Two experiments were undertaken. The objective of Experiment One was to identify the lower limb muscles that were most frequently active during the early period of a step turning task for further testing in Experiment Two. In Experiment Two participants undertook multiple trials of a step-turning task, 30 and 60° to the left and right of midline, at a self-selected pace in response to a visual cue. There were five objectives to Experiment Two. Firstly, to identify the predominant order in the onset of foot movement so that anticipatory muscle activity could be defined for this task. Secondly, to identify whether there is a consistent temporal order in movement onset between the head and the feet. Thirdly, to identify whether and how consistently anticipatory lower limb muscle activity is present bilaterally. Fourthly, to assess whether there is a consistent sequence in the onset of anticipatory muscle activity among muscles active in at least 80% of trials. The final objective was to identity whether there was a consistent temporal relationship in the onset of the anticipatory muscle activity present in at least 80% of trials, with the onset of head and foot movement. Study Design: A repeated measures design was used. Background: Anticipatory lower limb muscle activity in gait initiation and forward stepping studies has been reported to be consistently present, and associated with initial and important balance responses. Falls during turning are associated with a high incidence of hip fractures in the elderly population. The presence of anticipatory lower limb muscle activity turning has not been previously reported. Participants: There were five participants in Experiment One, and ten in Experiment Two. All were between 18 and 40 years of age and did not have neurological or musculoskeletal disorders, or severe visual loss. Results: In Experiment One, four muscles were consistently active bilaterally, during the early period of step-turning and were: tibialis anterior, gastrocnemius, biceps femoris and gluteus medius. In Experiment Two the ipsilateral foot moved before the contralateral foot in 68% of trials towards the left, and 79% of trials towards the right. The onset of head movement consistently occurred before the onset of foot movement during turns towards both directions. The percentage of trials in which the four muscles were active in an anticipatory manner was low bilaterally, ranging from 12 to 38% of trials. Objectives that involved the further analysis of muscles active in at least 80% of trials were unable to be completed. Conclusions: During a step-turning task young healthy adults predominantly move their ipsilateral foot before their contralateral foot. The consistent onset of head movement prior to that of the feet, indirectly suggests that the visual system might influence the temporal onset of the feet. The low levels of anticipatory muscle activity during step-turning suggest that the lower limbs are not involved with the initial balance responses for this task thus making it inherently different to gait initiation and forward stepping.

[Truncated abstract] The inclusion of a warm-up in the form of prior exercise (PE) is generally advocated as a preparatory strategy of choice to improve sprint performance. Although there is evidence that both increasing muscle temperature and mobilising the cardiorespiratory system prior to exercise contribute largely to the benefit of PE on sprint performance, their relative importance is unknown. Another important question relates to situations where an athlete has to engage in a sprint shortly after one or several earlier sprints. Under these conditions, is engaging in mild exercise also the most effective preparatory strategy to adopt prior to sprinting when performed after a previous sprint(s)? It was the primary aim of this thesis to address these questions. Firstly, we hypothesised that there is a temporal shift in the mechanisms responsible for the effect of PE on power output during a maximal sprint effort, with temperature-dependent mechanisms playing a more important role at the onset of the sprint and mobilisation of the cardiorespiratory system playing a more important role later. To test this hypothesis, we compared the responses of a 30-s sprint to different PE protocols designed to control for either muscle temperature or pre-exercise VO2. ... A group of trained athletes was subjected to four consecutive bouts of 30-s sprint, each separated by 20 min of either active recovery at 40% VO2 peak or passive recovery. Our results show that PP, MP-20 and MP-10 did not fall between the first and last sprints, and were not affected by active recovery. In contrast, we found that MP10 and MP30 decrease significantly between the first and last sprint of the passive recovery trial, but not when active recovery is performed between consecutive sprints. Finally, this study also showed that the fall in mean power associated with repeated 30-s sprints in the passive recovery trial resulted primarily from a fall in early, but not late power output. These findings show that the early and late mean power output of repeated sprints respond differently to active and passive recovery, with the decrease in total mean power with repeated 30-s sprints resulting primarily from a fall in early as opposed to either late power output or peak power, thus highlighting the benefit of active recovery as a favourable preparatory strategy for the performance of repeated sprints of short (<10s) or longer duration (<30s), but not for repeated peak power.

