Inter-individual differences in strength are not fully explained by muscle size, suggesting that muscle specific tension [force per unit physiological cross-sectional area (PCSA)] varies between untrained individuals. Furthermore, many reports demonstrate greater gains in muscle strength than size following resistance training, thus indicating an increase in specific tension. Moreover, there is considerable variation in the response to training that may have a genetic origin. The aims of the work described in this thesis were i) to examine the degree of variability in muscle specific tension; ii) to investigate whether specific tension changed following resistance training; iii) to quantify the variability in the response of human muscle to resistance training; iv) to identify gene variants that may be associated with the variable training responses. In a group of untrained young men and before and after 9 weeks of resistance training, the quadriceps femoris (QF) muscle specific tension was calculated from the maximum isometric voluntary contraction (MVC) torque, taking into account the contribution of voluntary activation, antagonist muscle co-activation, moment arm length, QF volume, muscle fascicle length and pennation angle. Correcting for these factors made little difference to the between subjects variance of MVC torque, thus demonstrating that muscle specific tension varies considerably between individuals. Resistance training increased QF muscle force much more than PCSA, indicating that most of the increase in force was a result of increased specific tension. This increase was not associated with a change in myosin heavy chain expression and was not accompanied by an increase in single fibre specific tension, or an increase in power per unit muscle volume measured during isokinetic cycling. The results are consistent with an increase in lateral force transmission in the muscle. Substantial variation in the training responses was observed and the final part of this thesis is concerned with linking this variation with specific gene variants.

It is common knowledge that resistance exercise promotes muscle growth (hypertrophy) and increased strength and function: thus, regular exercise can help minimize the loss of muscle mass and function in healthy ageing. Skeletal muscle can contract by either shortening or lengthening (concentrically or eccentrically, respectively). A substantial number of studies focused on the effect of concentric versus eccentric training protocols on muscle morphological and functional changes: eccentric contractions are generally thought to result in more increased muscle hypertrophy and strength, because of the higher force produced by the muscle and the more severe exercise induced muscle damage, which may lead to a stronger adaptations in muscle remodeling and repair processes. Study 1 shows that ECC and CON exercise protocols lead instead to similar gains in muscle size, but through different architectural remodeling mechanisms: moreover, acute contraction-specific molecular responses have been characterised. Study 2 and Study 3 were then performed in order to gain novel insights into the relationship between these morphological adaptations and the metabolic responses (MPS, muscle protein synthesis) of human skeletal muscle in response to chronic ECC vs. CON loading paradigms. Study 2 was first carried out in order to validate the use of deuterium oxide isotope tracing technique for measuring changes in MPS in free-living subjects over longerterm periods (compared to normal AA infusion studies) of resistance exercise. After assessing the feasibility of deuterium oxide tracing technique in measuring MPS response during resitance-training protocols, study 3 investigated the chronic responses in MPS to ECC vs. CON loading in two 3 different sites of the human vastus lateralis, presenting novel insights into MPS and skeletal muscle homogeneity, attempting to link MPS changes to the different mechanisms of muscle morphological remodelling occurring after ECC vs. CON training.

Spastic cerebral palsy (SCP) relates to a specific movement-related impairment characterised by a velocity-dependent resistance to stretch. Muscle weakness and decreased range of motion (ROM) are characteristics of the paretic limb in individuals with SCP. However, there are no data on the in vivo determinants of strength and ROM in adults with SCP. The aim of the thesis was to examine the factors associated with impaired plantarflexion, maximal voluntary isometric contraction (MVIC) and joint ROM in the paretic limb of physically active men with SCP compared to the contralateral non-paretic limb and individuals without neurological impairment. Passive stiffness, myotendinous junction displacement and ROM of the paretic gastrocnemius medialis (GM) were not different from the control muscles. However, the elastic modulus of the paretic GM was two times stiffer than the control GM muscles. MVIC torque of the paretic plantarflexors was 42% and 52% less than the non-paretic (P = 0.007) and control limbs (P < 0.001), respectively. The paretic gastrocnemius ACSA was 20% smaller than the control group (P = 0.004) only. Paretic agonist activation was 36% and 39% less than the non-paretic (P < 0.001) and control groups (P < 0.001), whereas paretic antagonist coactivation was 3-fold higher compared to the non-paretic (P < 0.001) and control group (P < 0.001). Agonist muscle activation accounted for 57% of variation in paretic plantarflexion MVIC torque (P = 0.007). When accounting for GM architecture, neural properties and moment arm length, no difference in GM specific force was established. Finally when the tendon elastic properties and Young’s modulus were calculated at a standardised force, no difference was observed in tendon stiffness properties across all experimental groups. These findings suggest that in active adults with SCP, weakness is due to a reduction in muscle size and impaired muscle activation. Furthermore, in the presence of no decline in ROM there remained an alteration in the passive elastic properties of the muscle, but not the tendon.

