Current study demonstrated the impact of heat therapy on skeletal muscle function in a model of Duchenne muscular dystrophy (DMD). The aim of this study was to: (1) examine the impact of treatment temperature on the skeletal muscle adaptation in DBA/2J mice; and (2) determine the impact of repeated HT for 3 consecutive weeks on body composition and skeletal muscle function in D2.mdx, a model of DMD. From study 1, we revealed that HT at 39℃ for 3 weeks significantly promoted relative muscle mass of both EDL and soleus muscle in DBA/2J mice. However, from study 2, HT at 39℃ for 3 weeks does not improve muscle function or increase muscle mass in a mouse model of DMD.

<p>Obesity is associated with an increase in low grade systemic inflammation. Skeletal muscle of individuals with obesity undergo numerous biochemical and morphological alterations including an increase in ectopic lipid accumulation in skeletal muscle and increased macrophage infiltration. Increased intermuscular adipose tissue and macrophages contribute to skeletal muscle inflammation and insulin resistance by secreting elevated proinflammatory cytokines and lipids. This also contributes to reduction in skeletal muscle quality, increasing the susceptibility of muscle to damage and impairing the regenerative response to muscle. Exercise training can reduce inflammation and improve skeletal muscle quality. Importantly reductions in inflammation occur without change in adiposity. Peroxisome proliferator activated receptor g coactivator 1-a (PGC-1a) exerts protective effects on skeletal muscle against damaging insults and may improve muscle regeneration.</p><p> The primary aim of my dissertation was to determine the mechanisms that lead to deficits in skeletal muscle integrity and regeneration in persons with obesity. In Chapter 1, an introduction to the various physiological, pathological, and clinical topics is provided. In Chapter 2, we investigated how exercise training and obesity independently alter skeletal muscle extracellular vesicle (EV) miRNA (miR) content. We found that obesity alters EV miR content indicative of altered anabolic signaling, while exercise training altered EV miR content in a manner indicative of reduced inflammation. In Chapter 3, we report that overexpression of PGC-1a reduces cardiotoxin induced damage of primary human myotubes but limits the ability of undifferentiated cells to reenter the cell cycle and produce progeny that could aid in the restoration of myotubes. In Chapter 4, we demonstrate that exposure to an obesogenic environment increases cardiotoxin induced damage of primary human myotubes from obese donors. In this study we also found that the restoration of myotube fusion index was reduced in lean and obese subjects when incubated with obesogenic media. In Chapter 5 is a review and summary of the outcomes described in Chapters 2-4, a discussion of the limitations of these experiments, and a discussion of future directions.</p>

The magnitude of improvements in muscular strength and size are influenced by the volume and intensity of a resistance training program. While it is clearly advantageous for resistance-trained individuals to utilize programming specific to these goals, it not clear which is more important. Therefore the purpose of the present investigation was to determine the effect of focusing on training volume versus intensity on changes in muscle size and strength. Changes in muscular strength and size were examined in 29 resistance-trained men following 8 weeks of resistance training. Participants were randomly assigned to either a high volume (VOL, n = 14, 4 x 10 – 12RM, 1min rest) or high intensity (INT, n = 15, 4 x 3 – 5RM, 3min rest) resistance training program. Lean body mass, lean arm and leg mass, were assessed by dual energy X-ray absorptiometry, while ultrasound images (VL-vastus lateralis, RF-rectus femoris, PM-pectoralis major, and TB-triceps brachii) were used to assess changes in muscle cross-sectional area (CSA) and thickness (MT). Strength was measured by one repetition-maximum (1RM) squat (SQ) and bench press (BP). Changes in muscular (RF & VL) activation in response to increases in submaximal SQ intensity (40-, 60-, 80-, & 100%-1RM) were assessed via surface electromyography. Blood samples were collected at baseline, immediately post, 30min post, and 60min post-exercise at week 3 (WK3) and week 10 (WK10), to assess plasma/serum testosterone, growth hormone (GH), insulin-like growth factor-1 (IGF1), cortisol (CORT), and insulin. Area under the curve analysis revealed a greater (p < 0.05) increase for VOL (WK3: GH & CORT; WK10: CORT) compared to INT. Compared to WK3, WK10 showed reduced responses for VOL (GH and CORT) and INT (IGF1). Significant group differences were observed for changes in lean arm mass (INT: 5.2 ± 2.9%, VOL: 2.2 5.6%) and BP 1RM (INT: 14.8 ± 9.7%, VOL: 6.9 ± 9.0%). Over the course of 8 weeks, our data indicate that trained men would benefit more when focusing on training intensity, rather than volume, for strength and size improvements.