Muscular dystrophy is a genetic disease which affects the morphology, physiology and biochemical nature of the muscle fiber. This study was designed to examine the progressive effects of muscular dystrophy on the differentiation process of skeletal muscle. Chapter 1 examines the neonatal development of muscle spindles and their intrafusal fibers in the soleus and extensor digitorum longus (EDL) of genetically dystrophic mice according to histochemical, quantitative, and ultrastructural parameters. Despite alterations in the surrounding extrafusal fibers, muscle spindles and their intrafusal fibers appeared enzymatically and histologically unaffected in incipient stages of murine dystrophy. In the second chapter the distribution and concentration of parvalbumin (PV), a calcium-binding protein, in 32 and 2-week-old dystrophic mice was mapped by immunohistochemical and biochemical procedures. The number of parvalbumin-immunoreactive fibers was significantly reduced in the adult dystrophic EDL but slightly increased in the adult dystrophic soleus. No differences between strains were observed in the 2-week samples. These findings were supported by routine myosin ATPase histochemistry. Parvalbumin was isolated on SDS-PAGE gels and the concentration of PV was estimated by a RIA. These results confirmed the immunohistochemical data in that PV content was dramatically reduced in the adult dystrophic EDL and significantly increased in the dystrophic soleus. No changes were detected in the samples of the 2-week-old muscles. The similarity in the distribution and content of PV between the fast and slow dystrophic muscles at 32 weeks of age suggests an alteration in the distribution and phenotypic expression of fiber types in muscular dystrophy and supports the hypothesis that dystrophy alters the normal differentiation process of skeletal muscle. / Medicine, Faculty of / Cellular and Physiological Sciences, Department of / Graduate

Le but de cette dissertation doctorale était de mieux comprendre les mécanismes de contrôle tant centraux que périphériques qui sont à l’origine de la régulation neuromusculaire lors de mouvement impliquant des contractions de type excentrique. Lors d’une première étude réalisée sur le muscle jambier antérieur, nous avons montré qu’un exercice utilisant des contractions excentriques présentait une meilleure résistance à la fatigue que lorsque des contractions concentriques étaient impliquées puisque celui-ci conduit à une moindre diminution du couple de force et de l’activité électromyographique. L’absence de fatigue nerveuse centrale et l’observation d’un comportement spécifique du couple de force et de l’activité électromyographique lors de ces épreuves de fatigue semblait traduire la mise en jeu de processus périphériques différents. La plus grande fatigue observée lors de l’épreuve concentrique suggérait une activation plus importante que pour l’épreuve excentrique, dont les conséquences métaboliques renforcent les altérations du couplage excitation-contraction. Dans un second temps, nous avons étudié l’effet des modifications de longueur de fascicule du muscle jambier antérieur sur le comportement spécifique des unités motrices (ordre, fréquence et seuil de recrutement) lors de contractions isométriques. Nous avons ensuite analysé le comportement d’unités motrices selon les différentes modalités de contractions (concentrique vs. excentrique) sur ce même muscle. Pour y répondre, différentes techniques d’analyse ont été utilisées dont l’enregistrement électromyographique intramusculaire et l’ultrasonographie. Enfin, nous avons cherché à analyser l’évolution des différents mécanismes de régulation d’origine périphérique et /ou central susceptible de modifier l’excitabilité du pool de motoneurone lors de contractions concentriques et excentriques. Pour y répondre, les modulations d’une part, du réflexe de Hoffmann (réflexe H) par stimulation électrique et d’autre part, celles du potentiel moteur évoqué (MEP) par stimulation magnétique transcorticale, ont été investiguées. Ces réponses ont été enregistrées à différents angles de la plage articulaires étudiée lors des contractions concentriques et excentriques, ainsi qu’aux deux extrémités angulaires lors de contraction isométriques. Notre travail indique que l’ordre de recrutement des unités motrices entre les contractions concentriques et excentriques étant identique, le système nerveux n’utilise qu’une seule et même stratégie d’activation liée à la taille des motoneurones impliqués dans ces deux types de contractions. En