No description available.

The aim of this work was to study the relationship between UVB and LC by examining the influence of moderate, suberythemal doses of UVB, such as are used to treat psoriasis, on epidermal LC morphology, numbers and surface expression of CD1a and major histocompatibility class II (MHC II) antigens in human skin. A six week course of UVB irradiation, using our standard therapeutic regimen for the treatment of psoriasis (total doses of UVB ranged from 2.58-5.58 J/cm<SUP>2</SUP>), was administered to nine healthy subjects. The morphology and number of LCs, and the distribution and expression of certain LC surface antigens were studied in control and in UVB-irradiated epidermis. The study of LC morphology prior to UVB irradiation, using the technique of confocal laser scanning microscopy, revealed that their dendrites extended mainly in the horizontal plane of the epidermis and dendrite numbers ranged between two and nine per cell. Adjacent LCs were in close apposition, but there was little contact between them The majority of normal unirradiated epidermal LCs expressed HLA-DP, HLA-DQ and HLA-DR antigens, which were demonstrated by quantitative ultrastructural immunogold method using image analysis, although a small proportion either did not express these antigens or expressed them at high surface densities. In conclusion, a true reduction in the number of LCs occurs after UVB exposure which cannot be explained simply by the loss of LC surface antigen expression. These studies have defined the UVB-induced changes in LC morphology, number and antigen expression in normal human skin.

The drug succinylcholine (SCh) is known to produce contracture in two of the three classes of intrafusal muscle fibre whilst paralysing the third. Since the effects on afferent stretch sensitivity of contraction in each class of intrafusal muscle fibre are known, SCh can be used to assess the pattern of intrafusal termination of afferents studied electrophysiologically. This approach has previously been used to differentiate primary afferents from secondaries when alternative means were not applicable, but the aim of the present experiments has been to extend this work to allow the differentiation of primary afferents from classical spindle encapsulations (which have the full complement of intrafusal muscle fibres) and those from tandem encapsulations which lack a bag<SUB>1</SUB> fibre which would otherwise be activated by SCh. Three sets of experiments were performed. In the first, afferents from the cat neck extensor muscle biventer cervicis were studied, since this muscle is known to be particularly rich in tandem spindles. Four types of afferent response to intraarterial infusion of SCh were identified, three corresponding to the behaviour previously reported for hindlimb muscle spindle afferents. The fourth had not previously been seen, and showed features which indicated that the afferents activated by SCh in this way were probably the b<SUB>2</SUB>c primary afferents arising in tandem muscle spindles. Other evidence in the form of the passive properties of these afferents was adduced to support this diagnosis. In the second series of experiments using the medial gastrocnemius muscle of the hindlimb, four patterns of SCh activation were again seen for muscle spindle afferents; these were all very similar to the patterns seen for biventer afferents, including that presumed to belong to b<SUB>2</SUB>c primary afferents from tandem spindles. Additional evidence that b<SUB>2</SUB>c primary afferents from tandem muscle spindles had been correctly identifed came from the measurement of their conduction velocities, which indicated that the majority of presumed b<SUB>2</SUB>c primary afferents from tandem muscle spindles had conduction velocities which overlapped with those of slower b<SUB>1</SUB>b<SUB>2</SUB>c primary afferents from classical encapsulations, as was expected on histological grounds. In the final series of experiments, the spindles of origin of afferents from the tenuissimus muscle which had been studied electrophysiologically were located in the muscle, excised and studied histologically in serial transverse sections. Seven afferents were diagnosed by SCh as primaries arising in classical muscle spindles, and the histological reconstruction indicated that their parent spindles indeed contained all three intrafusal muscle fibre types. In contrast, the single afferent diagnosed by SCh and a b<SUB>2</SUB>c primary arising in a tandem muscle spindle was subsequently found to innervate an encapsulation of a tandem spindle containing only two types of intrafusal muscle fibre. The histological evidence thus supports the SCh-based classification of primary afferents, and in particular indicates that b<SUB>2</SUB>c primary afferents from tandem muscle spindles can be readily identified during electrophysiological experiments.

