Obesity
Conditions
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.
Interventions
OTHERExercise
Exercise at 65% of heart rate reserve
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
SINGLE_GROUP
Primary purpose
BASIC_SCIENCE
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 45 Years
Healthy volunteers
Yes
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
Countries
United States
Participant flow
Recruitment details
A total of 48 participants signed informed consent.
Pre-assignment details
Of the participants that signed the consent form, 10 were screen failures, 11 withdrew, 4 declined participation, and 1 was enrolled but did not proceed. Twenty-three completed the entire study with one participant had data collected as did part of the study, for a total of 22 with data collected.
Participants by arm
| Arm | Count |
|---|---|
| Participants with Obesity Participants with Obesity performing acute aerobic exercise followed by infusion of amino acids, with measurements take before and after exercise+amino acid infusion | 10 |
| Lean paticipants Healthy lean participants performing acute aerobic exercise followed by infusion of amino acids, with measurements take before and after exercise+amino acid infusion | 12 |
| Total | 22 |
Baseline characteristics
| Characteristic | Participants with Obesity | Lean paticipants | Total |
|---|---|---|---|
| Age, Continuous | 30 Years STANDARD_DEVIATION 2 | 29 Years STANDARD_DEVIATION 2 | 29 Years STANDARD_DEVIATION 2 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 3 Participants | 4 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 9 Participants | 18 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 8 Participants | 11 Participants | 19 Participants |
| Sex: Female, Male Female | 6 Participants | 7 Participants | 13 Participants |
| Sex: Female, Male Male | 4 Participants | 5 Participants | 9 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 12 |
| other Total, other adverse events | 2 / 10 | 6 / 12 |
| serious Total, serious adverse events | 0 / 10 | 0 / 12 |
Outcome results
Primary
Messenger RNA (mRNA) Expression of Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx)
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.
Time frame: 9 Hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants with Obesity | Messenger RNA (mRNA) Expression of Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx) | MHC-I | 1.1 Arbitrary Units | Standard Deviation 0.5 |
| Participants with Obesity | Messenger RNA (mRNA) Expression of Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx) | MHC-IIa | 0.5 Arbitrary Units | Standard Deviation 0.2 |
| Lean participants | Messenger RNA (mRNA) Expression of Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx) | MHC-I | 1.0 Arbitrary Units | Standard Deviation 0.4 |
| Lean participants | Messenger RNA (mRNA) Expression of Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx) | MHC-IIa | 0.6 Arbitrary Units | Standard Deviation 0.3 |
Primary
Synthesis Rates of the Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx)
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.
Time frame: 9 Hours
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Participants with Obesity | Synthesis Rates of the Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx) | Myosin Heavy Chain - I (MHC-I) | 0.005 %/hr | Standard Deviation 0.001 |
| Participants with Obesity | Synthesis Rates of the Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx) | Myosin Heavy Chain -IIa (MHC-IIa) | 0.004 %/hr | Standard Deviation 0.001 |
| Lean participants | Synthesis Rates of the Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx) | Myosin Heavy Chain - I (MHC-I) | 0.006 %/hr | Standard Deviation 0.001 |
| Lean participants | Synthesis Rates of the Three Myosin Heavy Chain Isoforms (MHC I, MHC IIa, and MHC IIx) | Myosin Heavy Chain -IIa (MHC-IIa) | 0.005 %/hr | Standard Deviation 0.001 |
Primary
Whole-Muscle Protein Synthesis
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.
Time frame: 9 Hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Participants with Obesity | Whole-Muscle Protein Synthesis | 0.004 %/hr | Standard Deviation 0.011 |
| Lean participants | Whole-Muscle Protein Synthesis | 0.015 %/hr | Standard Deviation 0.005 |