outre, les contractions excentriques lorsqu’elles sont réalisées à vitesse constante, sont associées à une modulation spécifique de la fréquence de décharge des unités motrices. Ce comportement diffère de celui observé lors de contractions concentriques, malgré une modification linéaire et similaire de la longueur des fascicules et du couple de force au cours de ces deux tâches. Les modulations du recrutement des unités motrices semblent davantage dépendre de la longueur musculaire tandis que les modulations de fréquence prédominent pendant les contractions en raccourcissement. Ce comportement spécifique semble dépendant de mécanismes de régulation principalement localisés au niveau spinal. Ainsi, le degré d’inhibition des afférences fusoriales affectant le pool de motoneurones du muscle tibial antérieur lors de sollicitations actives du muscle, dépend davantage de l’angle articulaire et donc de la longueur du muscle plutôt que du mode de contraction. Lors de sollicitations isométriques, le retour sensoriel Ia est principalement contrôlé au niveau présynaptique en fonction de la longueur du muscle. Lors de sollicitations concentriques et excentriques, ces mécanismes présynaptiques réguleraient l'excitabilité spinale de manière similaire entre les deux modes. Néanmoins, bien que l'inhibition présynaptique soit probablement plus marquée lors des sollicitations excentriques, ce mode de contraction semble également régulé par des mécanismes d'inhibition intervenant au niveau postsynaptique tel que l'inhibition récurrente de Renshaw. Ce mécanisme localisé au niveau postsynaptique permettrait de réguler la fréquence de pulsation des unités motrices lors de sollicitations excentriques dans le but le faciliter l'exécution du mouvement. L'originalité de notre travail a été d’étudier le comportement d’une même unité dans les deux modes de contractions alors que la méthode d’analyse généralement adoptée consistait à comparer des populations d’unités motrices entre-elles. De plus, les changements de la longueur du muscle au cours du mouvement ainsi que les vitesses de raccourcissement ou d'allongement ont été estimés à partir de la mesure directe de la longueur des fascicules musculaires. Cette dernière présente l’avantage de fournir une information de longueur et de vitesse sur la portion de muscle à partir de laquelle les enregistrements d’unités motrices ont été obtenus. Enfin, étant donné les modulations possibles tant au niveau spinal que supraspinal des mécanismes nerveux mis en jeu, il semblait important d’analyser celles-ci pendant le mouvement et aux différents angles investigués. Cette précision méthodologique a permis d'élargir la discussion concernant les possibles modifications de la balance "excitation-inhibition" lors de sollicitations excentriques, qui, jusqu’à présent, n'avaient été analysées que pour un angle articulaire donné. / Doctorat en Sciences de la motricité / info:eu-repo/semantics/nonPublished

Thesis (MSc)--University of Stellenbosch, 2007. / ENGLISH ABSTRACT: Human studies on the response of muscle to contusion injury are limited, probably due to the large variability in injury severity and the non-specificity of clinical symptoms reported. To circumvent this problem, several experimental animal models have been designed to study muscle damage and regeneration after contusion injuries. However, the majority of techniques currently used to induce contusion injury are very invasive and therefore not optimal. Furthermore, published studies regarding clinical treatment of such injuries are limited. The main aims of this study were therefore: a) to establish and characterise an in vivo model of non-invasive contusion injury, and b) to assess the effect of pre-injury chronic administration of the antioxidant supplement Oxiprovin™ - a natural grape seed extract (GSE) - on skeletal muscle recovery after experimentallyinduced injury. Two groups of male Wistar rats were subjected to 14 days of oral administration of isovolaemic placebo (sterile isotonic saline) or GSE (20 mg/kg/day) prior to induced contusion. Contusion injury was induced with the mass-drop technique, and recovery parameters assessed for up to 14 days post-injury. Placebotreated rats on average exhibited a 56 % higher creatine kinase (CK) activity when compared to the GSE-treated rats when area under the curve (AUC) was calculated for 14 days post-injury (p < 0.001). In the placebo group, plasma oxygen radical absorbance capacity (ORAC) was unchanged over time, but muscle ORAC was significantly increased