A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand Gauteng, May 2018 / Background The trunk is the centre of the kinetic chain, connecting upper and lower limbs and transferring energy during movement. Proximal stability serves as a base for quality movements distally. Trunk muscle stability and strength-endurance are associated with sporting performance. Asymmetrical sport-specific adaptation in the morphometry of the trunk muscles has been investigated and described in cricket pace bowlers, but not linked to or described in terms of the association with bowling performance. Aim The aim of this study is to investigate the association between bowling performance and trunk muscle stability, strength-endurance and thickness in adolescent pace bowlers. Method In this observational cross-sectional study, bowling performance, namely ball release speed and accuracy, was measured by means of a radar gun and accuracy target in the outdoor nets of the respective schools, where the 46 pace bowlers, aged 13-18 years old, were invited from. Trunk muscle stability was measured as the level passed on the Sahrmann Stability Scale and strength-endurance as the failing time in seconds according to the Bourbon Trunk Muscle Strength Test. Ultrasound imaging measured the thickness of external oblique, internal oblique, transversus abdominis and lumbar multifidus in millimetre. Spearman’s correlations were used to determine associations between individual variables and a multiple linear regression analysis calculated predictors of bowling performance, including independent variables such as age, height and weight. Statistical significance was set at p<0.05. Results No association was found between trunk muscle stability and ball release speed (r=0.278; p=0.061) or accuracy (r=0.026; p=0.866). Stability, however, accounted for a 60.7% variance in ball release speed (p=0.004), increasing ball release speed by 3.570 units per unit increase in stability. Strength-endurance of the trunk muscle chains did not correlate to ball release speed (r=-0.039-0.214; p=0.154-0.796) or accuracy (r=-0.062-0.131; p=0.385-0.801). A moderate and fair relationship was found between ball release speed and transversus abdominis (r=0.543; p=0.0001) at rest and contracted (r=0.440; p=0.002), respectively. Non-dominant transversus abdominis showed a fair relationship with height at rest (r=0.458, p=0.001) and a moderate correlation with weight (r=0.625, p<0.001). On the dominant side, transversus abdominis at rest, showed a moderate relationship to ball release speed (r=0.564; p<0.001), height (r=0.539; p<0.001) and weight (r=0.611; p<0.001). Thickness of bilateral transversus abdominis at rest had an R-square value of .67 and ball release speed increased with 5.133 units for each unit increase in the thickness of the non-dominant transversus abdominis and 4.677 for that on the dominant side. Accuracy did not correlate with any independent variable, but weight (R-square value .207) was found to increase accuracy by .766 units for each unit increase. Bowling performance was found to be predicted by age (R-square value 0.084). Conclusion A direct association between bowling performance and trunk muscle stability and strength-endurance was not found. Trunk muscle stability – as a suppressor variable – was found to be a predictor of ball release speed. Trunk muscle thickness accounted for the variance in ball release speed and weight for that of accuracy. These findings implicate that adolescent pace bowlers may be able to improve ball release speed by increasing trunk muscle stability and bilateral transversus abdominis thickness. However, future research is needed to confirm this statement. / LG2018

There is a saturable, dose-response relationship between the amount of protein ingested at a meal, the ensuing hyperaminoacidemia, and the subsequent skeletal muscle protein synthesis (MPS) response. Imposition of an external load, usually practiced as resistance exercise, on skeletal muscle is also a potent stimulus for increasing MPS and adds synergistically to the hyperaminoacidemia-induced rise in MPS. The current thesis examined the potential for meal-focused protein/leucine intake strategies, alone and in combination with resistance exercise, to augment MPS in older men. MPS was measured acutely (hours) using the continuous infusion of L-[ring-13C6]phenylalanine (Study 1) or over longer-term, integrated periods via ingestion of deuterated water (Study 2: 2-wk and Study 3: 3-d) while participants were free-living. In Studies 1 and 2 we examined whether a balanced versus a skewed pattern of protein intake across daily meals would enhance MPS during energy restriction (ER) in overweight/obese older men. Study 1 showed that a balanced consumption of protein during ER stimulated acute (%/h) myofibrillar protein synthesis (MyoPS) more effectively than a traditional, skewed distribution. Combining resistance training (RT) with a balanced protein intake pattern restored the lower acute rates of MyoPS during ER to the higher levels observed in energy balance. Study 2 showed no effect of daily protein intake pattern during ER on longer-term integrated MyoPS (%/d). However, the inclusion of RT during ER enhanced integrated MyoPS and the synthesis of numerous individual contractile, sarcoplasmic and mitochondrial skeletal muscle proteins with both protein intake patterns. Study 3 showed that leucine co-ingestion with daily meals enhanced integrated (%/d) MyoPS in healthy older men who were in energy balance and was equally effective among those consuming higher (1.2 g/kg/d) and lower (0.8 g/kg/d) protein intakes. Furthermore, the stimulatory effect of leucine co-ingestion on integrated MyoPS was further potentiated with the performance of resistance exercise. Collectively, these studies support the potential for per-meal recommendations, optimizing the protein dose consumed on a per-meal basis and leucine co-ingestion with meals, to augment MyoPS in older men, especially when combined with RT. These data have implications for recommendations to optimize MyoPS and possibly muscle mass in aging persons. / Thesis / Doctor of Philosophy (PhD)

