End-stage osteoarthritis is characterised by pain and reduced physical function, for which total knee arthroplasty (TKA) is recognised to be a highly effective procedure. Post-operative outcome and resultant function however is variable. Many factors are thought to influence outcome; in particular quadriceps muscle strength is one of the strongest predictors of the patient’s ability to perform functional tasks. Muscle atrophy has been shown to account for only a third of the variance in muscle power, the remainder is currently unexplained. In this thesis it is hypothesised that physiological and mechanical factors will affect muscle power post TKA. A new design of prosthesis with an axis of rotation of the knee based on new kinematical observations has been suggested to confer a mechanical advantage to the knee extensor mechanism by lengthening its moment arm, and thus reducing the muscular effort required to extend the knee, however this has not as yet been clinically demonstrated. A strong extensor mechanism is recognised as being paramount to the patients return to functional activity following TKA, but there has been no consideration as to the mechanisms how and to what extent the muscle tissue actually recovers. It is known that muscle satellite cells are essential for the regeneration of skeletal muscle and that these cells are activated following damage, but these have not been considered in relation to recovery from orthopaedic procedures. It is hypothesised that the number of satellite cells in the extensor mechanism will vary in the patient population and will influence muscle recovery. A double blind randomised controlled trial of 212 TKA patients was conducted to compare the new implant design with a traditional model. Patient outcome was assessed at four points over a one year period. The new implant was superior in measures of knee flexion, lower limb power output and by patient report questionnaire (Oxford Knee Score) Two-way ANOVA, p = <0.001 in all cases. Extensor mechanism power was significantly increased between all four assessment points in the new implant group, the control group demonstrating change between the second and third assessment only (p= <0.001). Analysis of the outcome assessments used demonstrated a changing relationship between function and patient report of that function. Regression models demonstrated that patient report of function became more consistent with direct functional assessment as the influence of pain diminished post-operatively. A hierarchical model is presented that highlights the limitation of patient report data in isolation. Muscle satellite cells were isolated from biopsies of the quadriceps muscle of 18 patients at the time of surgery and counted by an immunofluorescent staining technique. The number of satellite cells detected accounted for a third of the postoperative variance in power output (R2 = 36.6%). This was confirmed in another cohort of 11 patients with a more sensitive qPCR technique. It was further found that the activated satellite cells accounted for around two thirds of the change in postoperative power output (R2 = 66.7%). In conclusion, both mechanical and physiological factors have a significant effect on muscle power post total knee arthroplasty.

No abstract Provided / Thesis / Master of Science (MSc)

Cachexia affects up to two thirds of all cancer patients with progressive disease. It is a syndrome characterised by weight-loss, anorexia, fatigue, asthenia, peripheral oedema, and is responsible for around 20% of cancer deaths. Cachectic patients suffer loss of both muscle mass and adipose tissue (with comparative sparing of visceral protein) and the lean tissue loss appears resistant to nutritional support. Progress in the treatment of cancer cachexia has been hampered due to poor understanding of the molecular mechanisms of skeletal muscle wasting in humans (rather than preclinical models) combined with a lack of accurate phenotyping particularly with respect to loss of skeletal muscle mass and function. The aim of the present thesis was to improve the knowledge and tools available for early intervention studies. The thesis focused on skeletal muscle as a key compartment in cancer cachexia. The experimental model was patients with upper gastrointestinal (UGI) cancer undergoing potentially curative surgery due to the associated higher incidence of cachexia along with the ability to access tissue biopsies. The thesis broadly divides into two sections. Part I reports a series of cancer cachexia biomarker discovery studies based on direct biopsy and analysis of human skeletal muscle. Part II focused on assessment and phenotyping of skeletal muscle mass and function in cachectic UGI cancer patients. In addition, the feasibility of longitudinal clinical studies that utilise such methodology is reported. Intramuscular β-dystroglycan protein content (assessed using Western blot) was identified as a potential biomarker of cancer cachexia whereas changes in the structural elements of muscle (myosin heavy chain or dystrophin) appeared to be survival biomarkers. Using transcriptomics, an 82-gene signature was demonstrated to correlate with weight-loss. Quantitative real-time polymerase chain reaction (qRT-PCR) was carried out to examine the genes from this signature that were most upregulated. The exercise activated genes, CAMk2β and TIE1, correlated positively with weight-loss across different muscle groups (Rectus abdominis, Vastus lateralis, Diaphragma) indicating that cachexia was not simply due to inactivity and suggesting that these genes could be used as biomarkers of cachexia. None of the biomarkers discovered were consistent with pre-clinical models and therefore require further study before progressing to a validation programme. Electron microscopy of muscle biopsies demonstrated that the number and size of intramyocellular lipid droplets was increased in the presence of cancer and increases further with weightloss/ loss of adipose mass in other body compartments. The specific mechanisms and drivers of this phenomenon remain to be elucidated, but could relate to enhanced lipolysis or mitochondrial dysfunction in skeletal muscle as well as influencing muscle mechanical quality. Physiological assessment of patients with cancer cachexia established the negative impact that cachexia can have on muscle mass, function, muscle quality and quality of life, but demonstrated that the degree of impairment varies with sex and between muscle groups. Furthermore, the challenge of longitudinal studies in this patient group where frailty and clinical deterioration limit repeated assessments was highlighted. Such issues emphasise the need for a dual approach to the classification of cancer cachexia: if molecular markers prove difficult to discover or validate, then more specific and robust physiological indices of skeletal muscle mass and function may be the more important route to improve clinical trial design and cachexia classification.