by day 7 post-injury (p < 0.001). In the GSE group, a significant decrease in both plasma (p < 0.01) and muscle ORAC (p < 0.001) was evident 4 hr after injury, followed by a significant increase by day 3 (p < 0.05 and p < 0.001 respectively). CD34+ satellite cell (SC) numbers (quiescent and activated) peaked earlier in GSE-treated rats when compared to placebo-treated rats (4 hours vs. day 7 post-injury). Total satellite cell number (CD56+) also peaked earlier in GSE-treated rats than in placebo-treated rats (4 hours vs. 3 days post-injury), while M-cadherin+ SC numbers (quiescent, activated or proliferating) in both treatment groups were significantly increased 4 hours post-injury (p < 0.001), but more so in the placebo group. In GSE-treated rats when compared to placebo-treated rats, newly generated muscle fibres (displaying central nuclei and MHCf +) both appeared (day 3 vs. day 7 post-injury) and peaked in number (day 3 vs. day 7 post-injury; increase from baseline p < 0.001 for both) earlier. The results of this study demonstrate that we have successfully established an in vivo model for non-invasive contusion injury in rats. Furthermore, we have shown that Oxiprovin™: a) increased the ability to scavenge reactive species generated after injury and b) resulted in the activation of satellite cells and formation of newly generated muscle fibres at an earlier time point, thus accelerating the recovery of skeletal muscle after a standardised contusion injury. / AFRIKAANSE OPSOMMING: Eksperimente aangaande die reaksie van spier op kneusings in mense is beperk, waarskynlik as gevolg van die groot verskeidenheid simptome wat mag voorkom en die verskille in die ernstigheid van beserings. Ten einde hierdie problem te oorbrug, is verskeie eksperimentele diermodelle opgestel om kneusings en die herstel van spier daarna te ondersoek. Die tegnieke wat grootendeels vandag gebruik word om kneusings te veroorsaak, maak inbraak op die spier deur die spier te ontbloot voor besering, en is dus nie ideaal nie. Daar is ook nie baie bewyse aangaande die mees geskikte manier om so ‘n besering klinies te behandel nie. Die doel van hierdie studie was dus om: a) ‘n in vivo model van kneusings op te stel en te omskryf, en b) die effek van chroniese toediening van die antioksidant Oxiprovin™ - ‘n natuurlike druifsaad ekstrak (DSE) – op die herstel van skeletspier na ‘n kneusing te ondersoek. Twee groepe manlike Wistar rotte is onderwerp aan mondelikse toediening van isovolemiese plasebo (steriele isotoniese soutoplossing) of DSE (20 mg/kg/dag) vir ‘n tydperk van 14 dae voor kneusing. Kneusing is geïnduseer met die “massdrop” tegniek, en parameters van herstel is ondersoek tot en met 14 dae na besering. Plasebo-behandelde rotte het gemiddeld 56 % hoër kreatien kinase (KK) aktiwiteit in vergelyking met DSE-behandelde rotte (p < 0.001), toe die oppervlak onder die kurwe (OOK) tot en met 14 dae na besering bereken is. Geen verskil oor tyd is in die plasebo groep opgemerk toe plasma suurstof radikaal absorpsie kapasiteit (SRAK) bepaal is nie, maar ‘n betekenisvolle toename in spier SRAK teen dag 7 (p < 0.001) is waargeneem. ‘n Betekenisvolle afname in beide plasma (p < 0.01) en spier (p < 0.001) SRAK van die DSE is teen 4 hr waargeneem, gevolg deur ‘n betekenisvolle toename teen dag 3 na besering (p < 0.05 en p < 0.001 onderskeidelik). Die aantal CD34+ satelliet selle (SS – rustend en geaktiveerd) het beduidend vroeër in die DSE groep gestyg in vergelyking met die plasebo groep (4 uur vs. 7 dae na besering). Die totale aantal SS (CD56+) het ook vroeër in die DSE-behandelde rotte as die plasebobehandelde rotte gestyg (4 uur vs. 3 dae na besering), terwyl die aantal Mcadherin+ SS (rustend, geaktiveerd of prolifererend) betenisvol gestyg het in beide groepe teen 4 uur (p < 0.001) na besering, maar hoër in die plasebo groep was. Die aantal nuutgevormde spiervesels (met sentraal geleë nukleï en MHCf +) het beide vroeër verskyn en gepiek in die DSE-behandelde rotte in vergelyking met die plasebo-behandelde rotte (dag 3 vs. dag 7 na besering). Die resultate van hierdie studie dui aan dat ons instaat was om ‘n in vivo model van nie-indringende kneusing in rotte op te stel. Verder, het ons ook bewys dat Oxiprovin™ toediening die vermoë verleen het om: a) reaktiewe spesies wat na beserings gevorm word, meer doeltreffend te verwyder en b) satelliet selle vroeër te aktiveer en die vorming van nuwe skeletspiervesels te vervroeg, om sodoende die herstel van skeletspier na ‘n gestandardiseerde kneusing vinniger te bewerkstellig.

