Aging is characterized by a progressive decline in cardiac function. A critical contributor to the age-related impairment in heart function is the loss of cardiac myocytes through ??apoptosis??, or programmed cell death. A dramatic increase in the rate of apoptosis has been reported with aging in the rat left ventricle. In contrast, exercise training not only improves cardiac function, but also reduces the risk of heart disease. However, the ability of exercise training to modulate apoptotic signaling and apoptosis in the aging heart remains unknown. Therefore, the purpose of this study was to determine the effects of exercise training on apoptotic signaling and apoptosis in the aging heart. We hypothesized that (1) aging would increase pro-apoptotic signaling and apoptosis in the rat left ventricle, and (2) exercise training would ameliorate upregulation of Bcl-2 family-driven apoptosis in the heart. Four and 25 month old Fischer-344 rats were assigned to four groups: young control (YC), young trained (YT), old control (OC), and old trained (OT). Exercise training groups ran on a treadmill for 60 min/day at 15 m/min (15˚ incline), 5 d/wk for 12 wk. Protein expression of Bax, Bcl-2, caspase-9, and cleaved caspase-3 was measured using Western immunoblot analysis. Apoptosis (DNA fragmentation) was assessed using a cell death detection ELISA. Bax levels in OC were dramatically higher (+176.0%) compared to YC. In contrast, exercise training resulted in a significant decrease (-53.4%) in Bax in OT compared to OC. Bcl-2 levels in OC were lower (-26.3%) compared to YC. Conversely, exercise training significantly increased Bcl-2 levels by 117.8% in OT compared to OC. Caspase-9 levels were higher (+98.7%) in OC than YC, while exercise training significantly reduced caspase-9 levels in YT (-52.6%) and OT (-76.9%), respectively. Aging resulted in a dramatic increase (+122.8%) in cleaved caspase-3 levels and a significant decrease (-32.9%) with exercise training. Finally, apoptosis (DNA fragmentation) significantly increased (+163.8%) with aging and decreased (-43.9%) with exercise training. These novel data indicate that aging increases pro-apoptotic signaling and apoptosis in the left ventricle, while exercise training is effective in diminishing pro-apoptotic signaling and apoptosis in the aging heart.

Aging is characterized by a progressive decline in cardiac function. A critical contributor to the age-related impairment in heart function is the loss of cardiac myocytes through ??apoptosis??, or programmed cell death. A dramatic increase in the rate of apoptosis has been reported with aging in the rat left ventricle. In contrast, exercise training not only improves cardiac function, but also reduces the risk of heart disease. However, the ability of exercise training to modulate apoptotic signaling and apoptosis in the aging heart remains unknown. Therefore, the purpose of this study was to determine the effects of exercise training on apoptotic signaling and apoptosis in the aging heart. We hypothesized that (1) aging would increase pro-apoptotic signaling and apoptosis in the rat left ventricle, and (2) exercise training would ameliorate upregulation of Bcl-2 family-driven apoptosis in the heart. Four and 25 month old Fischer-344 rats were assigned to four groups: young control (YC), young trained (YT), old control (OC), and old trained (OT). Exercise training groups ran on a treadmill for 60 min/day at 15 m/min (15˚ incline), 5 d/wk for 12 wk. Protein expression of Bax, Bcl-2, caspase-9, and cleaved caspase-3 was measured using Western immunoblot analysis. Apoptosis (DNA fragmentation) was assessed using a cell death detection ELISA. Bax levels in OC were dramatically higher (+176.0%) compared to YC. In contrast, exercise training resulted in a significant decrease (-53.4%) in Bax in OT compared to OC. Bcl-2 levels in OC were lower (-26.3%) compared to YC. Conversely, exercise training significantly increased Bcl-2 levels by 117.8% in OT compared to OC. Caspase-9 levels were higher (+98.7%) in OC than YC, while exercise training significantly reduced caspase-9 levels in YT (-52.6%) and OT (-76.9%), respectively. Aging resulted in a dramatic increase (+122.8%) in cleaved caspase-3 levels and a significant decrease (-32.9%) with exercise training. Finally, apoptosis (DNA fragmentation) significantly increased (+163.8%) with aging and decreased (-43.9%) with exercise training. These novel data indicate that aging increases pro-apoptotic signaling and apoptosis in the left ventricle, while exercise training is effective in diminishing pro-apoptotic signaling and apoptosis in the aging heart.

No description available.