A protein (M<SUB>r</SUB> 24 kDa) that co-purifies with porcine skin lysyl oxidase (M<SUB>r</SUB> 34 kDa) has been characterised. Five variants of the 24 kDa protein were identified by Mono Q FPLC, as were 4 variants of lysyl oxidase. By amino acid analysis the 24 kDa protein is particularly rich in tyrosine, and isoelectric focussing shows it to be acidic, so the name TRAMP (Tyrosine Rich Acidic Matrix Protein) is used to identify this protein. By amino acid sequence analysis and immunoblotting, TRAMP is unrelated to lysyl oxidase, though it is identical (in all but 4 residues) to a 22 kDa extracellular matrix protein from bovine skin that associates with dermatan sulphate proteoglycan. TRAMP is not a proteoglycan however, as mass spectrometry indicates a molecular mass only 150 Da greater than that predicted from the amino acid sequence, and treatment with a number of deglycosylating enzymes does not alter the electrophoretic migration of the protein. Sequence analysis, mass spectrometry and susceptibility to sulphatase treatment, indicates the presence of sulphated tyrosine residues in TRAMP. Although TRAMP occurs as a quantitatively minor component in skin, it shows a widespread tissue distribution. TRAMP does not appear to affect the activity of lysyl oxidase on an elastin substrate. However turbidity time data, shows that sub-equimolar concentrations of TRAMP accelerate the <i>in vitro</i> formation of fibrils from purified, lathyritic (i.e. non cross-linked) rat skin type I collagen. The fibrils which form are well ordered with a D-periodicity similar to those observed <i>in vivo</i>, though fibrils formed in the presence of TRAMP are significantly thinner. TRAMP binds to collagen fibrils as shown by co-sedimentation, and once formed, fibrils are more resistant to low temperature solubilisation. TRAMP may have a important role in the early, nucleation stages of fibril formation.

Positive changes in bone metabolism, structural characteristics, size and mass are commonly associated with weight-bearing exercise. Despite this, negative effects of exercise on bone phenotypes, such as stress fracture injuries have been reported. Little is known about the extent of the genetic mediation of changes in bone characteristics, stress fracture injury and bone resorption in response to exercise. Accordingly, this thesis investigated: the genotype dependent changes in bone phenotypes in academy footballers before and after an increase in training volume; genetic associations with stress fracture injury in elite athletes and a preliminary investigation into genetic associations with bone resorption following 120 min of treadmill running. The tibial bone characteristics of 80, full-time academy footballers was determined using pQCT before and after 12 weeks of increased volume football training. Genetic associations with baseline, post increased training and change in bone characteristics were then determined. Secondly, radiologically confirmed stress fracture history was reported in 518 elite athletes, forming the Stress Fracture Elite Athlete (SFEA) cohort. Genetic associations were analysed for the whole group, and were also sub-stratified. Finally, recreationally active healthy male participants (n=42) performed a 120 min run at 70% O2max. Genetic associations with bone resorption at baseline, immediately, 24, 48 and 72 hours post run were investigated. SNPs in the proximity of genes in P2X7R and the RANK/RANKL/OPG signalling and Wnt signalling pathways were associated with bone phenotypes before and following 12 weeks of increased volume football training (P<0.05). SNPs in close proximity to SOST, P2X7R, RANK, RANKL, OPG, Bradykinin and VDR genes were associated with stress fracture injury in the whole cohort and in various sub-classifications of elite athletes (P<0.05). No associations were shown in bone resorption prior to, immediately following or in the 3 days following 120 min of treadmill running. The data suggest a role for specific genes and SNPs in bone phenotypic changes as a result of exercise training and in the susceptibility to stress fracture injury. The association of SNPs in P2X7R and the RANK/RANKL/OPG signalling and Wnt signalling pathways with bone phenotypes and stress fracture injury susceptibility highlights their role in the maintenance of bone health, and offers potential targets for therapeutic interventions.

The intelligibility of accented speech in noise depends on the interaction of the accents of the talker and the listener. However, it is not yet clear how this influence arises. Accent familiarity is commonly proposed to be a major contributor to accent intelligibility, but recent evidence suggests that the similarity between talker and listener accents may also be able to account for accent intelligibility across talker-listener pairings. In addition, differences in accent intelligibility are also often only found in the presence of other adverse conditions, so it is not clear if the talker-listener pairing also influences speech processing in quiet conditions. This research had two main aims; to further investigate the relationship between accent similarity and intelligibility, and to use online EEG methods to explore the possible presence of talker-listener pairing related differences on speech perception in quiet conditions. English and Spanish listeners listened to Standard Southern British English (SSBE), Glaswegian English (GE) and Spanish-accented English (SpE) in a speech-in-noise recognition task, and also completed an event-related potential (ERP) task to elicit the PMN and N400 responses. Accent similarity was measured using the ACCDIST metric. Results showed the same (or extremely similar) patterns in accent intelligibility and accent similarity for both listener groups, giving further support to the hypothesis that accent similarity can contribute to the level of intelligibility of an accent within a talker-listener pairing. ERP data also suggest that speech processing in quiet is influenced by the talker-listener pairing. The PMN, which relates to phonological processing, seems particularly dependent on a match between talker and listener accent, but the more semantic N400 showed some flexibility in the ability to process accented speech.

No description available.