Ataxia-telangiectasia mutated kinase (ATM) is a serine/threonine kinase. Mutations in the ATM gene cause a rare autosomal multisystemic disease known as Ataxia-telangiectasia (AT). Individuals with mutations in both copies of the ATM gene suffer from increased susceptibility to ionizing radiation, predisposition to cancer, insulin resistance, immune deficiency, and premature aging. Patients with one mutated allele make-up ~1.4 to 2% of the general population. These individuals are spared from most of the symptoms of the disease. However, they are predisposed to developing cancer or ischemic heart disease, and die 7-8 years earlier than the non-carriers. DNA double-strand breaks activate ATM, and active ATM is known to phosphorylate an extensive array of proteins involved in cell cycle arrest, DNA repair, and apoptosis. The importance of ATM in the regulation of DNA damage response signaling is fairly well-established. This review summarizes the role of ATM in the heart, specifically in cardiac remodeling following β-adrenergic receptor stimulation and myocardial infarction.

While strength is indeed a skill, most discussions have primarily considered structural adaptations rather than ultrastructural augmentation to improve performance. Altering the structural component of the muscle is often the aim of hypertrophic training, yet not all hypertrophy is equal; such alterations are dependent upon how the muscle adapts to the training stimuli and overall training stress. When comparing bodybuilders to strength and power athletes such as powerlifters, weightlifters, and throwers, while muscle size may be similar, the ability to produce force and power is often inequivalent. Thus, performance differences go beyond structural changes and may be due to the muscle's ultrastructural constituents and training induced adaptations. Relative to potentiating strength and power performances, eliciting specific ultrastructural changes should be a variable of interest during hypertrophic training phases. By focusing on task-specific hypertrophy, it may be possible to achieve an optimal amount of hypertrophy while deemphasizing metabolic and aerobic components that are often associated with high-volume training. Therefore, the purpose of this article is to briefly address different types of hypertrophy and provide directions for practitioners who are aiming to achieve optimal rather than maximal hypertrophy, as it relates to altering ultrastructural muscular components, to potentiate strength and power performance.

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.

京都大学 / 新制・論文博士 / 博士(医学) / 乙第13540号 / 論医博第2280号 / 新制||医||1066(附属図書館) / (主査)教授 小濱 和貴, 教授 近藤 尚己, 教授 妹尾 浩 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

Background: A major problem in the treatment of human hypertension is the late diagnosis of hypertension and, hence, the delayed start of treatment. Very often, hypertension has existed for a long time and cardiac damage has already developed. Therefore, we tested whether late- onset antihypertensive treatment is effective in lowering blood pressure (BP) and in reducing or even preventing left ventricular hypertrophy and fibrosis. Methods: Twenty-one male 60-week-old spontaneously hypertensive rats (SHR) were included. Fourteen rats received oral treatment with captopril (CAP) either as monotherapy or combined with nifedipine (CAP + NIF) over 22 weeks. Seven untreated SHR served as controls. We examined the therapeutic effects on BP, heart weight and histological and biochemical markers of left ventricular remodeling and fibrosis. Results: At 82 weeks of age, BP was reduced in the CAP and CAP + NIF groups by 44 and 51 mmHg, respectively (p < 0.001), but not in untreated controls. Despite the late therapy start, cardiac hypertrophy and fibrosis were attenuated compared to controls. Both treatments reduced heart weight by 1.2 mg/g (25%, p = 0.001) and collagens I and III by 66% and 60%, respectively (p < 0.001), thus proving nearly equivalent cardioprotective efficacy. Conclusion: These data clearly emphasize the benefit of antihypertensive treatment in reducing BP and mitigating the development of cardiac amage even when treatment is started late in life.

Skeletal muscle is a plastic tissue capable of responding to environmental perturbations. Increased loading via resistance exercise (RE) activates muscle protein synthesis (MPS) and, to a lesser extent, muscle protein breakdown (MPB). The ingestion of protein further stimulates MPS and suppresses MPB, inducing a positive net protein balance and protein accretion – i.e., muscle hypertrophy. In contrast, muscle unloading reduces MPS, which is thought to be the key driver underpinning skeletal muscle atrophy. The degree of muscle hypertrophy and atrophy in response to loading and unloading varies significantly between individuals and provides an opportunity to investigate the molecular regulators of skeletal muscle remodelling. To that end, we developed a novel unilateral model in which one leg was subjected to RE to induce hypertrophy (Hyp) and the contralateral limb was immobilized to induce atrophy (At). In study 1, we characterized the morphological changes induced by our HypAt model and validated the use of ultrasonography to measure changes in muscle size in both limbs. We discovered that by assessing the differential change in muscle size between legs we reduced the coefficient of variation between subjects. This enabled a more in-depth means-based characterization of the molecular regulators of skeletal muscle remodelling. Indeed, we discovered significantly more genes regulated by muscle remodelling than similarly-sized studies. We also identified a transcriptional signature that scaled with lean mass gains in three independent cohorts and included RNA species that were only modulated at their untranslated regions. Finally, in study 3 we simultaneously measured MPS and MPB in response to short-term immobilization (4 days) and demonstrated for the first time that MPB is statistically unchanged by unloading. Taken together, these studies contribute significantly to our understanding of skeletal muscle remodelling under different loading states and provide a valuable hypothesis-generating resource for future research in the field. / Thesis / Doctor of Philosophy (PhD) / Adaptations of skeletal muscle to loading and unloading are variable between individuals. Herein, we employed a unilateral approach to better understand the drivers of this variability by assessing the influence of resistance training (RT) and disuse on muscle protein turnover and gene expression. First, we validated the use of ultrasound for measuring changes in muscle size in response to loading and unloading. We then identified thousands of genes regulated by loading status and discovered many that were correlated with lean mass gain – some of which would not have been detected without our model. We also demonstrated that RT-induced increases in muscle protein synthesis were not associated with changes in muscle size; however, reductions in muscle protein synthesis were associated with the degree of muscle atrophy observed in response to disuse. Together, these studies contribute significantly to our understanding of how skeletal muscle size is regulated by muscle loading and unloading.

No description available.

No description available.

No description available.

No description available.