Thesis (MSc (Physiological Sciences))--University of Stellenbosch, 2006. / This study aimed to assess the effect of mild psychological stress in male Wistar rats using incremental, intermittent stress on parameters of atrophy, including body mass, soleus and extensor digitorum longus (EDL) muscle mass, and mechanisms possibly contributing to atrophy. Serum corticosterone concentrations, 20s proteasome activity, glutamine synthetase (GS) and tyrosine amino-transferase (TAT) activities were determined. I also assessed whether Sutherlandia (Su) or resistance exercise was able to reverse the effects of stress on any of these parameters.

Thesis (PhD)--University of Stellenbosch, 2005. / ENGLISH ABSTRACT: Skeletal muscle adapts to stimuli by modifying structural and metabolic protein expression. Furthermore, a muscle group may vary within itself to accommodate specialisation in regions. Structural and metabolic characteristics of an individual are regulated partly by genotype, but contraction duration and intensity may play a greater role in muscle phenotype. The aims of this dissertation were to investigate: structural and metabolic regionalisation in a muscle group, possible relationships between training volume and intensity and hybrid fibres, muscle characteristics of athletes from two different ethnic groups, and muscle adaptation in already well-trained athletes subjected to high intensity interval training. Myosin heavy chain (MHC) isoform content and citrate synthase (CS) activities were measured in the Quadriceps femoris (QF) muscle of 18 female rats. Muscle was divided into superficial, middle and deep, distal, central and proximal parts. MHC IIb and IIx were more abundant in superficial regions (P < 0.05) with low CS activities compared to deeper parts. Isoform content varied along the length of deep regions. This study showed that the QF has regional specialisation. Therefore, standardisation of sampling site is important. Hybrid fibre proportions in muscle biopsies of 12 middle distance runners and 12 non-runners were investigated. MHC IIa/IIx correlated with training volume/week in runners (r = -0.66, P < 0.05) and MHC IIa/IIx correlated with exercise hours/week in non-runners (r = -0.72, P < 0.01). Average preferred racing distance (PRDA) correlated better with MHC IIa/IIx in runners (r = -0.85, P < 0.001). MHC IIa/IIx may therefore be more closely related to exercise intensity than previously thought. Fibre type characteristics and performance markers were investigated in 13 Xhosa and 13 Caucasian distance runners, matched for performance, training volume and PRDA. Xhosa runners had less MHC I and more MHC IIa fibres in muscle biopsies than Caucasian runners (P < 0.05). Xhosa runners had lower plasma lactate at 80% peak treadmill speed (PTS) (P < 0.05), but higher lactate dehydrogenase (LDH) (P < 0.01) and phosphofructokinase (P = 0.07) activities in homogenate muscle samples. LDH activities in MHC I (P = 0.05) and IIa (P < 0.05) fibre pools were higher in Xhosa runners. Xhosa athletes may thus have a genetic advantage or they may have adapted to running at a higher intensity. Six weeks of individually standardised high intensity interval treadmill training (HIIT) were investigated in 15 well-trained runners. PTS increased after HIIT (P < 0.01), while maximum oxygen consumption (VO2max) only showed a tendency to have increased as a result of HIIT (P = 0.06). Sub-maximal tests showed lower plasma lactate at 64% PTS (P = 0.06), with lower heart rates at workloads from 64% to 80% PTS (P < 0.01) after HIIT. No changes were observed for cross-sectional area, capillary supply and enzyme activities in homogenates muscle samples. LDH