Resistance training (RT)-induced skeletal muscle hypertrophy is partly responsible for the RT-induced increase in strength. Previously, we reported that exercise repetition load played a minimal role in the promotion of RT-induced gains in hypertrophy and strength gains in RT-naïve participants performing RE to volitional failure. Thus, the main aim of this study were to determine the effects of 12 weeks of RT on muscle strength and hypertrophy in a trained population. 49 resistance-trained men (mean ± SEM, 23 ± 1 years, 85.9 ± 2.2 kg, 181 ± 1 cm) were randomly allocated into a lower load-high-repetition group (HR, n=24) or a higher load-low-repetition group (LR, n=25). Repetition load was set so that volitional lifting failure was achieved within the repetition ranges of 20-25 (~35-50% of 1RM) for HR or 8-12 for LR (~70-85% of 1RM). Strength as one repetition maximum (1RM) was assessed pre and post. Changes in lean body mass (LBM), appendicular lean mass (ALM) and leg lean mass (LLM) were assessed using dual-energy x-ray absorptiometry (DXA). There were significant increases in strength in all exercises with no differences between groups (p > 0.05) with the exception of bench press where LR showed a greater increase in 1RM than HR (p = 0.012). Similarly, LBM, ALM, and LLM increased significantly following training in the HR group (1.0 ± 0.9kg, p < .001; 0.8 ± 1.1 kg, p < 0.05; 0.7 ± 0.9 kg, p < 0.01 respectively) and the LR group (1.6 ± 1.4 kg, p < .001; 1.0 ± 1.2 kg, p < 0.05; 0.7 ± 1.0 kg, p < 0.01 respectively) with no significant differences between groups (all p > 0.05). These data show that RE performed to volitional failure using either HR or LR induces similar adaptations strength and lean mass accrual in young resistance-trained men. / Thesis / Master of Science in Kinesiology / Resistance training (RT) results in an increase in muscle growth and an increase in strength. Previously, we have shown in young untrained males, that when exercise is performed until failure, or until the weight can no longer be lifted, that gains in muscle and strength were similar with the use of either light or heavy weights. The purpose of the study was to determine the effects of 12 weeks of RT on muscle growth and strength in young men who were already regularly participating in resistance exercise when performing either lower load high repetition RT (HR) or higher load low repetition RT (LR). Maximum strength and changes in muscle mass were assessed prior to and upon completion of the training protocol. Following 12 weeks of RT both groups increased muscle mass and strength to a similar extent with the exception of bench press which increased more in the LR group.

Oxidative stress is commonly associated with diet-induced metabolic syndrome (MetS) and left ventricular cardiac remodeling, but much remains unknown about the role of redox signaling, sensors, and switches in mediating the effects of high fat and sugar intake. In this work, I describe and apply an optimized method for quantifying changes in reversible protein-cysteine oxidation in the heart. This method uses isobaric tagging of cysteine thiols and mass spectrometry in a modified biotin switch on whole tissue lysate. Analyzing the resulting data with systems biology approaches helped delineate redox pathways playing a role in disease development, while cysteine-specificity provided exact targets for mutation-based mechanistic studies. Initial findings in a mouse model for MetS, wherein C57Bl6J mice were fed a high fat/high sucrose diet, identified energy pathways as the primary target of changing reversible cysteine oxidation. In follow-up studies, our collaborators helped validate the pathophysiological role of two particular cysteines in complex II; their early reversible oxidation and later irreversible oxidation contributed to decreased ATP output from cardiac mitochondria. A subsequent, more robust study revealed a weakness in our original method. While investigating the role of hydrogen peroxide-induced oxidative post-translational modifications (OPTMs) in the development of MetS sequelae, analysis of four mouse groups, each with an n=5, revealed that measurements of reversibly oxidized cysteine thiols were highly variable compared to those of all available thiols. Thus, I developed a strategy to address the source of variability and, in the process, improved many additional steps in the switch protocol. Finally, in an effort to clarify the role of the most stable reversible OPTM, glutathionylation (RSSG), we characterized the HFHS diet response in mice engineered to have more or less RSSG via genetic manipulation of glutaredoxin-1 expression. Those with more RSSG suffered worsened cardiac function, making them an ideal model for future studies with the methods optimized in this work. Studying the progression from poor diet to cardiac involvement in these and other mouse models using the methods described herein will aid in the design of diagnostics and targeted therapies against the growing burden of metabolic CVD.