The assessment of rehabilitation effectiveness in the post-stroke hemiparetic population has primarily focused on walking speed. Walking speed, however, may be improved through a number of mechanisms; increased speed can be achieved through a combination of increased propulsion (propelling the center of mass forward) and swing initiation (resulting in longer and faster steps) in either the paretic or nonparetic leg. Therefore the objective of this study was to use a detailed musculoskeletal model and forward dynamics simulations to identify the individual muscle contributions to forward propulsion and swing initiation following locomotor training in two post-stroke hemiparetic patients who had similar speed increases following training, one utilizing an “ankle strategy” (increases in ankle power generation to accelerate the trunk forward) and one a “hip strategy” (increases in hip flexor generation of the swing leg to accelerate the leg forward) to increase speed. Each subject participated in locomotor therapy training using a body weight supported treadmill modality. Strategy classification was based on inverse dynamics analysis pre- and post-training. The simulation analyses revealed that forward propulsion was achieved primarily through the uniarticular plantarflexors and the contralateral knee extensors in both subjects. The main difference between the two strategies occurred primarily in the hip muscle contributions to swing initiation. The “hip strategy” subject, in addition to using the hip flexors to accelerate the leg forward, had higher contributions from the contralateral non-sagittal plane hip muscles to generate energy to the leg to initiate swing. These results suggest that using either the “ankle strategy” or the “hip strategy” to increase speed post-training results in similar muscle function post-training walking with differences primarily occurring in the hip muscle contributions to swing initiation. Future studies analyzing both pre- and post-training may reveal changes in muscle function that correspond more with the strategy classifications. / text

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The purpose of this study was to determine the effects of short-term (14d) unilateral leg immobilization using a simple knee brace (60° flexion)/crutchmediated model on muscle function and morphology in men (M, N=13) and women (W, N=14). Isometric and isokinetic (concentric SLOW, 0.52 rad•s-1 and FAST, 5.24 rad•s-1) knee extensor peak torque was determined at three time points (PRE, DAY -2, and DAY -14). At the same time points, magnetic resonance imaging was used to measure the cross-sectional area of the quadriceps femoris and DEXA scanning was used to calculate leg lean mass. Muscle biopsies were taken from vastus lateralis at PRE and DAY-14 for myosin ATPase and myosin heavy chain analysh Women showed greater decreases (PRE vs. DAY-14) compared to men in specific strength (N•cm-2) for isometric (M=3.1±13.3, W=17.1±15.9%; p= 0.055, [mean±SD]) and concentric SLOW (M=4.7±11.3, W=16.6±18.4%; p<0.05) contractions. There were no immobilization-induced sex-specific differences in the decrease in quadriceps femoris cross-sectional area (M=5.7±5.0, W=5.9±:5.2%) or leg lean mass (M=3.7±4.2, W=2.7±2.8%). There were no fiber type transformations, and the decrease in Type I (M=4.8±5.0, W=5.9±3.4%), IIa (M=7.9±9.9, W=8.8±8.0%) and Ilx (M=10.7±10.8, W=10.8±12.1 %) fiber areas was similar between sexes. These findings indicate that immobilization-indt: ced loss of knee extensor muscle strength is greater in women compared tc men in spite of a similar extent of atrophy at the myofiber and whole muscle levels after only 14d of unilateral leg immobilization. Furthermore, we have described an effective and safe method of knee immobilization that results in significant reductions in quadriceps muscle strength and fiber size. / Thesis / Master of Science (MS)

<p>Abstract</p><p>Elderly people are going to be a growing number in Europe. Between one third are going to be 60 years or older at 2025. For Sweden the situation is going to be similar. A reduced muscle function could lead to complications for the individual to perform daily tasks and will lead to a higher rate for falling and getting bone fractures. The positive sides are that for men and women there are a possibility for maintaining physical function and strength even in older years. The purpose of this study was to investigate the possibility of gaining strength in M. Quadriceps femoris among five elderly people. The training schedule followed over 6 weeks of time with training sessions twice a week, training the Quadriceps muscle with one set of each training session. The result shows that for the three people that completed the study, all of them managed to gain strength. Further the study examines resistance training comparing single and multiple sets. Is there any difference in gaining strength between training programs with single set training versus multiple sets training?</p>

Abstract Elderly people are going to be a growing number in Europe. Between one third are going to be 60 years or older at 2025. For Sweden the situation is going to be similar. A reduced muscle function could lead to complications for the individual to perform daily tasks and will lead to a higher rate for falling and getting bone fractures. The positive sides are that for men and women there are a possibility for maintaining physical function and strength even in older years. The purpose of this study was to investigate the possibility of gaining strength in M. Quadriceps femoris among five elderly people. The training schedule followed over 6 weeks of time with training sessions twice a week, training the Quadriceps muscle with one set of each training session. The result shows that for the three people that completed the study, all of them managed to gain strength. Further the study examines resistance training comparing single and multiple sets. Is there any difference in gaining strength between training programs with single set training versus multiple sets training?