Les statines sont des inhibiteurs de l’enzyme HMG-CoA réductase, une étape limitant la biosynthèse du cholestérol [1]. Elles sont efficaces dans la prévention primaire et secondaire des maladies cardiovasculaires [2-7]. L’utilisation de statines est associée à des effets néfastes au niveau du muscle squelettique d’environ 15% des patients, condition qui est nommée; myopathie induite par les statines (MIS) [8-15]. Les hypothèses concernant la MIS abondent mais il semble que les causes soient multifactorielles et que l’orchestration soit toujours mal comprise. Dans un premier temps, la structure générale et la compartimentalisation cellulaire seront abordées. Par la suite seront traités les acteurs et étapes du couplage excitation-contraction. Par après, les types de fibres et la plasticité phénotypique seront décrits. Puis, les mécanismes d’hypertrophie et d’atrophie seront passés en revue. Finalement, la dernière section portera sur l’utilisation des statines et la myopathie associée. Suite à cette introduction, les expériences à l’étude seront présentées sous forme d’article scientifique. Ce manuscrit en préparation élucide l’effet du traitement aux statines sur les ATP-ases calciques du réticulum sarcoplasmique. Il touche en effet les caractéristiques fonctionnelles et moléculaires de ces pompes en ce qui concerne les muscles rapides et les cellules musculaires en culture. Il contribue donc à une meilleure compréhension de la problématique multifactorielle que représente la MIS, s’insérant dans le portrait des connaissances en comblant un manque probant d’informations.

The robust regenerative capacity of muscle stem cells (MuSCs) and their progenitors depends on their ability to undergo rapid and vast changes to their transcriptome during cell state changes. While transcription factors and epigenetic remodelling proteins are critical to render genes permissive for transcription, often these genes are found to have paused promoter proximal RNA Polymerase II (Pol II) which remains in a rate-limiting poised state. Indeed, while prior studies have shown poised Pol II is often regulated by the Negative Elongation Factor (NELF) to induce rapid changes in gene expression, the specific need for NELF in somatic stem cell populations has not been previously examined. In this thesis, we identify a specific requirement for NELF-dependent promoter proximal Pol II pausing in proliferating myogenic progenitors. Here, NELF stabilizes nascent transcripts associated with the paused RNA Pol II at genes required to maintain muscle progenitors in cell cycle. This promotes expansion of the pool of myogenic progenitors required to adequately repair damaged skeletal muscle. Our molecular analysis suggests that in proliferating progenitors, NELF-bound Pol II ensures the stabilization of transcripts, and continued expression of genes that prevent p53-mediated cell cycle withdrawal and terminal differentiation. Unexpectedly, this work revealed a previously unappreciated contribution of proliferating myogenic progenitors to replenish the stem cell niche in support of MuSC self-renewal during skeletal muscle regeneration. Based on our results, new therapeutic avenues which could treat muscle wasting disease are also discussed.

Note:

CARM1 and skeletal muscle atrophy / Coactivator-associated arginine methyltransferase 1 (CARM1) is emerging as an important player in skeletal muscle biology. We sought to elucidate the role of CARM1 in mediating muscle mass and function, as well as in the induction and progression of the muscle atrophy program. To this end, we engineered CARM1 skeletal muscle-specific knockout (mKO) mice and employed distinct, but complementary models of muscle atrophy, including neurogenic muscle disuse, food deprivation, and the sarcopenia of aging. CARM1 mKO resulted in reduced muscle mass and myofiber cross-sectional area concomitant with dysregulated autophagic and atrophic signaling, which indicates the requirement of CARM1 for the maintenance of muscle biology. Interestingly, CARM1 deletion mitigated the progression of both denervation- and fasting-induced skeletal muscle atrophy as compared to wild-type (WT) mice. Key mechanistic findings revealed that CARM1 interacts with the master neuromuscular regulator AMPK and attenuates the expression and activity of its downstream autophagy and atrophy networks. Surprisingly, both male and female mKO mice have a significantly shorter lifespan versus their WT littermates, revealed by a ~50% reduction in survival at 22-months-old, which is equivalent to ~70 years-old in humans. As such, we observed significantly reduced functional outcomes of integrative physiology in old mKO mice compared to old WT animals, such as strength and motor performance. Taken together, these results indicate that skeletal muscle CARM1 is indispensable for maintaining muscle mass, function, and lifespan. Targeting the interplay between CARM1 and AMPK may offer a viable therapeutic strategy for combating life-limiting muscle wasting conditions. / Thesis / Doctor of Philosophy (PhD) / While muscle wasting and weakness remains a widespread issue, the mechanisms that control muscle atrophy are not entirely understood. Previous evidence suggests that coactivator-associated arginine methyltransferase 1 (CARM1) regulates skeletal muscle remodeling. However, the role of CARM1 during muscle atrophy is unknown. Therefore, the purpose of this work was to investigate the function of CARM1 during muscle wasting. We generated mice with CARM1 deleted in skeletal muscle and studied the impact of CARM1 deficiency on the loss of skeletal muscle mass during muscle disuse, food deprivation, and aging. We found that CARM1 is required to maintain muscle mass under basal conditions. Interestingly, knocking out CARM1 in muscle attenuated the progression of denervation- and fasting-induced atrophy. However, CARM1 deletion in muscle resulted in lower muscle strength and a reduced lifespan. CARM1 deficiency did not prevent aging-induced muscle loss. Overall, these findings advance our understanding of CARM1 in skeletal muscle biology.

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.