Resistance Training and Cardiometabolic Health
Resistance Training and Cardiometabolic Health
This study will investigate the relationship between resistance training load and repetitions
 on cardiometabolic outcomes. The primary objective of this clinical trial is to determine
 whether high load or low load resistance exercise training affects arterial stiffness in
 overweight or obese men and women. Our secondary objectives are to investigate the effects of
 high and low load RT on vascular function, cardiac structure, and markers of insulin
 sensitivity. Finally, we are going to preliminarily explore the effects of resistance
 training on intestinal bacteria.
While it has been firmly established that aerobic exercise training is an effective modality
 for managing cardiometabolic disease risk, the influence of resistance training (RT) is not
 as well characterized. It is well established that RT improves muscular strength, size, cross
 sectional area, and bone mineral density. Alterations in muscle fiber type, glycolytic and
 oxidative enzyme profile, skeletal muscle proteins, and rates of protein synthesis also occur
 in response to RT and are obtained from skeletal muscle biopsies. Data from
 quasi-experimental studies suggest that moderate-to-high repetition RT with lower training
 loads may positively affect skeletal muscle proteins (Glucose Transporter Type 4 (GLUT4),
 Hexokinase 2 (HK2), and Adenylate kinase 2 (AK2) involved in insulin signaling in
 non-diabetic, obese men. However, data on high load, low rep RT on these variables is
 lacking. Thus, we will collect skeletal muscle biopsies to determine if changes in insulin
 signaling skeletal muscle proteins are present in response to both training with both high
 and low training loads. There is also a body of evidence suggesting that RT may improve
 VO2peak values in individuals with low baseline VO2peak values via a possible increase in
 capillary density, however, results are currently mixed. Low VO2peak values in overweight and
 obese individuals are positively associated with high risk of cardiovascular and all-cause
 mortality. Thus, we will measure VO2peak values to determine if (A) starting previously
 untrained obese individuals with RT can also improve VO2peak and (B) potential changes in
 VO2peak are load dependent. RT has also been reported to improve insulin sensitivity and
 central pressure. Additionally, aerobic exercise training may positively influence
 alterations in the intestinal microbiome, with no currently available evidence on the effects
 of RT, Although RT has been shown to be beneficial for improving arterial stiffness and
 insulin sensitivity, most of the available literature is based on protocols prescribing
 moderate-to-high repetitions and thus lower training loads. Thus, the effects of prescribing
 higher training loads on the aforementioned variables are not fully understood.

 Increased arterial stiffness (as characterized by carotid-femoral pulse wave velocity (PWV)
 and augmentation index) is a clinical marker for cardiovascular disease and an independent
 risk factor for adverse cardiovascular events and all-cause mortality. Increased arterial
 stiffness has is positively associated with insulin resistance and type II diabetes. In the
 early stages of insulin resistance, peripheral insulin action, which occurs primarily in the
 skeletal muscle is impaired. This leads to a compensatory increase in insulin release in
 order to maintain glucose homeostasis, thus leading to hypertrophy of the pancreatic β cells.
 During the early stages of insulin resistance, fasting glucose levels will remain normal,
 with hyperglycemia manifesting in the later stages. Chronic hyperinsulinemia and
 hyperglycemia in turn cause increases in the renin-angiotensin aldosterone system as well
 expression of the angiotensin type I receptor in vascular tissue, thus stimulating VSMC
 proliferation, which leads to an increase in arterial stiffness. Chronic hyperglycemia and/or
 type II diabetes can lead to an increase in the production of advanced glycation end products
 (AGEs), which are proteins or lipids that become glycated due to exposure to glucose.
 Excessive production of AGEs can lead to an increase in collagen cross linking in the
 vascular walls, which thus leads to an increase in arterial stiffness.

 Thus, it appears that increases in arterial stiffness occur due to perturbations in pulsatile
 shear and flow, which leads to abnormal turnover of scaffolding proteins, specifically
 excessive collagen production, and the proliferation of VSMCs, which results in a stiffer
 vasculature. This is exacerbated by the insulin resistant and/or hyperglycemic state due to
 an increase in local activity of the RAAS and expression of angiotensin I receptor activation
 in the vascular wall and an increase in age production, which leads to an increase in VSMCs
 and collagen cross-linking, respectively, thus further contributing to the development of a
 stiffer vasculature. These structural changes can have deleterious downstream consequences
 that include ischemic heart disease, myocardial infarction, and heart failure.

