<p>Is it possible for a minimal model of anaerobic muscle contraction to describe measured data? There have been many models trying to describe separate parts of the human body with various results. In this thesis a model has been created to describe all the essential biochemical reactions of anaerobic muscle metabolism during contraction but with as few states and parameters as possible. A toolbox in Matlab was used for simulation and also for parameter estimation. The best model eventually got validated to see statistically how well it can describe the measured data. During the simulations an unnecessary assumption got revealed which helped us to understand the system better. The vision of a whole-body model may not be so far into the future as many think and the first step is to understand smaller biochemical systems like muscle contraction.</p>

Thesis (Ph. D. in Pharmacology)--Vanderbilt University, Dec. 2009. / Title from title screen. Includes bibliographical references.

Thesis (Ph. D.)--University of Missouri--Columbia, 2001. / Typescript. Vita. Includes bibliographical references (leaves 122-137). Also available on the Internet.

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2009. / Härtill 5 uppsatser.

Is it possible for a minimal model of anaerobic muscle contraction to describe measured data? There have been many models trying to describe separate parts of the human body with various results. In this thesis a model has been created to describe all the essential biochemical reactions of anaerobic muscle metabolism during contraction but with as few states and parameters as possible. A toolbox in Matlab was used for simulation and also for parameter estimation. The best model eventually got validated to see statistically how well it can describe the measured data. During the simulations an unnecessary assumption got revealed which helped us to understand the system better. The vision of a whole-body model may not be so far into the future as many think and the first step is to understand smaller biochemical systems like muscle contraction.

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In male athletes from different sports, isokinetic knee extensor, and in orienteers also plantar flexor peak torque (PT), contractional work (CW) and integrated surface electromyograms (iEMG) were analysed. Single contraction PT, CW and iEMG in sprinters and marathon runners were signi­ficantly correlated to the cross-sectional area (CSA) of m. quadriceps, and to the Type II fibre area of m. vastus lateralis. When correcting PT, CW and iEMG for CSA of m. quadriceps, such correlations were found only for Type IIA fibre area at 180° s~1. Elec- tromyographically, m. vastus lateralis (biopsied muscle) was representative for m. quadriceps. Calculated optimal mean power (CW s~1) and electrical efficacy (CW/iEMG) approximated for sprinters 450° s-1 and for marathon runners 270° s~1, i.e. velocities at or above the upper limit of the dynamometers. In orienteers, plantar flexor PT increased during winter training, but decreased during competitive season. Knee extensor PT increased over the whole year. At 30 and 60° s~1 only knee extensor PT was negatively associated with the running velocity at onset of blood lactate accu­mulation (VOBLA)- Changes in VOBLA during winter period were negatively associated with changes in knee extensor PT at 180° s~1. During competitive season, changes in Vobla were negatively associated with the ratio quality : quantity running. In ice hockey players PT varied non-systematically with training and games. The biopsy specimens of marathon runners showed irregular fibre shapes, an in­creased amount of connective tissue and central fibre nuclei, indicating an early strain disease or functional adaptation to extreme demands. During repetitive contractions in sprinters and marathon runners, fatigue, i.e. slope of decline in CW, was significantly associated with the Type II fibre area of m. vastus lateralis. For knee extensors of sprinters, ice hockey players and orienteers, a steep de­crease in CW/iEMG was observed. In contrast, knee extensors of marathon runners and plantar flexors of orienteers showed an almost unaltered CW/iEMG throughout the test. The knee extensor endurance level (CW/iEMG) was significantly correlated to the maximal oxygen uptake. In orienteers, an increase in endurance level of both tested muscle groups during winter training parallelled an increase in VOBLA and V02obla- In hockey players, fatigue and endurance pattern (CW and CW/iEMG) changed non-systematically with training and games. In conclusion, isokinetic measurements and iEMG reflect the structural properties of the knee extensor muscles in sprinters and marathon runners. The demonstrated characteristics and changes in leg muscle function in different groups of athletes apparently reflect varying demands from different sports activities. / <p>S. 1-31: sammanfattning, s. 33-84: 6 uppsatser</p> / digitalisering@umu

Congenital myopathies are a rare and heterogeneous group of diseases. They are primarily characterised by skeletal muscle weakness and disease-specific pathological features. They harshly limit ordinary life and in severe cases, these myopathies are associated with early death of the affected individuals. The congenital myopathies investigated in this thesis are nemaline myopathy and myofibrillar myopathy. These diseases are usually caused by missense mutations in genes encoding myofibrillar proteins, but the exact mechanisms by which the point mutations in these proteins cause the overall weakness remain mysterious. Hence, in this thesis two different nemaline myopathy-causing actin mutations and one myofibrillar myopathy-causing myosin-mutation found in both human patients and mouse models were used to investigate the cascades of molecular and cellular events leading to weakness. I performed a broad range of functional and structural experiments including skinned muscle fibre mechanics, small-angle X-ray scattering as well as immunoblotting and histochemical techniques. Interestingly, according to my results, point mutations in myosin and actin differently modify myosin binding to actin, cross-bridge formation and muscle fibre force production revealing divergent mechanisms, that is, gain versus loss of function (papers I, II and IV). In addition, one point mutation in actin appears to have muscle-specific effects.  The presence of that mutant protein in respiratory muscles, i.e. diaphragm, has indeed more damaging consequences on myofibrillar structure than in limb muscles complexifying the pathophysiological mechanisms (paper II). As numerous atrophic muscle fibres can be seen in congenital myopathies, I also considered this phenomenon as a contributing factor to weakness and characterised the underlying causes in presence of one actin mutation. My results highlighted a direct muscle-specific up-regulation of the ubiquitin-proteasome system (paper III). All together, my research work demonstrates that mutation- and muscle-specific mechanisms trigger the muscle weakness in congenital myopathies. This gives important insights into the pathophysiology of congenital myopathies and will undoubtedly help in designing future therapies.

