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- Apró, William
(författare)
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Regulation of protein synthesis in human skeletal muscle : separate and combined effects of exercise and amino acids
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Skeletal muscle is a highly plastic tissue which has the ability to adapt to various forms of external stimuli such as diverse modes of contractile activity. Thus, performance of endurance exercise over several of weeks results in increased oxidative capacity. In contrast, prolonged performance of resistance exercise ultimately results in increased muscle mass. These adaptations are brought about by transient alterations in gene expression and mRNA translation which result in altered protein turnover, i.e. the balance between protein synthesis and protein breakdown. Protein synthesis is the major determinant of muscle growth, which at the molecular level, is regulated by the mTORC1 pathway. This pathway is potently activated by resistance exercise and amino acids, but the stimulatory role of individual amino acids in human skeletal muscle is unclear. Muscle adaptations in response to endurance exercise are largely dependent on the PGC-1 α pathway, which regulates mitochondrial biogenesis. Given the different training adaptations after resistance and endurance exercise, it has been suggested that these exercise modalities may be incompatible when combined. Such potential interference could be exerted at the molecular level between the pathways responsible for each adaptive response. AMPK, an enzyme usually activated by endurance exercise and, when pharmacologically activated in cell culture and rodent models, has been shown to inhibit mTORC1 and protein synthesis. However, it is not known if activation of AMPK by endurance exercise inhibits resistance exercise induced signaling through the mTORC1 pathway in human skeletal muscle.Thus, the main objective of this thesis was to examine the molecular mechanisms regulating protein synthesis in response to amino acids and various modes of exercise in human skeletal muscle.In study I, the role of BCAAs in stimulating the mTORC1 pathway was examined in both resting and exercising muscle. BCAA increased mTORC1 activity, as assessed by S6K1 phosphorylation, in both resting and exercising muscle, but more so when exercise and BCAA were combined. In study II, the effect of leucine was compared to that of essential amino acids with or without leucine. It was found that when leucine was combined with the remaining essential amino acids, S6K1 phosphorylation was more pronounced than when leucine was provided alone. Furthermore, when leucine was removed from the essential amino acids, the effect was equal to that of placebo. In study III, the impact of endurance exercise on resistance exercise induced mTORC1 signaling was examined. When performed after resistance exercise, endurance exercise did not inhibit S6K1 phosphorylation compared to when single mode resistance exercise was performed. In study IV, performance of high intensity endurance exercise prior to resistance exercise did not inhibit S6K1 phosphorylation compared to single mode resistance exercise, despite prior activation of AMPK.In conclusion, amino acids and resistance exercise activate mTORC1 signaling, as assessed by S6K1 phosphorylation, in a synergistic manner. Leucine is crucial in mediating the amino acid response, however, additional amino acids appear to be required to induce a maximal response downstream of mTORC1. Activation of the mTORC1 pathway in response to heavy resistance exercise is robust and this activation does not appear to be inhibited by prior or by subsequent endurance exercise. As such, these results do not lend support to the existence of molecular interference when resistance and endurance exercise are combined acutely.
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- Ehrenborg, Christian, 1970-
(författare)
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Bartonella Infections in Sweden: : Clinical Investigations and Molecular Epidemiology
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Characteristically, in infections that are caused by the zoonotic pathogen Bartonella naturally infected reservoir hosts are asymptomatic, where infected incidental, non-natural, hosts develop symptomatic disease. Cat-scratch disease (CSD) is a well known example. Bartonella infections in humans may be self-limiting or fulminant and affect different organ systems. The objectives of the present thesis were to (1) identify and characterise Bartonella infection cases in Sweden, (2) to investigate certain human populations regarding Bartonella infections, and (3) compare natural populations of different Bartonella species. Cases with typical and atypical CSD were recognised by using a combination of PCR and serology. Gene sequence comparisons of different genes in B. henselae isolates from the United States and Europe showed that ftsZ gene variation is a useful tool for Bartonella genotyping. Myocarditis was a common finding among Swedish elite orienteers succumbing to sudden unexpected cardiac death (SUCD). The natural cycle of Bartonella spp., the life style of orienteers, elevated antibody titres to Bartonella antigens, Bartonella DNA amplified from myocardium and the lack of another feasible explanation make Bartonella a plausible aetiological factor. The first reported case of Bartonella endocarditis (B. quintana) was identified in an immunocompromised patient who underwent heart valve replacement. The patient had been body louse-infested during his childhood. It is hypothesised that a chronic B. quintana infection was activated by the immunosuppression. There was no evidence of an ongoing trench fever (TF) epidemic in a Swedish homeless population, although an increased risk for exposure to Bartonella antigens was demonstrated. The lack of louse infestation might explain the absence of B. quintana bacteremia and low B. quintana antibody titres. Comparisons of genetic loci and the whole genomes of environmental B. grahamii isolates from the Uppsala region, Sweden displayed variants that were not related to specific host species but to geographic locality. Natural boundaries seemed to restrict gene flow.
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