Molecular Mechanisms of Exercise Benefits to Insulin Resistant People
- Conditions
- ObesityInsulin Resistance
- Interventions
- Behavioral: Resistance Exercise
- Registration Number
- NCT04158375
- Lead Sponsor
- Mayo Clinic
- Brief Summary
This proposal will investigate the underlying mechanisms of enhanced insulin sensitivity and improvement of muscle loss and performance in insulin resistant people by resistance exercise training. Based on the investigator's preliminary data, they hypothesize that the key regulators of health benefits of resistance training are two genes: PGC-1a4 and PPARB;, and that the increased expression of these genes following resistance training facilitates storage of glucose in muscle and enhances its utilization for the energy need of muscle for contraction as well as enhancing muscle mass and performance. The investigators will also determine whether resistance training can reduce the higher oxidative stress in insulin resistant humans and improve their muscle protein quality.
- Detailed Description
Identification of the molecular regulatory points of exercise benefits is of high national priority because of the opportunity to develop targeted novel therapeutics benefiting populations suffering from inactivity-related health problems, including T2DM and pre-diabetes, characterized by insulin resistance (IR). IR is most prevalent in the older population associated with sarcopenia. The investigators propose a novel metabolic regulatory role of PGC-1α4 (α4), a hypertrophy gene, enhanced by resistance exercise (RE). Based on substantial preliminary data, the investigators hypothesize that α4, in cooperation with PPARβ (Rβ), promotes muscle glycolysis and insulin sensitivity (IS) as well as increasing muscle mass and performance. Based on their novel preliminary data, they will also investigate whether by deacetylation of glycolytic proteins, RE enhances muscle glycolytic capacity. Rβ also reduces oxidative stress that not only enhances IS but also contributes to other health benefits. New mRNA based data indicates that RE reduces protein degradation which will be investigated in the current proposal. The investigators will determine whether 3 months of RE training enhances insulin sensitivity and muscle performance and mass in IR people through pathways of enhanced glycolysis, deacetylation of glycolytic proteins reducing protein degradation and enhancing synthesis and ameliorating oxidative stress. They will study 48 IR people 50-75 yrs before and after 3 months of either 4-times/week resistance training or sedentary life and compare them with lean IS people. They will collect vastus lateralis muscle biopsy samples before and after an acute exercise bout and following a mixed meal to measure markers of glycolysis, energy metabolites, glycogen synthase, glycogen content, α4, Rβ, insulin signaling proteins and proteome analysis. They will also measure markers of oxidative stress including 8-OXO-dg (measure of DNA damage), oxidative damage to proteins and subsequent muscle protein degradation, which they hypothesize is reduced by increased anti-oxidant effect of Rβ with RE training. They also will use in vivo labeling of specific muscle proteins utilizing stable isotope labeled tracers to determine whether α4 induced muscle hypertrophy occurs not only by reducing degradation but also by enhancing contractile protein synthesis. These studies will render the necessary mechanistic explanation on how RE enhances IS, glycolysis, reduces oxidative stress and promote muscle performance and mass in IR people, thus substantially contributing to health and life span.
Recruitment & Eligibility
- Status
- COMPLETED
- Sex
- All
- Target Recruitment
- 64
Not provided
Not provided
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description Insulin Resistant Exercise Group Resistance Exercise Resistance (RE) training will be performed 4 days per week using a combination of upper and lower body exercises at 8-12 repetitions per set. Resistance training will be performed using a combination of upper and lower body exercises using machine and free weights. Upper body exercises are chest press, incline press, seated row, lat pull down, triceps extension, biceps curl and lateral raises. Major muscle groups for upper body exercises will include chest (pectoralis major and minor), arm (biceps and triceps), shoulder (deltoids) and back (latissimus dorsi and rhomboids). Lower body exercises are leg press, lunge (with body weight progressing to dumbbells), seated leg extension, seated leg curl, calf raises and abdominal crunches. Major muscle groups for the lower body exercises will be thighs (quadriceps and hamstrings), calves (gastrocnemius and soleus) and core (rectus abdominus and obliques).
- Primary Outcome Measures
Name Time Method Change in PGC1a Expression Baseline and after 3 months Measures of PGC1a4 mRNA at baseline and after 3 months in IR people - in both randomization arms. Specifically, this analysis will be a linear regression of change in PGC1a4 from baseline to 3 months, with randomization group (binary) and baseline PGC1a4 as explanatory variables. Prior to analysis, PGC1a4 mRNA measures will be log transformed so that estimated effect sizes from the analysis can be exponentiated and interpreted as relative levels or 'fold changes'; in addition to testing we shall obtain a 95% confidence interval (CI) for these estimated effects.
Change in PPARb Expression Baseline and after 3 months Measures of PPARb mRNA at baseline and after 3 months in IR people - in both randomization arms. Specifically, this analysis will be a linear regression of change in PPARb from baseline to 3 months, with randomization group (binary) and baseline PPARb as explanatory variables. Prior to analysis, PPARb mRNA measures will be log transformed so that estimated effect sizes from the analysis can be exponentiated and interpreted as relative levels or 'fold changes'; in addition to testing we shall obtain a 95% confidence interval (CI) for these estimated effects.
Change in Protein degradation Baseline and after 3 months The primary analysis for outcome 3 will involve measures of protein degradation as fragment counts from multiple proteins. As there are counts for multiple proteins, some with high variability for which power will be relatively low to detect modest changes, we shall focus on the subset of proteins for which the estimated coefficient in variation (CV) of changes is less than 1.0 and we will perform this analysis in the RE-trained arm only. We will perform a simple paired t-test to assess changes; or possibly a test based on a negative binomial regression as the data are counts. These tests will be performed on each protein separately. To take account of multiple testing we shall estimate the false discovery rate (FDR) among those proteins with significance at the unadjusted 5% level and use global permutation-based tests to assess overall significance. We shall also perform informal comparison with protein degradation measures in the control arm.
- Secondary Outcome Measures
Name Time Method Change in Glycogen Content Baseline and after 3 months We will assess whether there are changes in glycogen content in muscle, and whether such changes are associated with changes in PGC1a4.
Change in Glycogen Synthase Baseline and after 3 months We will assess whether there are changes in glycogen synthase in muscle, and whether such changes are associated with changes in PGC1a4.
Trial Locations
- Locations (3)
Mayo Clinic in Arizona
🇺🇸Scottsdale, Arizona, United States
Mayo Clinic in Florida
🇺🇸Jacksonville, Florida, United States
Mayo Clinic in Rochester
🇺🇸Rochester, Minnesota, United States