The FGLa/ASTs are one family of allatostatin peptides and share an amidated C-terminal sequence (FGL-amide). The inhibitory effect of FGLa/ASTs on juvenile hormone (JH) biosynthesis in Diploptera punctata led to their discovery, but there is a lack of allatostatic function across most insect species that suggests this function may not be their primary role. Rather, the FGLa/ASTs are implicated as brain/gut peptides, modulating gut physiology. This thesis demonstrates the pleiotropic nature of FGLa/ASTs in Locusta migratoria and emphasizes the role of FGLa/ASTs as brain/gut peptides involved in homeostatic processes. FGLa/AST-like immunoreactivity (FLI) is associated with the corpus cardiacum (CC) and corpus allatum (CA). FGLa/ASTs increase adipokinetic hormone release from the CC and alter JH biosynthesis from the CA, suggesting roles in energy utilization and in growth and metamorphosis. Each region of the gut exhibits FLI. The gut is dually innervated: neurons in the abdominal ganglia of the central nervous system (CNS) innervate the posterior gut and some contain FLI, while neurons within the stomatogastric nervous system (STNS) that innervate the anterior gut do not seem to contain FLI, indicating that source of FLI on the gut are cells within the CNS, which may release FGLa/ASTs at the gut to alter aspects of gut physiology. FGLa/ASTs are involved in peristalsis, neural control of foregut contractions, and ileal K+ transport. In particular, FGLa/ASTs inhibit contractions of each gut region and also modulate the rhythmic motor output of a central pattern generator within the ventricular ganglion of the STNS. FGLa/ASTs also inhibit ileal K+ efflux, suggesting a diuretic action and implicating FGLa/ASTs in fluid and ion homeostasis. This work provides a comprehensive picture of how FGLa/ASTs play an integral role in nutrient processing, energy mobilization, and growth and metamorphosis to contribute to the overall maintenance of homeostasis. This reinforces the role of FGLa/ASTs as brain/gut peptides and emphasizes their involvement in the flexibility of nervous communication and integration of the endocrine system with the CNS to achieve homeostasis.

The FGLa/ASTs are one family of allatostatin peptides and share an amidated C-terminal sequence (FGL-amide). The inhibitory effect of FGLa/ASTs on juvenile hormone (JH) biosynthesis in Diploptera punctata led to their discovery, but there is a lack of allatostatic function across most insect species that suggests this function may not be their primary role. Rather, the FGLa/ASTs are implicated as brain/gut peptides, modulating gut physiology. This thesis demonstrates the pleiotropic nature of FGLa/ASTs in Locusta migratoria and emphasizes the role of FGLa/ASTs as brain/gut peptides involved in homeostatic processes. FGLa/AST-like immunoreactivity (FLI) is associated with the corpus cardiacum (CC) and corpus allatum (CA). FGLa/ASTs increase adipokinetic hormone release from the CC and alter JH biosynthesis from the CA, suggesting roles in energy utilization and in growth and metamorphosis. Each region of the gut exhibits FLI. The gut is dually innervated: neurons in the abdominal ganglia of the central nervous system (CNS) innervate the posterior gut and some contain FLI, while neurons within the stomatogastric nervous system (STNS) that innervate the anterior gut do not seem to contain FLI, indicating that source of FLI on the gut are cells within the CNS, which may release FGLa/ASTs at the gut to alter aspects of gut physiology. FGLa/ASTs are involved in peristalsis, neural control of foregut contractions, and ileal K+ transport. In particular, FGLa/ASTs inhibit contractions of each gut region and also modulate the rhythmic motor output of a central pattern generator within the ventricular ganglion of the STNS. FGLa/ASTs also inhibit ileal K+ efflux, suggesting a diuretic action and implicating FGLa/ASTs in fluid and ion homeostasis. This work provides a comprehensive picture of how FGLa/ASTs play an integral role in nutrient processing, energy mobilization, and growth and metamorphosis to contribute to the overall maintenance of homeostasis. This reinforces the role of FGLa/ASTs as brain/gut peptides and emphasizes their involvement in the flexibility of nervous communication and integration of the endocrine system with the CNS to achieve homeostasis.