Age-related deficits in muscle mass, strength, and function place an increased burden of work on existing skeletal muscle and may lead to early onset of neuromuscular fatigue (NMF) during activities of daily living. Resistance exercise (RE) is the proven method for improving neuromuscular function in healthy older adults. PURPOSE: To investigate the effects of 6 weeks of RE on the NMF threshold as well as strength and functional performance in older adults. METHODS: Twenty-four older adults were randomly assigned to 6 weeks of RE (EXE; n = 12; age 72 ± 6.3 y; BMI 28.4 kg/m2 ) or control (CONT; n = 12; age 70.3 ± 5.6 y; BMI 27.6 kg/m2 ). Body fat percent (BF%), lean mass (LM), and fat mass (FM) were measured using DEXA and participants performed a discontinuous cycle ergometer test, physical working capacity at fatigue threshold (PWCFT), to determine the onset of NMF. Functional performance was assessed by time to complete 5 chair rises (CHAIR) and walk an 8-foot course (WALK). Lower body strength was assessed by predicted 1-RM leg extension (1RM). Two-way Analysis of Variance (ANOVA; time [PRE, POST] x group [EXE and CONT]) and magnitude based inferences were used to compare dependent variables. RESULTS: RE significantly increased 1RM (35%; p = 0.001) and CHAIR (20%; p = 0.047). RE had a likely beneficial effect on WALK (15%) and a possibly beneficial effect on PWCFT (14%). There were no significant changes to LM or FM, however, women in EXE significantly decreased BF% (p = 0.020). CONCLUSION: Results suggest that RE improves measures of strength and functional performance and possibly the onset of NMF in older adults.

The purpose of this study was to observe physiological metrics relative to training-induced adaptations in conjunction with laboratory- and competition-based performances in a super-heavyweight weightlifter recovering from a meniscus injury. A retrospective analysis was conducted on a collegiate level male weightlifter (23.2 yrs; 131.9 kg; 187.3 cm) over the course of 21-weeks post-meniscus surgery. Body mass, body fat percentage, hydration status, vastus lateralis muscle cross-sectional area, jump performance, and isometric midthigh pull were regularly assessed as part of an ongoing athlete monitoring program. Pre-injury baseline (T0) measurements were collected relative to a major national competition (COMP1). Post-injury measurements took place at the end of sequential training blocks: strength-endurance training block 1 (T1), basic strength block 2 (T2), and transmutation block 3 (T3). The final measurement session (T4) was conducted three-days post-local competition (COMP2). Only statistically significant increases were observed from T0-T4 for muscle CSA (p=0.0367), isometric peak force (pp=0.0367), and rate of force development at 250ms (p=.0367). While non-significant changes were observed for jumping performance, jump height and net impulse did, however, return to baseline. Competition based performances also showed marked improvements from pre-to-post injury via an increase in weightlifting total (3.2%∆, +9kg) and Sinclair score (1.8%∆, +5.3au). Thus, based on these findings, implementing an evidence-based training program along with a sound athlete monitoring protocol can aid with reducing an athlete’s return-to-train timeline while improving physiological, laboratory- and competition-based performance outcomes.