Skeletal muscle has the remarkable ability to remodel and repair when exposed to various stimuli such as exercise training and injury. Many factors contribute to the maintenance of healthy muscle mass throughout the lifespan including a functional population of resident muscle stem cells, commonly referred to as satellite cells (SC). When SC become active in response to a stimulus they proliferate and differentiate, eventually fusing to existing myofibres or to each other giving rise to new myotubes; while some SC revert to quiescence to maintain the SC pool. This process is termed 'the myogenic programme' and is governed by a complex network of transcription factors termed myogenic regulatory factors. SC are absolutely necessary for the repair of skeletal muscle, however, their role in mediating skeletal muscle remodelling following exercise training remains debatable. The effect of resistance exercise on SC content has been extensively studied in humans. However, a paucity of information exists in regards to the effect of 'non-resistance' type exercise training on SC content and function in healthy young adults. The purpose of this thesis was to determine the impact of nonhypertrophic exercise training on SC content. We examined the effect of high intensity interval training on the SC pool and determined that there was an increase in SC associated with remodelling hybrid fibres. We extended upon these findings by demonstrating that several high intensity interval training paradigms and traditional endurance training all resulted in an increase in SC pool activity without an overall expansion of the SC pool. Skeletal muscle regeneration is impaired in old rodents and is associated with a reduction in SC content. We therefore sought to determine whether nonhypertrophic exercise training in old mice was able to improve the regenerative response following injury. Exercise training resulted in an increase in SC content and improved skeletal muscle regeneration in old mice. In addition to previous work implicating SC in mediating skeletal muscle hypertrophy induced by resistance exercise training, this thesis provides evidence that SC are able to respond to exercise stimuli that are nonhypertrophic in nature. In addition, we demonstrate that nonhypertrophic exercise training results in an increase in SC content in old mice and this likely contributed to the improvement in skeletal muscle regeneration observed in old mice pre-conditioned with regular exercise. / Thesis / Doctor of Philosophy (PhD)

Master of Science / Department of Kinesiology / Katie M. Heinrich / Firefighting is an inherently dangerous occupation with high rates of injuries and fatalities, with the majority of line of duty fatalities due to cardiovascular events. Additionally, firefighters struggle with poor health and low levels of fitness, including very high (>80%) rates of overweight and obesity likely related to the culture of the fire service. Limited resources exist for fire departments that are sensitive to the culture and work requirements of these “tactical athletes”. Though there has been increasing interest in circuit-type high intensity exercise training programs, key research data are lacking for the firefighter population and few studies have focused on training firefighter recruits. PURPOSE: The purpose of this pilot investigation was to examine a novel physical training program on fire academy recruits’ health, fitness, and performance, in addition to examining the programs’ acceptability, feasibility, and future efficacy. METHODS: Thirteen participants were recruited from an entry level fire academy and were randomly assigned to either the control (CG, n=6) or intervention exercise group (TF20, n=7). Due to attrition within the first two weeks of the study, 10 male fire recruits (23±3 years) completed the study (CG, n=3, TF20, n=7). The CG were asked to continue their current exercise habits. TF20 were provided an online-based training program (The First 20) that included periodized workouts, nutritional information, and mental readiness education. All participants completed baseline and post-intervention assessments and 10-weeks of exercise training. Health assessments included resting and post-exercise heart rate and blood pressure and estimated VO₂[subscript]max. Anthropometric measures included height, weight, % body fat, % lean mass, and BMI. Performance was measured using the Candidate Physical Ability Test (CPAT). Psychosocial measures were assessed by a short questionnaire. A feasibility analysis was also completed for those in TF20 group. Due to the small sample size and group differences at baseline, descriptive statistics were calculated and each participant was reviewed as an individual case study. The Wilcoxon Signed Rank Test was used to test for significance among TF20 group. RESULTS: This pilot investigation provided effect sizes and parameter estimates necessary for the design of a larger randomized controlled trial. Even with a small sample size, TF20 group showed improvement on numerous outcome measures including CPAT performance (40% passing at baseline to 86% passing post-intervention). Of five TF20 participants completing the CPAT at baseline and post-intervention, four improved their passing time. TF20 participants significantly increased estimated VO₂[subscript]max (p=0.028) and significantly improved body composition (decreased fat mass (kg) and % fat mass, p=0.028). TF20 participants also significantly improved grip strength (p=0.018). The CG saw no statistically significant differences from baseline to post-intervention. TF20 group completed approximately 75% of the assigned workouts. Participants reported enjoying the workouts and stated a program like this should be offered for fire academy recruits in the future. CONCLUSION: While TF20 participants showed significant fitness gains, the small sample size limited comparisons to the control group or other covariates. TF20 program was well-received although there may be a better way to implement the intervention to increase participation. Participants mentioned they would like group workouts led by a certified strength and conditioning coach/peer fitness trainer as opposed to self-guided workouts. This investigation provides promising results for the efficacy of high-intensity training programs in firefighter recruits. Additionally, this study provides alternative guidance for exercise prescription designed specifically for the firefighter population.

