The main purpose of this dissertation was to compare performance and physiological outcomes of between a repetition maximum (RM) and a relative intensity using sets-and-repetitions (RISR) resistance training (RT) program in well-trained lifters. Fifteen subjects underwent RT 3 d·wk-1 for 10-weeks in either a RM group (n=8) or RISR group (n=7). The RM group achieved a relative maximum each day while the RISR group trained based on percentages. Testing included percutaneous needle biopsies of the vastus lateralis, ultrasonography, unweighted (g to assess within and between-group alterations. RISR from pre-to-post yielded statistically significant increases in Type I CSA (p=0.018), Type II CSA (p=0.012), ACSA (p=0.002), unweighted (p=0.009) and 20 kg SJ JH (p=0.012), unweighted (p=0.003) and 20kg SJ PPa (p=0.026), IPF (ppSR increased in unweighted (p=0.023) and 20kg SJ JH (p=0.014), and 20kg SJ PPa (p=0.026) from pre-to-post taper. RM yielded statistically significant increases from only pre-to-post taper for 20kg SJ JH (p=0.003) and CMJ JH (p=0.031). Additionally, RM had a statistically significant pre-to-post decrease in RFD from 0-50ms (p=0.018) and 0-100ms (p=0.014). Between-group effect sizes supported RISR for Type I CSA (g=0.48), Type II CSA (g=0.50), ACSA (g=1.03), all MYH isoforms (g=0.31-0.87), all SJ variables (g=0.64-1.07), unweighted and 20kg CMJ JH (g=0.76-0.97), unweighted CMJ PPa (g=0.35), IPFa (g=0.20), and all RFD (g=0.31-1.25) time-points except 0-200ms; with all other effects being of trivial magnitude (gSR training yielded greater improvements in vertical jump, RFD and maximal strength compared RM training. These performances results may, in part, be explained mechanistically by the superior physiological adaptations observed in the RISR group within the skeletal muscle. Taken together, these data support the use of RISR training in well-trained populations.

Skeletal muscle has the ability to increase in size (hypertrophy) after resistance is placed upon it. This hypertrophy is marked by significant upregulation of the mammalian target of rapamycin (mTOR) and its downstream targets. The upstream kinases, protein kinase B (also known as Akt) and AMP-activated protein kinase (AMPK), are two of the many regulators of the mTOR pathway. Recent studies suggest that the widely consumed neuroactive compound caffeine could potentially inhibit mTOR by acting through Akt and/or AMPK. The purpose of this thesis was to: 1) determine if caffeine can inhibit the mTOR pathway and ultimately attenuate skeletal muscle hypertrophy and 2) determine if this inhibition is through LKB1, an upstream regulator of AMPK. First, 3 month old male rats underwent unilateral tenotomy of the gastrocnemius, resulting in overloading (OVLD) of the synergistic plantaris muscle. The contralateral limb was sham-operated (SHAM) on. Rats were given ad libitum access to tap water or tap water + caffeine (1 g/L). The OVLD procedure resulted in significant hypertrophy of the plantaris which was attenuated after 1 wk of caffeine treatment. However, after two wks this effect was not observed. mTOR targets were examined in both the SHAM and OVLD plantaris muscle which showed significant upregulation with OVLD but no impact with caffeine treatment. Akt and AMPK was also assessed in the plantaris muscle which showed diminished Akt phosphorylation in 1 wk treated rats while the phosphorylation of AMPK remained relatively unaffected. Notably, caffeine caused decreased atrophy of the tenotomized gastrocnemius after 1 wk along with decreased body weight gains, food consumption, and retroperitoneal fat pad weight in both 1 and 2 wk treated rats. Second, to elucidate how caffeine could be impacting the mTOR pathway and how LKB1/AMPK might be involved, skeletal muscle specific LKB1 knockout (skmLKB1-KO) mice were subjected to high-frequency electrical stimulation (HFES) of the sciatic nerve resulting in contraction of the tibialis anterior (TA) and extensor digitorum longus (EDL) muscles against the larger gastrocnemius. All mice were given an intraperitoneal injection of saline or saline + caffeine (20 mg/kg BW at 1 g/L). HFES resulted in marked upregulation of mTOR targets in the TA/EDL of mice 0, 3, and 8 h post HFES. mTOR targets remained relatively unchanged with caffeine treatment. We also observed that these markers were consistently upregulated in our skmLKB1-KO mice with or without HFES. Our findings indicate that caffeine, at physiological concentrations, does not impact anabolic signaling. Furthermore, diminished LKB1 levels resulted in increased levels and activation of markers of protein synthesis.

No description available.

No description available.

No description available.

No description available.

No description available.

