Resistance Training and Cardiometabolic Health

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