Aging is associated with increases in regional and systemic vascular resistance and impaired ability to increase blood flow to active muscles during exercise. Aging enhances vasoconstrictor responsiveness in both humans and animals, and an increase in Angiotensin II-induced vasoconstriction is one possible mechanism for old age-associated increase in muscle vascular resistance. The purpose of this study was to determine 1) whether aging alters Ang II-induced vasoconstriction, 2) whether exercise training attenuates the age-associated alteration in Ang II-mediated vasoconstriction, and 3) the mechanism(s) through which aging and exercise training alter Ang II-induced vasoconstriction in rat skeletal muscle arterioles. Male Fischer 344 rats were assigned to 4 groups: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT). Exercise-trained groups performed treadmill exercises for 60 min/day at 15 m/min, on a 15º incline for 5 days/week for 10-12 weeks. First-order (1A) arterioles were isolated from soleus and gastrocnemius muscles for in vitro experimentation. Intraluminal diameter changes were determined in response to the cumulative addition of Ang II (3×10-11 - 3×10-5 M). Ang II dose responses were then determined following the removal of endothelium and treatment with NG-nitro-L-arginine methyl ester (L-NAME, 10-5 M), a nitric oxide synthase (NOS) inhibitor. Ang II-induced vasoconstriction was augmented in the aged skeletal muscle arterioles, both in soleus and gastrocnemius muscles, and age-associated increases in Ang II-induced vasoconstriction were abolished with the removal of endothelium and with L-NAME. Exercise training ameliorated the age-induced increase in Ang II-vasoconstriction, and this alteration was eliminated by the removal of endothelium and with NOS inhibition. These findings suggest that aging enhances Ang II-induced vasoconstrictor responses in the arterioles from both soleus, high oxidative, and white portion of gastrocnemius, low oxidative glycolytic muscles, and this age-associated change occurs through an endothelium-dependent NOS signaling pathway. These results also demonstrated that exercise training can ameliorate the age-associated increase in Ang II vasoconstriction in the arterioles from both high oxidative and low oxidative glycolytic muscles through an endothelium-mediated NOS mechanism.

Changes in intracellular Ca2+ ([Ca2+]f) and high-energy phosphates are known to induce adaptive changes in skeletal muscle during endurance exercising training, including mitochondrial biogenesis. Levels of [Ca2+]f are regulated by sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs) which are further regulated by sarcolipin (SLN), through a reduction in the apparent affinity of SERCAs for Ca2+. Furthermore, SLN reduces the efficiency of Ca2+ transport by SERCAs supporting a thermogenic role for SLN in skeletal muscle. Thus, it is possible SLN ablation could reduce Ca2+ and metabolic signaling during exercise training and attenuate increases in mitochondrial content. To investigate the potential role of SLN in the exercise-induced adaptive response of skeletal muscle, mice devoid of SLN (SLNKO) underwent endurance training for 8 weeks and were compared to WT controls. Maximal oxygen uptake (V̇O2 max) was measured with an exercise stress test while mitochondrial content was assessed through measurement of protein expression and maximal enzyme activities of several mitochondrial enzymes in soleus and extensor digitorum longus (EDL) muscles, which express high and low levels of SLN, respectively. All data were analyzed using a two-way analysis of variance (ANOVA) and student t-tests were conducted on enzyme data. V̇O2 max was found to not be significantly altered with exercise training in either genotype. Exercise training significantly increased the contents of adenine nucleotide translocase (ANT), cytochrome-c (cyt-c) and cytochrome-c oxidase subunit IV (COXIV) in soleus independent of genotype. Likewise, exercise training significantly increased cyt-c and COXIV expression (P<0.04), while increases in ANT expression were not significant (P=0.13) in the EDL. Two-way ANOVAs of mitochondrial enzymes in soleus revealed an interaction existed for succinate dehydrogenase (SDH) where its activity was increased only in the SLNKO mice (P<0.02). In comparison, exercise training significantly elevated activities of cytochrome c oxidase (COX) and citrate synthase (CS) activities (P<0.02) but not β-hydroxyacyl-CoA dehydrogenase (β-HAD; P=0.08), independent of genotype. Upon closer examination using student t-tests, it was determined that exercise training induced greater increases in COX and CS activity in SLNKO compared to WT controls (P<0.02), similar to and consistent with SDH data. In EDL, only SDH activity increased following exercise training, an effect that was independent of genotype. In conclusion, these data suggest that SLN ablation does not attenuate exercise-induced mitochondrial adaptations and may increase mitochondrial enzyme adaptations to exercise training in slow-twitch muscle. Further examination of the effects of SLN on Ca2+ and metabolic signaling may provide mechanisms explaining the results of this thesis.