<p>The extent of skeletal muscle hypertrophy in response to resistance training is highly variable in humans. To explain the nature of this variability, we focused on the myogenic stem cell population, the satellite cell (SC) as a potential mediator of hypertrophy. Twenty-three males (aged 18-35yrs) underwent 16wk of progressive, whole body resistance training, resulting in changes of 7.9%±1.6 (range of -1.9 – 24.7%) and 21.0%±4.0 (range of -7.0 to 51.7%) in quadriceps volume and myofibre cross-sectional area (CSA) respectively. The SC response to a single bout of resistance exercise (80% 1RM), resulted in an expansion in type one fibre associated SC (MHCI-SC) content of 43.7%±10.4 24h post-exercise pre-training, that shifted, post-training, to an increase in type two fibre associated SC (MHCII-SC) content of 47.6%±21.2 72h post-exercise. Analysis of individual SC responses revealed a correlation between the relative change in MHCII-SC content between 24-72h pre-training and the percentage increase in quadriceps lean tissue mass assessed by MRI (r=0.663, p=0.001). The proportion of SC co-localized with MSTN decreased progressively in the acute time-course following exercise and correlated with SC expansion between Pre-24h (r=0.563, p=0.012) and Pre-72h (r=0.454, p=0.045) in the pre- and post-training time-courses. In conclusion, the SC response to exercise appears to become more specific with training; while individual capacity to invoke the SC response is predictive of training induced muscular hypertrophy and may be limited by the degree of MSTN co-localization.</p> / Master of Science (MSc)

