Regulation of Muscle Protein Phenotype in Humans With Obesity

Study Overview
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Brief Summary
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Maintenance of protein homeostasis is impaired in skeletal muscle of humans with obesity. A hallmark of this defect is distorted expression of isoforms of the myosin heavy chain (MHC) protein, and this defect is linked to obesity-associated adverse health outcomes. By employing exercise and increase in plasma amino acids as investigational tools the investigators intend to modulate the metabolism of muscle MHC isoforms in order to unravel the biological mechanisms that sustain distorted MHC protein metabolism in muscle of humans with obesity.

Detailed Description
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Distorted expression of isoforms of the skeletal muscle myosin heavy chain (MHC) protein is a hallmark of altered protein metabolism in muscle of humans with obesity. The most striking feature of this, is a characteristic reduction in the content of the slow MHC-I isoform, which is responsible for determining the content of Type I muscle fibers. These fibers are characterized by increased capacity for glucose uptake, and in contrast to Type II fibers, maintain sensitivity to fuel metabolism within the adverse metabolic environment of obesity. Increased content of Type I fibers in skeletal muscle, and thus favorable metabolic effects in muscle, require increased expression of MHC-I in muscle. Importantly, the slow MHC-I gene drives the molecular mechanisms that determine the overall MHC protein metabolism and fiber type phenotype in skeletal muscle. The project seeks to determine the underlying biology that sustains distorted MHC protein metabolism in skeletal muscle of humans with obesity. The investigators evaluate protein metabolism in skeletal muscle of humans with obesity and lean controls, and focus specifically on that of MHC isoforms. The investigators determine gene expression of the MHC isoforms and associated molecular factors implicated in activating Type I muscle fiber programming. Acute aerobic exercise and increase in plasma amino acids are employed as experimental tools to target biological processes of transcription and translation related to MHC genes expression in skeletal muscle. The overall findings will provide an understanding of mechanisms responsible for unfavorable MHC proteome and fiber type phenotype in skeletal muscle of humans with obesity.

Official Title
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Regulation of Muscle Protein Phenotype in Humans With Obesity

Conditions
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Obesity

Intervention / Treatment
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* Other: Exercise
* Other: Infusion of Amino Acids


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: ability to sign informed consent form body mass index (BMI), 18-26 kg/m2 (lean subjects), 32-50 kg/m2 (subjects with obesity) Exclusion Criteria: prescription or over-the-counter medication supplements known to affect protein metabolism (i.e., amino acids, protein, omega-3 fatty acids) diabetes acute illness liver disease uncontrolled metabolic disease, including renal disease heart disease related to atrial fibrillation, history of syncope, limiting or unstable angina, congestive heart failure or ECG documented abnormalities low hemoglobin or hematocrit use of anabolic steroids or corticosteroids (within 3 months) not classified as inactive/sedentary based on the Stanford Brief Activity Survey and accelerometry data participation in a weight-loss regimen extreme dietary practices (i.e., vegan, vegetarian) smoking pregnancy gastro-intestinal surgery any other condition or event considered exclusionary by the PI and the study physician.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 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
Allocation: Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Exercise, Infusion of Amino Acids<br>Exercise followed by infusion of amino acids, or infusion of amino acids alone. | Other: Exercise<br>* Acute cycle-ergometer exercise for 45 minutes at 65% of peak oxygen uptake<br>Other: Infusion of Amino Acids<br>* Intravenous infusion of mixture of amino acids<br>|
| Active Comparator: Exercise<br>Exercise with no infusion of amino acids | Other: Exercise<br>* Acute cycle-ergometer exercise for 45 minutes at 65% of peak oxygen uptake<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Protein Synthesis | Change from baseline in the synthesis rates of overall protein, overall mitochondrial protein, and myosin heavy chain (MHC) isoforms in skeletal muscle will be evaluated in response to the following interventions: exercise+amino acid infusion amino acid infusion exercise | 9 Hours on 2 separate days one month apart | 
| Change in Eukaryotic initiation factor 4F (eIF4F) | Change from baseline in the formation of the active eIF4F complex in skeletal muscle will be evaluated in response to the following interventions: exercise+amino acid infusion amino acid infusion exercise | 9 Hours on 2 separate days one month apart | 
| Change in messenger RNA (mRNA) | Change from baseline in mRNA content of MHC isoforms in skeletal muscle will be evaluated in response to the following interventions: exercise+amino acid infusion amino acid infusion exercise | 9 Hours on 2 separate days one month apart | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Protein breakdown | Change from baseline in the breakdown rates of overall protein and myosin heavy chain (MHC) isoforms in skeletal muscle will be evaluated in response to the following interventions: exercise+amino acid infusion amino acid infusion exercise | 9 Hours on 2 separate days one month apart |