determinants of muscular endurance as a function of recruitment intensity | Acute measurements less than 1 day. The exact duration is an individual response that is an outcome of unknown minutes consistent with the fatiguability of different movements. | 
| Change in postprandial glucose regulation | Glucose concentration response during the postprandial period after an oral glucose tolerance test | The change through the completion of the postprandial period, an average of 180 minutes | 
| Change in very low density lipoprotein (VLDL) - Triglyceride | The concentration of triglyceride in the plasma VLDL lipoprotein | The change through the completion of an acute fasting period, approximately 8-12 hours | 
| The change in muscular inactivity time as a result of isolated contractile activity of the soleus | Development of an objective method(s) to quantify sedentary vs. non sedentary time. | Throughout the waking day ( 16 hours). | 
| Angiopoietin-like protein 4 | One of the molecular determinants of lipoprotein lipase regulation | The acute time course during the onset of muscular inactivity and contractile activity within 30 minutes to 8 hours | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recruited mass of the soleus and other muscles in the triceps surae during isolated plantarflexion | grams of the soleus, lateral gastrocnemius and medial gastrocnemius | During acute contractile activity of at least 3 minutes | 
| Electrical activity of muscle, Electromyography (EMG) | The activation of the triceps surae muscle group | At least 3 minute recording periods | 
| Local rate of oxygen consumption of working muscle | oxygen cost per kg muscle during isolated contractile activity and treadmill exercise | Steady-state measurements taken for  6 continuous minutes of contractile activity | 
| The ratio of carbohydrate vs. fat oxidation | The change in the ratio of the fat vs. carbohydrate utilization during acute contractile activity | Acute responses within less than 24 hours. | 
| Plasma insulin change | Plasma insulin concentration | The change through the completion of the postprandial period, an average of 180 minutes | 
| Sedentary/muscular inactivity time vs. intermittent non-seated standing behaviors | Sedentary time is defined as sitting with a low rate of muscle metabolism due to inactivity | Throughout the waking day ( 16 hours). | 
| apolipoprotein B100 concentration change | Biochemical measurement in units of mg per dL | After at least 4 weeks of increased contractile activity | 
| Change in the concentration of GlycA (this is not an acronym; it is a biomarker of inflammation) | Nuclear magnetic resonance in units of umol per L | After at least 4 weeks of increased contractile activity | 
| Small dense LDL concentration change | This is an atherogenic lipoprotein particle | After at least 4 weeks of increased contractile activity | 
| Complement component 3 (C3) concentration change | This is an acute phase protein, a marker of inflammation | After at least 4 weeks of increased contractile activity | 
| Ferritin concentration change | This is a biomarker related to inflammation and diabetes | After at least 4 weeks of increased contractile activity | 
| Plasma triglyceride concentration change | Triglyceride concentration in VLDL and non-VLDL particles | After at least 4 weeks of increased contractile activity | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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sedentary, physical activity, muscle contractile activity