Circulating endothelial cells (CECs) and endothelial progenitor cells (EPCs) are sensitive markers of cardiovascular damage and repair, respectively. The aim of this thesis was to advance the state of knowledge regarding CECs and EPCs, and the factors affecting their concentrations, in children and adolescents. The first and second studies demonstrated that CECs and EPCs were similar when participants were split by sex, chronological age (8-10 vs. 14-16 years), and biological age (≤ -1 vs. ≥ +1 year from peak height velocity). Moreover, CECs, but not EPCs, were positively associated with aerobic fitness and negatively related to daily moderate-to-vigorous physical activity. Neither CECs nor EPCs were related to level of adiposity. Although there was a large degree of inter-individual variability in both cell types, most of our data were clustered towards one end of the reported range. These observations highlighted the need to examine these cells in children with chronic conditions associated with an increased risk of poor cardiovascular health. Therefore, CECs and EPCs were examined at rest and in response to acute exercise in juvenile idiopathic arthritis (JIA) and healthy controls. Resting levels of CECs and EPCs were similar in both groups, which may be attributable to the low disease activity in the participants with JIA. High intensity, intermittent exercise (HIIE) and moderate intensity, continuous exercise (MICE) had no effect on CECs in both groups. Conversely, MICE led to a robust increase in EPCs in healthy controls; no such change was observed in youth with JIA. This thesis represents the first comprehensive assessment of CECs and EPCs in the context of fitness, physical activity, and acute exercise in children and adolescents. Future research should examine the function and fate of these cells in youth, as well as the potential mechanisms underlying the blunted EPC response to exercise in JIA. / Thesis / Doctor of Philosophy (PhD) / Fitness and physical activity are critical for maintaining and improving cardiovascular health in children and adults. We don’t know exactly how they do this but the evidence in adults suggests it may be related to rare cells in the blood involved in repairing damaged blood vessels. The main objective of this thesis was to learn more about these cells, called circulating endothelial cells and endothelial progenitor cells, in children. We found that only circulating endothelial cells were related to fitness and physical activity. We also found that endothelial progenitor cells increased when healthy children performed 60 minutes of cycling. On the other hand, these cells did not change when children with juvenile idiopathic arthritis performed the same exercise. More research is needed to determine exactly why these cells responded to exercise in healthy but not sick children, and to help us identify the optimal exercise to improve these cells in youth.

No description available.

Stretching is commonly used by many athletes in different sports. Although acute stretching, as part of a warm-up, can enhance range of motion, it may also reduce performance. Acute stretching can reduce peak force, rate of force production, and power output. Chronic stretching may enhance performance, although the mechanism is unclear. Acute stretching has little effect on injury. However, chronic stretching (not part of warm-up) may have some injury reduction potential.

<p>Under hypoxia mammals face many challenges, especially in terms of energy production. To conserve O2, mammals may enter a hypometabolic state or rely more heavily on anaerobic metabolism. However, the latter strategy is not a viable option during chronic hypoxia and other cellular changes are needed. Under chronic hypoxia, mammals have been predicted to alter their metabolic machinery in an attempt to increase the efficiency of ATP production to reduce the amount of O2 used by the mitochondria. One way efficiency is believed to increase is through a change in the composition of cytochrome c oxidase (COX). Cell culture experiments have shown a decrease in the COX4-1 isoform and an increase in the COX4-2 isoform under hypoxia, leading to an increase in the reaction efficiency of COX. In the present study, I observed an increase in the mRNA levels of COX4-2 after 24hrs of hypoxia. However, this change was not mirrored by corresponding changes at the protein level. Further, I examined the phosphorylation state of pyruvate dehydrogenase (PDH) as an indicator of PDH activity. Under chronic hypoxia resting mice exhibited a significant rise in PDH phosphorylation. This increase may represent a decrease in PDH activity and a decreased reliance on carbohydrate derived acetyl-CoA.</p> <p>I also explored the effects plastic changes in muscle during chronic hypoxia had on muscle metabolism during acute exercise. In hypoxic post-exercise mice, a significant increase in muscle lactate levels was observed compared to rest. This rise was not present in control mice, suggesting that acclimated mice were relying more heavily on anaerobic metabolism. However, there were no significant changes in PDH phosphorylation in post-exercise mice which could help to explain elevated muscle lactate levels.</p> / Master of Science (MSc)