activity showed a trend (P = 0.06) to have increased in MHC IIa pools after HIIT. Higher HIIT speed was related to decreases in MHC I fibres, but increases in MHC IIa/IIx fibres (r = -0.70 and r = 0.68, respectively, P < 0.05). Therefore, HIIT may alter muscle fibre composition in well-trained runners, with a concomitant improvement in performance markers. / AFRIKAANSE OPSOMMING: Skeletspier kan adapteer deur strukturele en metaboliese protein ekspressie te verander as gevolg van stimulante. ‘n Spiergroep kan ook intern verskil om spesialisering in spierdele toe te laat. Strukturele en metaboliese karaktereienskappe van ‘n individu word deels gereguleer deur gene, maar kontraksie tydperk en intensiteit mag ‘n groter rol speel in spierfenotipe. Die doelwitte van hierdie tesis was om ondersoek in te stel in: strukturele en metaboliese eienskappe in spiergroepstreke, moontlike verhoudings tussen oefeningsvolume of intensiteit en baster vesels, spier eienskappe in atlete van twee etniese groepe, en spier adaptasie in goed geoefende atlete blootgestel aan hoë intensiteit interval oefening. Miosien swaar ketting (MSK) isovorm inhoud en sitraat sintase (SS) aktiwiteite is gemeet in die Quadriceps femoris (QF) spier van 18 wyfie rotte. Spiere was opgedeel in oppervlakkig, middel en diep, asook distaal, sentraal en proksimale dele. MSK IIb en IIx was meer oorvloedig in oppervlakkige dele (P < 0.05) met lae SS aktiwiteite in vergelyking met dieper dele. Isovorm inhoud het ook verskil oor die lengte van diep dele. Dus bevat die QF gespesialiseerde streke en is die area van monsterneming belangrik. Baster vesel proporsies is ondersoek in spiermonsters van 12 middel afstand hardlopers en 12 niehardlopers. MSK IIa/IIx van hardlopers het met oefeningsvolume/week gekorreleer (r = -0.66, P < 0.05), asook MSK IIa/IIx van nie-hardlopers met oefeningsure/week (r = -0.72, P < 0.01). Gemiddelde voorkeur wedloop afstand (VWAG) het beter met MSK IIa/IIx gekorreleer in hardlopers (r = -0.85, P < 0.001). MSK IIa/IIx mag dus meer verwant wees aan oefeningsintensiteit. Veseltipe eienskappe en prestasie merkers was ondersoek in 13 Xhosa en 13 Caucasian langafstand atlete, geëweknie vir prestasie, oefeningsvolume en VMAG. Xhosa hardlopers het minder tipe I en meer tipe IIA vesels in hul spiermonsters gehad as die Caucasian hardlopers (P < 0.05). Xhosa hardlopers het laer plasma laktaat by 80% van hul maksimale trapmeul spoed (MTS) (P < 0.05), maar hoër laktaat dihidrogenase (LDH) (P < 0.01) en fosfofruktokinase (P = 0.07) aktiwiteite in homogene spiermonsters gehad. LDH aktiwiteite in MSK I (P = 0.05) en IIa (P < 0.05) veselbondels was hoër in Xhosa hardlopers. Xhosa atlete mag dus ‘n genetiese voorsprong geniet, of hulle het geadapteer om by hoër intensiteite te hardloop. Ses weke van geïndividualiseerde gestandardiseerde hoë intensiteit interval trapmeul oefening (HIIT) was ondersoek in 15 goed geoefende hardlopers. MTS het verhoog na HIIT (P < 0.01), en maksimale surrstof verbruik (VO2max) het ‘n neiging getoon om te verhoog het na HIIT (P = 0.07). Submaksimale toetse het laer plasma laktaat by 64% MTS getoon (P = 0.06), met laer harttempos by werkladings 64% tot 80% MTS (P < 0.01). Geen veranderings was gemerk vir deursnit area, kapillêre toevoer en ensiem aktiwiteite in homogene spiermonsters nie. LDH aktiwiteit het ‘n neiging getoon om te verhoog het (P = 0.06) in MSK IIa veselbondels na HIIT. Hoër HIIT snelhede was verwant aan ‘n daling in MSK I vesels, maar ‘n verhoging in MSK IIa/IIx vesels (r = -0.70 en r = 0.68, respektiwelik, P < 0.05). HIIT mag dus spier veseltipe verander in goed geoefende hardlopers, met gevolglike verbetering in prestasie merkers.