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Purpose: In response to resistance exercise training, it has been shown that individuals with a previous training history acquire muscle volume at an accelerated rate. This phenomenon may be attributed, in part, to the myonuclear enrichment resulting from the proliferation of muscle progenitor cells, which promotes essential protein synthesis following subsequent muscle training. As a highly energy demand tissue, the successful hypertrophy of muscle fiber depends on mitochondrial biogenic progression. Moreover, the majority of genes that encode mitochondrial proteins are within nuclear genome. Therefore, in this study, we investigated the effect of increased number of myonuclei in response to the previous resistance exercise preconditioning on mitochondrial adaptations to subsequent resistance training. Our central hypothesis was that pre-trained muscles would show an accelerated acquisition of training-induced mitochondrial function leading to a greater skeletal muscle hypertrophy compared to previously non-trained muscles and this may be associated with increased number of myonuclei in the pre trained muscles. Methods: Thirty-two Sprague-Dawley rats were randomly assigned to four groups (n=8 per group) which include control, pre-training, training, and retraining group. Resistance exercise training was carried out by ladder climbing with weights attached to the tail at ages of either 8- (pre-training) and 36-week-old (training), or both (retraining). Each training session consisted of 3 sets of 5 repetitions, and the training protocol was performed every third day for 8 weeks. At 44 weeks of age, specific muscle groups were carefully collected and stored at -80 °C until further analyses. 4', 6-Diamidino-2-phenylindole staining, hematoxylin & eosin staining, cytochrome c oxidase and succinate dehydrogenase staining were performed. Western blotting and immunohistochemstry were performed to assess the abundance of mitochondrial regulatory proteins and the mitochondrial content. In complementary in vitro studies, confluent L6 myoblast cells were further grown in differentiation media for 4 days with or without insulin-like growth factor 1 (50 ng/ml) supplementation. Mitochondrial gene expression levels and mitochondrial respiratory function were assessed after 5-Aminoimidazole-4-carboxamide ribonucleotide (AICAR, 1 mM), a 5' AMP-activated protein kinase activator, treatment. Results: Myonuclei numbers were higher in training and retraining groups than control group (all, p &lt; 0.05), suggesting that ladder climbing training protocol increased myonuclei number. There was a significantly higher level of myonuclei number in pretraining group compared to the control group indicating that the acquired myonuclei during exercise preconditioning were retained over the 20-week detraining period. Muscle cross-sectional area, mitochondrial content and mitochondrial enzymatic activities (COX and SDH) were significantly greater in retraining group compared to training group (p &lt; 0.01, p &lt; 0.01 and p &lt; 0.05, respectively). In in vitro study, L6 myotubes preconditioned with IGF-1 showed increased myonuclei numbers within each myotube and presented a higher level of mitochondrial gene expression and oxygen consumption rate under AICAR treatment condition. Conclusions: These data provide physiological evidence that pre-trained muscle with more myonuclei make the muscles more responsive to subsequent training in terms of muscle hypertrophy and mitochondrial remodeling. Furthermore, this study provides a proof-of-concept of biological processes underlying potential nuclear-mitochondrial interplay during muscle hypertrophy. These findings warrant future studies to identify a novel target for mitochondrial medicine to treat muscle atrophy. / Kinesiology

