Regulation of Muscle Protein Phenotype in Humans With Obesity

Not Applicable

Completed

Conditions: Obesity

Registration Number: NCT04700800

Lead Sponsor: Mayo Clinic

Brief Summary: A hallmark of muscle changes in obesity is an altered muscle fiber type profile, characterized by a reduced proportion of Type I fibers - a shift associated with adverse obesity-related health outcomes. This alteration can be linked to changes in the expression of myosin heavy chain (MHC) protein isoforms in the skeletal muscle of individuals with obesity. The investigators aim to modulate the metabolism of muscle MHC isoforms to uncover the biological mechanisms underlying this disrupted expression pattern in muscle of humans with obesity.

Detailed Description: Humans with obesity have typically lower proportion of Type I muscle fibers in skeletal muscle. These fiber types, known for their high capacity for glucose uptake, have also greater sensitivity to fuel metabolism compared with Type II fibers, even within the adverse metabolic environment of obesity. Altered expression of skeletal muscle myosin heavy chain (MHC) protein isoforms, molecular marker of fiber types, may explain this shift.

This project aims to uncover the biological mechanisms sustaining disrupted MHC protein metabolism in the skeletal muscle of individuals with obesity. The investigators will compare overall protein metabolism between humans with obesity and lean controls, with a specific focus on MHC isoforms. They will assess MHC isoform gene expression, associated molecular regulators, and synthesis rates of the MHC isoforms involved in muscle fiber programming. Acute aerobic exercise and elevated plasma amino acids will be used as experimental tools to target transcriptional and translational processes related to MHC gene expression. The findings are expected to reveal mechanisms responsible for the unfavorable fiber type profile observed in the skeletal muscle of humans with obesity.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 48

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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Primary Outcome Measures

Name	Time	Method
Whole-Muscle Protein Synthesis	9 Hours	Protein synthesis rates in whole muscle were quantified as the fractional synthesis rate (FSR), expressed as %/hour - representing the percentage of the entire muscle protein pool newly synthesized per hour. Protein synthesis rates were determined by continuous infusion of a stable isotope-labeled amino acid tracer, followed by measurement of tracer incorporation into the muscle proteins over time. Changes in FSR from baseline were evaluated in response to combined exercise and amino acid infusion.
Synthesis Rates of the Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx)	9 Hours	Synthesis rates of the myosin heavy chain protein isoforms were quantified as the fractional synthesis rate (FSR), expressed as %/hour - representing the percentage of each of the three myosin heavy chain isoform protein pool newly synthesized per hour. Protein synthesis rates were determined by continuous infusion of a stable isotope-labeled amino acid tracer, followed by measurement of tracer incorporation into each of the three myosin heavy chain isoform protein Changes in FSR from baseline were evaluated in response to combined exercise and amino acid infusion.
Messenger RNA (mRNA) Expression of Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx)	9 Hours	Messenger RNA (mRNA) expressions of the myosin heavy chain isoforms were determined by measuring the abundance of the three specific transcripts of the myosin heavy chain isoforms. mRNA was measured using quantitative reverse transcription PCR (qRT-PCR). Changes in mRNA expression from baseline were evaluated in response to combined exercise and amino acid infusion.