The purpose of this thesis project was to elucidate the immune transcriptomic changes in the diaphragm of mdx mice treated with microdystrophin gene therapy with and without running wheel activity. Mdx mice are a model of Duchenne Muscular Dystrophy (DMD). Similar to DMD, mdx pathophysiology is associated with chronic inflammation due to sarcolemma fragility and cellular membrane leakage. Immune modulation has not yet been described when endurance exercise and AAV-microdystrophin gene therapy have been combined in mdx mice. An increase of physical activity in DMD individuals is a potential outcome of current clinical studies investigating microdystrophin treatment; therefore, understanding the impacts of physical activity on the immune system, particularly for the diaphragm, may be important to minimize risk. Recently, the Grange lab published the endurance and contractile property outcomes of combined microdystrophin gene therapy and running wheel activity in mdx mice.1 Diaphragm RNA-seq transcriptomic data were also collected from this study for gene expression analysis. Using this dataset, I tested the hypothesis that relative to mdxGT (mdx mice treated with gene therapy), transcripts related to the immune response such as immune cell recruitment, activation, and downstream signals that promote fibrosis deposition were unchanged or downregulated in mdxRGT (mdx mice treated with gene therapy and access to running wheel). DEGs (differentially expressed genes) were analyzed with Microsoft Excel, R, and bioinformatic tools such as KEGG and DAVID to explain immune system adaptations in response to combined microdystrophin treatment and running in mdx mice. Two major inflammatory signaling pathways, the IL-6/JAK/STAT and NF-kB signaling pathways translationally relevant to DMD patients were rescued by gene therapy towards WT expression levels. Although running maintained the majority of the rescued transcriptome profile (691 of 724 genes), some immune response-related gene expressions (33 of 724 genes) were modulated including genes related to chemotaxis and cellular migration. These changes suggested potential signaling for angiogenesis and a fast to slow fiber type shift; however, unbiased analysis with bioinformatic tools did not confirm either of these possibilities. The data from this study revealed inflammatory and fibrotic signaling pathways commonly observed in DMD patients and mdx mice were rescued by the AAV microdystrophin gene therapy and were maintained by voluntary wheel running / Master of Science / Duchenne Muscular Dystrophy (DMD) is an X chromosome-linked muscular dystrophy, a genetic disease that affects around 1 in 14,000 boys globally. DMD is lethal and currently there is no cure. Mutations in the DMD gene results in the absence of the protein dystrophin. The dystrophin protein and other proteins associated with it provide structural support to the skeletal muscle membrane. Without it, muscles are more easily damaged during contraction. This damage promotes recruitment of immune cells which initiates the first stage of muscle repair. Under normal circumstances, this inflammatory reaction caused by immune cells restores the skeletal muscles. However, in DMD patients, repeated breakdown and regeneration of skeletal muscles leads to abnormal inflammation which promotes negative outcomes such as increased fibrosis. Fibrosis impairs muscle function, especially the diaphragm . Hamm et al., 2021 from the Grange lab investigated the effects of microdystrophin gene therapy and increased physical activity in mdx mice, a mouse model of DMD, with the idea that some of the negative changes with muscular dystrophy could be improved. The results showed a positive increase of endurance capacity in mdx mice treated with gene therapy alone (mdxGT group) and a greater increase if the mice also used a running wheel (mdxRGT group) compared to untreated mdx mice (mdx group). These findings suggested that gene therapy can increase a DMD patient's ability to become more physically active. However, the effects of running and microdystrophin gene therapy on the damaging inflammatory response in the diaphragm were not reported. To address this question, gene expression data from diaphragm muscles of all treatment groups were collected in the Hamm et al., 2021 study for later analysis. In my study, these diaphragm gene expression data were used to compare inflammatory signals between the various treatment groups. Indicators of skeletal muscle damage, immune cell accumulation and fibrosis deposition were rescued (i.e., returned to healthy mice levels) by microdystrophin gene therapy (mdxGT group). Running did not exert any negative effects on the majority of genes rescued by the microdystrophin therapy (mdxRGT group). These results indicated that voluntary wheel running could maintain the reduced inflammatory signals due to the microdystrophin gene therapy in mdx mice. If the function of the skeletal muscle of dystrophic boys was similarly improved by microdystrophin gene therapy and exercise did not interfere with its positive effects, DMD boys could potentially be physically active similar to normal boys of their age.