Aging is associated with increases in regional and systemic vascular resistance and impaired ability to increase blood flow to active muscles during exercise. Aging enhances vasoconstrictor responsiveness in both humans and animals, and an increase in Angiotensin II-induced vasoconstriction is one possible mechanism for old age-associated increase in muscle vascular resistance. The purpose of this study was to determine 1) whether aging alters Ang II-induced vasoconstriction, 2) whether exercise training attenuates the age-associated alteration in Ang II-mediated vasoconstriction, and 3) the mechanism(s) through which aging and exercise training alter Ang II-induced vasoconstriction in rat skeletal muscle arterioles. Male Fischer 344 rats were assigned to 4 groups: Young sedentary (YS; 4 months), old sedentary (OS; 24 months), young trained (YT) and old trained (OT). Exercise-trained groups performed treadmill exercises for 60 min/day at 15 m/min, on a 15º incline for 5 days/week for 10-12 weeks. First-order (1A) arterioles were isolated from soleus and gastrocnemius muscles for in vitro experimentation. Intraluminal diameter changes were determined in response to the cumulative addition of Ang II (3×10-11 - 3×10-5 M). Ang II dose responses were then determined following the removal of endothelium and treatment with NG-nitro-L-arginine methyl ester (L-NAME, 10-5 M), a nitric oxide synthase (NOS) inhibitor. Ang II-induced vasoconstriction was augmented in the aged skeletal muscle arterioles, both in soleus and gastrocnemius muscles, and age-associated increases in Ang II-induced vasoconstriction were abolished with the removal of endothelium and with L-NAME. Exercise training ameliorated the age-induced increase in Ang II-vasoconstriction, and this alteration was eliminated by the removal of endothelium and with NOS inhibition. These findings suggest that aging enhances Ang II-induced vasoconstrictor responses in the arterioles from both soleus, high oxidative, and white portion of gastrocnemius, low oxidative glycolytic muscles, and this age-associated change occurs through an endothelium-dependent NOS signaling pathway. These results also demonstrated that exercise training can ameliorate the age-associated increase in Ang II vasoconstriction in the arterioles from both high oxidative and low oxidative glycolytic muscles through an endothelium-mediated NOS mechanism.

Changes in intracellular Ca2+ ([Ca2+]f) and high-energy phosphates are known to induce adaptive changes in skeletal muscle during endurance exercising training, including mitochondrial biogenesis. Levels of [Ca2+]f are regulated by sarco(endo)plasmic reticulum Ca2+-ATPases (SERCAs) which are further regulated by sarcolipin (SLN), through a reduction in the apparent affinity of SERCAs for Ca2+. Furthermore, SLN reduces the efficiency of Ca2+ transport by SERCAs supporting a thermogenic role for SLN in skeletal muscle. Thus, it is possible SLN ablation could reduce Ca2+ and metabolic signaling during exercise training and attenuate increases in mitochondrial content. To investigate the potential role of SLN in the exercise-induced adaptive response of skeletal muscle, mice devoid of SLN (SLNKO) underwent endurance training for 8 weeks and were compared to WT controls. Maximal oxygen uptake (V̇O2 max) was measured with an exercise stress test while mitochondrial content was assessed through measurement of protein expression and maximal enzyme activities of several mitochondrial enzymes in soleus and extensor digitorum longus (EDL) muscles, which express high and low levels of SLN, respectively. All data were analyzed using a two-way analysis of variance (ANOVA) and student t-tests were conducted on enzyme data. V̇O2 max was found to not be significantly altered with exercise training in either genotype. Exercise training significantly increased the contents of adenine nucleotide translocase (ANT), cytochrome-c (cyt-c) and cytochrome-c oxidase subunit IV (COXIV) in soleus independent of genotype. Likewise, exercise training significantly increased cyt-c and COXIV expression (P<0.04), while increases in ANT expression were not significant (P=0.13) in the EDL. Two-way ANOVAs of mitochondrial enzymes in soleus revealed an interaction existed for succinate dehydrogenase (SDH) where its activity was increased only in the SLNKO mice (P<0.02). In comparison, exercise training significantly elevated activities of cytochrome c oxidase (COX) and citrate synthase (CS) activities (P<0.02) but not β-hydroxyacyl-CoA dehydrogenase (β-HAD; P=0.08), independent of genotype. Upon closer examination using student t-tests, it was determined that exercise training induced greater increases in COX and CS activity in SLNKO compared to WT controls (P<0.02), similar to and consistent with SDH data. In EDL, only SDH activity increased following exercise training, an effect that was independent of genotype. In conclusion, these data suggest that SLN ablation does not attenuate exercise-induced mitochondrial adaptations and may increase mitochondrial enzyme adaptations to exercise training in slow-twitch muscle. Further examination of the effects of SLN on Ca2+ and metabolic signaling may provide mechanisms explaining the results of this thesis.

No description available.