- 10.00: Trial lecture
- 12.00: Public defence
The ordinary opponents are:
- First opponent: Assistant Professor David Rizo Roca, Karolinska Institutet, Sweden
- Second opponent: Professor Siv Kjøsrud Bøhn, Norwegian University of Life Sciences
- Leader of the evaluation committee: Professor Parisa Gazerani, OsloMet
The leader of the public defense is Professor Cecilie Johannessen Landmark, OsloMet.
The main supervisor is Professor Vigdis Aas, OsloMet.
The co-supervisors are Professor Colin Charnock, OsloMet and Associate Professor Ane Gedde-Dahl, OsloMet.
Thesis abstract
Skeletal muscle is a principal organ in whole-body metabolism and is the major site of insulin stimulated glucose disposal. Its capacity to utilise both glucose and fatty acids is critical for metabolic regulation, and disturbances in muscle substrate handling are closely linked to insulin resistance, obesity, and type 2 diabetes (T2D).
Furthermore, growing evidence suggests that microbial components and fermentation derived metabolites may influence energy metabolism. However, their direct effects on human skeletal muscle remain incompletely understood.
Aim
This thesis therefore aimed to investigate whether selected representatives of microbial and endogenous bioactive compounds, including toll like receptor (TLR) ligands, short chain fatty acids (SCFAs), and branched chain fatty acids (BCFAs) could directly modulate substrate handling and regulatory pathways in cultured primary human myotubes.
Three studies
Across three studies, functional assays using radiolabelled substrates, western blotting, thin layer chromatography, scintillation proximity analysis, and gene expression profiling were applied to examine glucose, oleic acid (OA), and leucine metabolism. All compound classes influenced substrate handling in human myotubes, although the effects were distinct and sometimes divergent.
Glucose metabolism was differentially affected across the studies. TLR3, TLR4, and TLR6 ligands increased glucose uptake and oxidation after 24 hours, while 12-MTD increased glucose uptake, oxidation, and glycogen synthesis. In contrast, SCFAs did not affect glucose uptake, oxidation or insulin responsiveness.
Prolonged exposure to TLR4 and TLR5 ligands enhanced OA uptake, and the TLR5 ligand also increased OA oxidation. Butyrate increased OA uptake and oxidation, while acetate and butyrate were readily taken up and oxidised, demonstrating that SCFAs can serve as mitochondrial substrates in human myotubes.
13-MTD, 14-MHD, and 15-MHD, increased OA uptake, and 13-MTD and 15-MHD also increased OA oxidation. In addition, 15-MHD elevated mitochondrial oxygen consumption. Propionate increased CPT1B mRNA expression, and butyrate tended to increase PDK4, and all BCFAs except 14-MHD increased PDK4 mRNA expression suggesting shifts toward fatty acid oxidation.
Butyrate promoted cellular leucine accumulation while reducing leucine incorporation into free fatty acids, indicating altered leucine handling.
TLR ligands induced secretion of IL (interleukin)-6, IL-8 and GM-CSF, and IL-6 alone increased OA oxidation, indicating that microbial cues can directly influence both substrate utilisation and myokine signalling in human myotubes. Following treatment with 13-MTD, 14-MHD, and 15-MHD, insulin-stimulated glycogen synthesis was reduced, while insulin responses at the level of IRS1 phosphorylation were attenuated or unchanged, indicating differential effects on insulin signalling.
What the findings demonstrate
Collectively, these findings demonstrate that TLR ligands, SCFAs and BCFAs elicit alterations in energy metabolism and metabolic regulation of cultured human myotubes. TLR ligands also induce myokine production and secretion.
The findings demonstrate that skeletal muscle is an active signalling hub, integrating microbial cues with metabolic and inflammatory responses, which may contribute to metabolic function or dysfunction.