This thesis examined the impact of oxygen (O2) availability on prefrontal cortex and muscle tissue oxygenation during repeated-sprint exercise (RSE) in men and women. Men and women matched for initial-sprint mechanical work performed during ten, 10-s sprints (30s of rest) in normoxia (21% FIO2) and acute hypoxia (13% FIO2). Mechanical work and arterial O2-saturation (SPO2) were obtained for every sprint. Oxy- and deoxygenated haemoglobin concentrations (O2Hb, HHb) were obtained via near-infrared spectroscopy. Hypoxia elicited lower SPO2 and work (14.8% & 7.4%, P < 0.05), larger (45.1%, P < 0.05) and earlier reductions in cortical oxygenation, and no differences between sexes. Cortical de-oxygenation and work decrement were strongly correlated (R2=0.85, P < 0.05). Muscle de-oxygenation was greater in men than women (67.3%, P < 0.05). These results show that O2 availability influences cortical oxygenation and performance equally in men and women, and suggest a more efficient muscle O2 uptake in women. / ix, 108 leaves : ill. ; 29 cm

[Truncated abstract] A reduction in the force-generating capacity of a muscle is the primary indicator of fatigue and the majority of this force loss is the result of peripheral fatigue. However, there is also evidence that the central nervous system (CNS) does not drive muscles maximally during fatiguing exercise, which has led to the concept of central fatigue. The strongest evidence for this comes from interpolated twitch studies showing that transcranial magnetic stimulation (TMS) during a maximal voluntary contraction can produce an increment in force which becomes greater as fatigue develops. In addition, the silent period (SP) duration increases during a fatiguing exercise, suggesting that there is a buildup of intracortical inhibition that might limit central motor drive. In contrast, motor evoked potential (MEP) amplitude increases during fatigue suggesting an increase in corticomotor excitability during exercise . . . The primary finding was a progressive increase in the fMRI signal during exercise, with a reduction following exercise, and signal changes were observed in all regions. These studies provide evidence that central adaptive processes occur during muscle fatigue and highlight the potential to facilitate these processes with interventional paradigms. The findings indicate the extent of cortical changes during fatigue and suggest that there may also be neurohaemodynamic and/or metabolic components to central adaptive processes. Understanding the central response to muscle fatigue should incorporate mechanisms both of central adaptation and central fatigue.

Indiana University-Purdue University Indianapolis (IUPUI) / Drug-drug interactions (DDIs) refer to situations where one drug affects the pharmacokinetics or pharmacodynamics of another. DDIs represent a major cause of morbidity and mortality. A common adverse drug reaction (ADR) that can result from, or be exacerbated by DDIs is drug-induced myopathy. Identifying DDIs and understanding their underlying mechanisms is key to the prevention of undesirable effects of DDIs and to efforts to optimize therapeutic outcomes. This dissertation is dedicated to identification of clinically important myopathic DDIs and to elucidation of their underlying mechanisms. Using data mined from the published cytochrome P450 (CYP) drug interaction literature, 13,197 drug pairs were predicted to potentially interact by pairing a substrate and an inhibitor of a major CYP isoform in humans. Prescribing data for these drug pairs and their associations with myopathy were then examined in a large electronic medical record database. The analyses identified fifteen drug pairs as DDIs significantly associated with an increased risk of myopathy. These significant myopathic DDIs involved clinically important drugs including alprazolam, chloroquine, duloxetine, hydroxychloroquine, loratadine, omeprazole, promethazine, quetiapine, risperidone, ropinirole, trazodone and simvastatin. Data from in vitro experiments indicated that the interaction between quetiapine and chloroquine (risk ratio, RR, 2.17, p-value 5.29E-05) may result from the inhibitory effects of quetiapine on chloroquine metabolism by cytochrome P450s (CYPs). The in vitro data also suggested that the interaction between simvastatin and loratadine (RR 1.6, p-value 4.75E-07) may result from synergistic toxicity of simvastatin and desloratadine, the major metabolite of loratadine, to muscle cells, and from the inhibitory effect of simvastatin acid, the active metabolite of simvastatin, on the hepatic uptake of desloratadine via OATP1B1/1B3. Our data not only identified unknown myopathic DDIs of clinical consequence, but also shed light on their underlying pharmacokinetic and pharmacodynamic mechanisms. More importantly, our approach exemplified a new strategy for identification and investigation of DDIs, one that combined literature mining using bioinformatic algorithms, ADR detection using a pharmacoepidemiologic design, and mechanistic studies employing in vitro experimental models.