 Current studies on the effects of RT on arterial stiffness have reported mixed results. It
 has been suggested that training with higher loads may cause greater increases in stiffness
 than training with lower loads due to greater acute elevations in blood pressure that occur
 with high load RT. Case control studies have reported that resistance trained young and
 middle aged non obese men demonstrated higher levels of arterial stiffness when compared to
 their aged-matched counterparts. Alternative cross-sectional studies reported that muscular
 strength was inversely related with arterial stiffness. Follow-up randomized control trials
 (RCT) investigated changes in arterial stiffness after several months of RT in non-obese,
 resistance training naïve adults. Improvements in central pressure, in the absence of changes
 in PWV, have been reported in non-diabetic obese adults after 12 weeks of RT but the study
 lacked an effective control group. Additionally, improvements in insulin sensitivity in
 non-diabetic obese males after 12 weeks of RT but was not a randomized controlled trial
 (RCT). Improvements in endothelial function has also been reported after six months of
 progressive RT that included both moderate and high training loads. This is significant
 because endothelial dysfunction is a downstream consequence of increased arterial stiffness,
 and thus an improvement in endothelial function, as measured by relative flow mediated
 dilation (%FMD), in response to RT is a reflects an improvement in vascular function, which
 is unlikely to occur in conjunction with an increase in vascular stiffness. To our knowledge,
 there are no current published RCTs on the effects of high load RT that have measured both
 arterial stiffness and endothelial function. This study will follow up on previous studies by
 comparing the effects of two distinct RT protocols (high load vs low load) on arterial
 stiffness as, measured by PWV and augmentation index, and endothelial function, as measured
 by %FMD, to a nonexercising control group.

 A body of literature exists to suggest that morphological changes of the left ventricle take
 place in response to resistance training. Case control studies have reported that elite
 resistance trained athletes demonstrate evidence of left ventricular wall thickening. The
 increase in left ventricular wall thickness is referred to as concentric hypertrophy, which
 occurs in response to a chronic increase in afterload. This occurs in the presence of
 increased arterial stiffness, uncontrolled hypertension, and aortic stenosis, all of which
 can lead to heart failure (HF). RT induced concentric hypertrophy appears to be a
 physiological training adaptation, similar to the eccentric hypertrophy that takes place in
 response to aerobic training, and thus does not appear to be deleterious. Furthermore,
 current RCTs on the effects of RT on morphological changes of the LV suggest that this
 adaptation does not always occur or may occur in response to specific training volumes,
 frequencies, intensities, and/or over a longer training duration. Since the main outcome of
 this study is arterial stiffness, which is a precursor for concentric hypertrophy of the LV,
 we will also measure left ventricular wall thickness to see if A) morphological changes in
 the LV take place and B) if LV morphological changes are influenced by training load.

 Thus, it appears that moderate training loads are shown to improve insulin sensitivity in
 obese individuals. This is significant because insulin resistance is a precursor to increases
 in arterial stiffness. However, the effects of training with higher loads on insulin
 sensitivity is a current gap in the literature. It has been previously proposed that high
 load RT may reduce arterial compliance and/or lead to concentric hypertrophy of the left
 ventricular walls. However, current evidence suggests that both moderate and high training
 loads improve endothelial function, without negatively affecting the left ventricular wall.
 Since endothelial dysfunction is a negative downstream consequence of an increase in arterial
 stiffness, it is unlikely that it would improve in conjunction with an increase in stiffness.
 Thus, this study will be the first to measure all of these variables to determine if and how
 they are influenced by training load.

 The intestinal human microbiome is a recent target of interest due to its role in metabolic
 disease risk. Current evidence reports a link between cardiometabolic diseases and changes in
 the intestinal microbiota. The effects of exercise training on changes in the intestinal
 microbiome is also currently under investigation. Evidence in rat models currently suggest
 that voluntary and controlled aerobic exercise training is associated with favorable changes
 in the gut microbiome. However, human studies on the effects of exercise on the intestinal
 microbiome are currently lacking. .

 The purpose of this study is to investigate the effects and potential differences between
 high load and low load RT on arterial stiffness. Based on the above described gaps in the
 literature the current study will serve as a follow up RCT to previous studies and will
 further explore the link between RT, arterial stiffness, and insulin sensitivity. From an
 exploratory stand-point we will examine changes if any in the gut microbiome following
 resistance training versus control. The proposed study will serve as a follow up RCT to
 investigate the differences between high load and low load RT on markers of arterial
 stiffness and insulin sensitivity. This study will also serve as the first RCT to investigate
 the long-term effects of RT in the intestinal microbiome. Studies investigating the effects
 of high load/low repetition RT on cardiometabolic biomarkers are currently lacking, with the
 current body of literature focusing on the effects of moderate and low loads and high
 repetitions, with limited data on the effects of high load RT.
Inclusion Criteria:

 -  Male and female

 -  18-55 years of age

 -  BMI 25-40

 -  No recent history of starting a structured exercise program or diet in the last 3
 months

 Exclusion Criteria:

 -  Current smoker and/or recreational drug user

 -  Answers "yes" to one or more questions on the Physical Activity Readiness
 Questionnaire

 -  Diagnosed diabetes, heart disease

 -  History of anabolic steroid use in the past six months

 -  Taking medications for treatment of diabetes, heart disease, and hypertension.

 -  Orthopedic or musculoskeletal contraindications to resistance training

 -  Unwilling to follow any aspect of the study protocol including blood sampling and
 weight training