Resistance exercise training (RET) can lead to muscle hypertrophy; however, the relative contribution that exogenous (protein supplementation and specific training variables) versus endogenous (biology inherent to the individual) factors have on RET-induced muscle hypertrophy is controversial. In Study 1, we provided an evidence-based conclusion that protein supplementation during periods of RET results in a small but statistically significant increase in RET-induced muscle hypertrophy. In Study 2, we corroborate previous research and observed that the amount of mass lifted per repetition (load) did not determine RET-induced muscle hypertrophy in resistance-trained men when RET was performed to volitional fatigue. In Study 4, we observed similar muscle fibre activation following resistance exercise with lighter versus heavier loads when both were lifted until volitional fatigue. In Studies 2 and 3, we observed no relationship between circulating anabolic hormones (e.g., testosterone) and RET-induced muscle hypertrophy. Nonetheless, in Study 3, we found significantly greater muscle androgen receptor content in the top versus the bottom quintile of respondents for muscle hypertrophy following 12 weeks of RET indicating that androgen receptor content, and not circulating androgen concentration, may be an important determinant of hypertrophy. Finally, in Study 5, we observed that RET-induced muscle hypertrophy was an consistent within an individual (independent of load and limb) but considerably different between participants. Together, these data suggest that the exogenous factors we studied – protein supplementation and load (when RET was performed to volitional fatigue) – had a relatively small influence on RET-induced muscle hypertrophy. In contrast, we found that endogenous variables, such as intramuscular androgen receptor content and likely other genetic influences, appear to contribute more to the significant heterogeneity seen in RET-induced muscle hypertrophy. Future research in this area should prioritize understanding the biology that underpins the individual variability in RET-induced muscle hypertrophy. / Thesis / Doctor of Philosophy (PhD) / Resistance exercise training (RET) increases muscle size (hypertrophy); however, the relative influence that protein supplementation, specific training variables, and individual (genetic) variation have on the RET-induced hypertrophy is controversial and largely unknown. Broadly, data in this thesis show that protein supplementation slightly augments RET-induced hypertrophy, and that the magnitude of RET-induced hypertrophy may be related to the number of androgen (e.g., testosterone) receptors inside an individual’s muscle. In contrast, we found that neither load nor hormones affect RET-induced hypertrophy. Interestingly, data in this thesis also show that RET-induced hypertrophy is consistent within an individual but varies considerably between people, which illustrates the greater influence that individual variation has on RET-induced hypertrophy. We conclude that when RET is performed with a high degree of effort, protein supplementation and specific training variables confer a relatively small benefit on RET-induced hypertrophy compared to the influence of biological variability between people.

Background: Resistance wheel running (RWR) can promote resistance-like training adaptations in mouse skeletal muscle (SkM), but its endurance-training effects are lesser known. Methods: Voluntary RWR was modulated as an exercise model to increase mouse hind-limb plantar-flexor torque and to promote endurance-training adaptations. Thirty male mice (cohort 1, n= 16; cohort 2, n= 14), were trained on a prototype RWR system that applied resistance relative to body mass (BM). Mice were sequentially, (1) screened for running ability (screening; 3-days); (2) trained with incremental adjustments to wheel loads (pre-training; 8-weeks); (3) grouped into cage-activity only (CA), and constant Low-0%, Med-15%, or High-25% BM resistance conditions (static training; 5-weeks); (4) trained with resistance adjusted in real-time (dynamic training; cohort 1, 7-weeks; cohort 2, 10-weeks); and (5) sacrificed for various assays. Plantar-flexor torque was determined during each training phase. After dynamic training, resistance runners in each cohort were sub-grouped post-hoc by work tertiles. Results: Wheel running distance varied between cohorts (cohort 2 > 1). During dynamic training, wheel running (±added-resistance) improved plantar flexor torque normalized to BM by 19% only in cohort 2 (p= 0.007). Muscle mass and cross-sectional area were unchanged. Runners in both cohorts (±added-resistance) improved maximal running capacity vs. CA-controls (+69% and +115%; both p < 0.05), but metabolic training adaptations were less evident. Conclusions: Wheel running promoted SkM strength and endurance, but there was a greater increase in endurance capacity than strength. This outcome may be due to adaptive signaling interference. / Master of Science