Cardiovascular diseases (CVDs) are the leading cause of death and disability worldwide. The aging population and the rapidly increasing prevalence of obesity and type 2 diabetes will contribute to a growing epidemic of CVDs globally. Despite the extensive investigations in etiology, the pathogenesis of CVDs still not fully understand, and the treatment and prevention for CVDs are still limited. Significant interest has been raised in gut microbiota-host interaction since increasing evidence revealed that gut microbiomes play an important role in human health and diseases, including CVDs. Among more than two thousand gut microbiota metabolites, a compound named trimethylamine N-oxide (TMAO) was revealed to be closely related to CVDs. However, the impact of TMAO on cardiovascular health is still full of controversy and the direct impact of TMAO on heart tissue and cardiomyocytes has not been fully understood yet. In the first chapter, we reviewed the literature on TMAO-related atherosclerosis and cardiomyopathy to give us a general aspect of current research progress in the role of TMAO on CVDs. In this context, we provide an overview of the potential mechanisms underlying TMAO-induced cardiovascular diseases at the cellular and molecular levels, with a focus on atherosclerosis and cardiomyopathy. We also address the direct effects of TMAO on cardiomyocytes (a new and under-researched area) and finally propose TMAO as a potential biomarker and/or therapeutic target for the diagnosis and treatment of patients with CVDs. In the second chapter, the direct impact of TMAO on cardiac function was tested in vivo using wild-type C57B6L mice model. Four experiment groups were enrolled in the feeding protocol, which included 3w (different time points), 6w, and 13w feeding time to reveal the impact of short and longer periods of TMAO consumption on cardiac function. The plasma TMAO was measured by liquid chromatography-tandem mass spectrometry (LC/MS/MS) method at the end of the feeding protocol. Echocardiography and electrocardiography (ECG) were performed to assess the overall heart function. The histopathology staining was used to evaluate the cardiac microstructure change. By the end of the feeding protocol, the plasma TMAO all increased significantly in the TMAO group compared to the control no matter the TMAO feeding period. Echocardiography showed that 6w and 13w TMAO intake could significantly decrease cardiac contractility evidenced by decreased eject fraction (EF) and fraction shortening (FS). The electrocardiography (ECG) showed decreased R wave aptitude in 6w and 13w TMAO feed group with sinus rhythm. However, 3w TMAO intake had no impact on both cardiac contractability and ECG. Moreover, chronic TMAO supplement (13w) showed increased left ventricle (LV) mass on echocardiography and increased LV thickness on the tissue section. Further histology analysis revealed cardiomyocyte hypertrophy in the 13w TMAO-treated male group. Notably, the female mice showed significantly higher TMAO levels both in the control and treated group compared to the male, however, no gender difference was observed as to the ECG and echocardiography. In addition, the plasma inflammation cytokines were also analyzed and the tumor necrosis factor-α (TNF- α), interleukin 10 (IL-10), Fibroblast growth factor 2 (FGF β) and leptin were all increased in the 13w TMAO treated group compared to the control. These results suggest that chronic TMAO exposure led to increased plasma TMAO levels, which contribute to system inflammation and cardiac dysfunction due to cardiac hypertrophy in mice models. Research in chapter 3 demonstrates the potential underlying mechanisms of TMAO-induced cardiac dysfunction using adult mouse cardiomyocytes. In this study, we examined the direct effect of TMAO on reactive oxidative species (ROS) generation and factors related to cardiomyocyte contractibility, including, microtubule, Connexin43 (Cx43) expression, and gap junction intracellular communication (GJIC), intracellular calcium dynamics and transversal-tubule (T-tubule) both in acute and chronic TMAO challenge. Moreover, we also tested whether TMAO can enter cardiomyocytes directly. The results suggested that TMAO could enter cardiomyocytes through organic cation transporters (OCTs) and promote increased ROS generation via augmentation of NADPH oxidase 4 (Nox4). Moreover, both acute and chronic TMAO exposure could induce microtubule densification, which plays a critical role in intracellular protein transportation and cardiomyocyte morphology maintenance. We also demonstrated chronic TMAO exposure could inhibit the Cx43 expression at both cellular and tissue level, and therefore impact the GJIC for the first time. Besides, we also revealed that TMAO could interrupt intracellular calcium handling both acutely and chronically, especially documented by decreased efficiency in intracellular calcium removal, related to decreased sarcoplasmic reticulum Ca2+-ATPase (Serca2) expression. However, TMAO showed no impact on cardiomyocyte T-tubule network organization. Taken together, we demonstrated a direct destructive role of TMAO on cardiomyocytes' functional properties and provided a novel potential mechanism for TMAO-induced cardiac dysfunction. Overall, the research in this dissertation demonstrated the direct impact of TMAO on cardiomyocytes and cardiac function both in vivo and in vitro and evaluated the effect of TMAO both acutely and chronically. The TMAO can enter cardiomyocytes and induce Nox4-mediated oxidative stress, which could connect to multiple intracellular pathways, including microtubule densification, decreased Cx43 expression, and GJIC, as well as calcium handling dysfunction. Meanwhile, all these changes were closely related to the cardiomyocyte swelling observed in mice cardiac tissue after chronic TMAO consumption, which could ultimately contribute to cardiac contractile dysfunction and electrophysiology change in mice models. / Doctor of Philosophy / Cardiovascular diseases (CVDs) are a group of diseases related to our heart and blood vessels, such as heart attack and stroke. It is the leading cause of death and disability around the world, more common than diabetes and cancer. According to the reports of the American Heart Association, CVDs cost America 555 billion US dollars in 2016 while by 2035, the cost will reach 1.1 trillion. The individual, population, and economic impact of CVDs are tremendous, making CVD one of the largest public health problems at present. Despite the extensive investigations into the cause of CVDs, the exact underlying reason still not fully understand. The microbiome inside our body has raised much attention recently due to its close relationship with human health, including CVDs. The microbiome from the gut can affect our heart health both by affecting the immune system and its metabolites after we eat daily foods. Among thousands of metabolites, one named trimethylamine N-oxide (TMAO) has been shown to be related to increased CVDs risks. After we eat choline-rich food such as red meat and eggs, the gut microbiome can use these nutrients and produce TMA as metabolite waste, the TMA then goes into the liver and convert to TMAO via liver enzymes. However, the impact of TMAO on cardiovascular health is not fully understood yet. Our study uses the mice model to test whether TMAO has a direct impact on heat cells and heart function. We fed the mice with water containing 0.12% TMAO for different times including 3w, 6w, and 13w, and then check the mice's heart function through heart ultrasound and ECG. The results showed that TMAO could significantly harm heart function after long-term exposure in mice (13w). Further histology analysis of heart tissue showed increased heart cell size, which may contribute to decreased heart function. Certain blood inflammation cytokines related to CVDs also increased. The experiments using isolated mice heart cells showed that the ROS, which could harm the heart cells and related to lots of other damage processes in human health, were increased after exposure to the TMAO. Several other factors, including cell skeleton, cell channels responsible for cell-to-cell communication, and cell calcium balance were all damaged by TMAO, which could finally induce heart damage and heart diseases.

Benign masseter hypertrophy causes swelling at the angulus mandibulae and may be associated with masticatory myofascial pain due to hyperfunction from bruxism. The aim of this research was to use the systematic review process to investigate the true or reliable scientific evidence contained in four major databases pertaining to the efficacy and safety of intra-muscular injections of botulinum toxin A (BTX-A) for the treatment of masticatory myofascial pain and benign masseter hypertrophy associated with bruxism, compared with placebo or other traditional treatments prescribed for bruxism such as occlusal splints, pharmacotherapy, or lifestyle modification. Using the PICO format, a research question was formulated, MeSH terms were derived, and an electronic literature search was conducted in PubMed, Embase, Web of Science, and Cochrane. This sequence was followed by a screening and selection of articles by two independent reviewers according to defined inclusion and exclusion criteria. The selected studies were then evaluated and assessed based on study quality and identification of biases, and the results were summarized and reported. This review highlighted the lack of well-designed, randomized controlled trials to evaluate the efficacy and safety of botulinum toxin A for reducing the size/volume of the masseter muscles and for improving masticatory myofascial pain in patients who present with bruxism. Thus, the results were inconclusive.